Show Summary Details

Page of

PRINTED FROM OXFORD HANDBOOKS ONLINE ( © Oxford University Press, 2018. All Rights Reserved. Under the terms of the licence agreement, an individual user may print out a PDF of a single chapter of a title in Oxford Handbooks Online for personal use (for details see Privacy Policy and Legal Notice).

date: 20 May 2019

Regulation of Synaptic Homeostasis by Translational Mechanisms

Abstract and Keywords

The ability of synapses to modify their functional properties and adjust the amount of neurotransmitter release at their terminals is essential for formation of appropriate neural circuits during development and crucial for higher brain functions throughout life. Many forms of synaptic plasticity can adjust synaptic strength down (depression) or up (potentiation); however, depending on the cellular context as the forces of change act upon the synapse, other synaptic mechanisms are activated to resist change. This form of synaptic plasticity is generally referred to as homeostatic synaptic plasticity. Accumulating experimental evidence indicates that translational mechanisms play a critical role in the regulation of homeostatic synaptic plasticity. This chapter will review studies that contribute to this body of evidence, including a role for the target of rapamycin in the retrograde regulation of synaptic homeostasis.

Keywords: synaptic plasticity, homeostatic synaptic plasticity, translational mechanisms, target of rapamaycin, retrograde regulation


A fundamental feature of synapses is their ability to adapt and modify their structural and functional properties in response to environmental cues and experience, a phenomenon known as synaptic plasticity. A well-studied form of synaptic plasticity manifests as changes in synaptic efficacy as a result of coordinated pre- and post-synaptic activity; this form of plasticity, first articulated by Donald Hebb in 1949, is referred to as Hebbian plasticity (Hebb, 1949). Coordinated, high-frequency presynaptic firing induces postsynaptic firing, strengthens synaptic connections, and increases the amplitude of postsynaptic responses, a process known as long-term potentiation (LTP). Conversely, other distinct patterns of presynaptic activity can weaken synaptic connections and decrease the amplitude of postsynaptic responses, a process known as long-term depression (LTD). These changes in synaptic efficacy can be long lasting and are believed to underlie learning and memory formation (Lisman, Grace, & Duzel, 2011; Nabavi et al., 2014). The strengthening of a particular synapse or neuronal circuit, during the formation of a memory, for instance, is a feed-forward process and would in effect create a positive feedback loop. As such, LTP would lead to runaway neuronal excitability and epileptic circuit activity if left unchecked. Similar problems would develop following synaptic depression, leading to little or no circuit activity. (G. G. Turrigiano & Nelson, 2000). The feed-forward nature of LTP and LTD, therefore, necessitates the presence of stabilizing forces that would curb these processes (Abbott & Nelson, 2000). These compensatory and homeostatic mechanisms are generally known as homeostatic plasticity, mechanisms that allow synapses to maintain their strength within a tightly regulated range, while functioning in concert with Hebbian forms of synaptic plasticity (G. G. Turrigiano, 2017; Vitureira & Goda, 2013; Zenke & Gerstner, 2017). Homeostatic plasticity can be detected at many central and peripheral synapses across species, and it is thought to play a major role in maintaining and stabilizing activity in neural circuits, including during sensory deprivation and disease (Braegelmann, Streeter, Fields, & Baker, 2017; Davis, 2013; Davis & Bezprozvanny, 2001; Davis & Muller, 2015; A. Goel et al., 2006; A. Goel & Lee, 2007; Maffei, Nelson, & Turrigiano, 2004; Maffei & Turrigiano, 2008; Perry, Han, Das, & Dickman, 2017; Plomp, 2017; Takamori, 2017; G. Turrigiano, 2012; G. G. Turrigiano & Nelson, 2004).

Many forms of synaptic plasticity can lead to lasting alterations in synaptic function, and a large body of experimental evidence indicates that these alterations depend critically on de novo protein synthesis and local translational regulation of synaptic components and signaling molecules (Costa-Mattioli, Sossin, Klann, & Sonenberg, 2009; Henry et al., 2018; Jakawich et al., 2010; Kauwe et al., 2016; Kelleher, Govindarajan, & Tonegawa, 2004; Penney et al., 2012; Penney et al., 2016; Schanzenbacher, Sambandan, Langer, & Schuman, 2016; Sutton et al., 2006; Sutton & Schuman, 2006). This article will review the experimental evidence for the importance of translational mechanisms in the regulation of synaptic plasticity with an emphasis on homeostatic synaptic plasticity.

Regulation of Translation

Translation in eukaryotes can be divided into four stages: initiation, elongation, termination, and ribosome recycling, of which translation initiation is thought to be the rate-limiting step. During initiation, the 40S and 60S ribosome subunits are separately recruited to the 5′ untranslated region (5′UTR) of the mRNA. First, the 40S ribosomal subunit binds to the initiator methionyl tRNA (Met-tRNAiMet) to form the 43S preinitiation complex. Following recruitment of the 43S complex to the mRNA and base-pairing of the Adenine Uracil Guanine (AUG) initiation codon with the Met-tRNAiMet anticodon, the 60S ribosome subunit is recruited to form the 80S ribosome, thus ending the initiation stage and starting the elongation step. Two critical steps during the initiation phase are the formation of the ternary complex and binding of the cap-binding protein complex (Sonenberg & Hinnebusch, 2009).

The Ternary Complex

The ternary complex is a multi-protein complex whose function is to deliver Met-tRNAiMet to the 40S ribosome subunit (Asano, Clayton, Shalev, & Hinnebusch, 2000). The attachment of the ternary complex to the 40S subunit, along with other components, forms the 43S preinitiation complex. The activity of the ternary complex is regulated primarily by the phosphorylation state of one of its constituents, the eukaryotic initiation factor 2α (eIF2α), which regulates the GTP-dependent recycling of Met-tRNAiMet (Pavitt, Ramaiah, Kimball, & Hinnebusch, 1998).

Phosphorylation of eIF2α occurs via one of four upstream kinases, and this inhibits Met-tRNAiMet recycling, slowing translation initiation (Thomas E. Dever, Dar, & Sicheri, 2007). Each eIF2α kinase is activated in response to different cellular stress; GCN2 (general control nonspecific 2) upon amino acid deprivation, HRI (heme regulated inhibitor) upon heme depletion, PKR (protein kinase RNA) upon DNA damage and PERK (PRK-like endoplasmic reticulum kinase) upon endoplasmic reticulum (ER) stress (J. J. Chen et al., 1991; Clemens, 1994; T. E. Dever et al., 1992; Kaufman, Davies, Pathak, & Hershey, 1989). As Met-tRNAiMet is required for all mRNA translation, phosphorylation of eIF2α can slow the rate of mRNA translation globally; counter-intuitively, however, specific mRNAs show increased translation under these conditions.

Cap-Dependent Translation

The 5′ termini of all mRNAs transcribed in the nucleus contain a 7-methylguanosine, m7GpppN (where N is any nucleotide), which is called a cap structure. A number of proteins, collectively known as initiation factors, come together to form the cap-binding protein complex, which interacts with the cap structure of mRNAs. Two of these important components are the eukaryotic initiation factor 4E (eIF4E) and 4A (eIF4A): eIF4E directly binds to the cap structure and is rate-limiting for the initiation of translation, while eIF4A is a helicase that is required for the unwinding of the secondary structure of the 5′UTR of the mRNA prior to the commencement of translation (Sonenberg & Hinnebusch, 2009). Only a small number of eukaryotic mRNAs are translated in a cap-independent manner, where the ribosome binds to the mRNA through a specialized secondary structure of the mRNA, known as an internal ribosome entry site (IRES; Pelletier & Sonenberg, 1988).

Regulation of Cap-Dependent Translation

The target of rapamycin (TOR), or mechanistic target of rapamycin (mTOR) in mammals, acts as a major promoter of cap-dependent translation. This evolutionarily conserved kinase plays a central role in linking many cellular and environmental cues to cell metabolism, growth, and proliferation in all eukaryotes, and its abnormal function is associated with a number of diseases (Buckmaster, Ingram, & Wen, 2009; Ehninger et al., 2008; Hoeffer & Klann, 2004; X. M. Ma & Blenis, 2009; Sharma et al., 2010; Swiech, Perycz, Malik, & Jaworski, 2008; Tang et al., 2002). Some of these diseases are characterized or accompanied by aberrant synaptic activity, including abnormal features in synaptic plasticity. TOR promotes cap-dependent translation primarily through phosphorylation of eIF4E binding protein (4E-BP) and S6 ribosomal protein kinase (S6K). TOR-induced phosphorylation of 4E-BP suppresses its ability to bind and inhibit eIF4E, thus enhancing the interaction of the cap-binding complex with the mRNA 5′ cap and promoting translation (Sonenberg & Hinnebusch, 2009). In parallel, phosphorylation by TOR activates S6K, in turn enhancing its ability to phosphorylate downstream targets that promote translation. S6K is best known for phosphorylating the ribosomal protein S6 (Hay & Sonenberg, 2004; X. M. Ma & Blenis, 2009). In addition, S6K activity leads to increased helicase activity of eIF4A, thereby promoting mRNA scanning and base-pairing of AUG start codon with the Met-tRNAiMet anticodon (Dorrello et al., 2006; Shahbazian et al., 2010). Primarily through 4E-BP and S6K, TOR can regulate various aspects of protein translation.

Hebbian Plasticity and Protein Translation

The development and refinement of protocols to induce LTP and LTD allowed for the dissection of the mechanisms underlying these processes. Experimentally, LTP is generally induced by short bursts of high-frequency neuronal stimulation, which results in persistent enhancement in the amplitude of synaptic responses lasting hours (Andersen, Krauth, & Nabavi, 2017; Bliss & Collingridge, 1993; Lynch, 2004). LTD, on the other hand, is usually induced by low-frequency stimulation, leading to a lasting decrease in the amplitude of synaptic responses (Collingridge, Peineau, Howland, & Wang, 2010; Dudek & Bear, 1992; Luscher & Malenka, 2012; Massey & Bashir, 2007). We now know that LTP and LTD are not counterparts of a singular phenomenon, but rather they are independent classes of synaptic plasticity with distinctive molecular mechanisms (Malenka & Bear, 2004; Massey & Bashir, 2007). The considerable evidence that cap-dependent protein synthesis and translation regulation are critical for both LTP and LTD (Costa-Mattioli et al., 2009; Kelleher, Govindarajan, & Tonegawa, 2004; Sutton & Schuman, 2006) will be briefly summarized here, followed by a more thorough examination of the role of protein translation in homeostatic synaptic plasticity.

LTP and Translation

Evidence for a role of de novo protein synthesis in memory formation dates back to more than 50 years ago when it was first shown that application of protein synthesis inhibitors disrupted motor learning and memory (Flexner, Flexner, & Stellar, 1963; Flexner, Flexner, Stellar, De La Haba, & Roberts, 1962). Observations that followed, however, indicated that the dependence of memory formation on protein synthesis was more complex: short-term memory formation was shown not to require de novo protein synthesis, while long-term memory formation was found to be critically dependent (Grecksch & Matthies, 1980; Montarolo et al., 1986; Squire & Davis, 1981). This led to the use of protein synthesis-dependency to distinguish short- from long-term memory formation. We now understand that at the synaptic level, LTP also has two distinct phases, early LTP and late LTP, which are mechanistically distinct. Late LTP is now considered a neo Hebbian form of plasticity, as it does not conform to classical criteria of Hebbian plasticity (Lisman et al., 2011). At some synapses, early LTP can be induced by a single burst of high-frequency stimulation or a short train of theta-burst stimulation, resulting in increased synaptic efficacy that lasts for 3 hours or less, without a requirement for de novo protein synthesis. In contrast, late LTP requires multiple sets of high-frequency stimuli or a longer theta-burst stimulation, culminating in greater postsynaptic efficacy that can last for at least 8 hours (Kelleher, Govindarajan, Jung, Kang, & Tonegawa, 2004). Late LTP can also be induced chemically, by application of factors such as cyclic adenosine monophosphate (cAMP) and bone derived neurotrophic factor (BDNF; Frey, Huang, & Kandel, 1993; Kang & Schuman, 1996). Considering that late LTP has longer-lasting effects on synaptic potentiation and is associated with increased growth of postsynaptic densities (Bosch et al., 2014), it is perhaps not surprising that late LTP is dependent on protein translation (Frey et al., 1993; Kang & Schuman, 1996; Nguyen & Kandel, 1997).

Since the requirement of protein synthesis is a defining factor for early versus late LTP, molecular regulators of translation are expected to act as a switch between the two phases of LTP. Indeed, removing the breaks on cap-dependent protein translation via knockout of 4E-BP, expressing unphosphorylatable forms of eIF2α, or knockout of the eIF2α kinase GCN2 all lower the threshold for stimulation required to elicit late LTP in hippocampal synapses (Banko et al., 2005; Costa-Mattioli et al., 2005; Costa-Mattioli et al., 2007). This effectively induces late LTP under stimulation protocols that normally would only elicit early LTP (Banko et al., 2005; Costa-Mattioli et al., 2005; Costa-Mattioli et al., 2007). Stimulation of protein translation via TOR is also sufficient to induce dendritic growth following subthreshold stimulation (Henry, Hockeimer, Chen, Mysore, & Sutton, 2017). Conversely, dampening active players in protein translation initiation disrupts the manifestation of late LTP (Costa-Mattioli et al., 2007) and impairs performance in behavioral tests of memory (Costa-Mattioli et al., 2007; Jian et al., 2014). These findings suggest that regulators of cap-dependent translation can act as switches that modulate the persistence of LTP and thereby influence memory formation.

LTD and Protein Translation

While LTP and LTD are mechanistically distinct processes, sustained expression of LTD also requires de novo protein synthesis. The precise mechanism of LTD induction varies at different synapses, but in general LTD occurs through low-frequency stimulation of N-Methyl-D-aspartic acid (NMDA) receptors or activation of metabotropic glutamate receptors (mGluRs) (Collingridge et al., 2010). Like LTP, LTD at hippocampal CA1 synapses can be divided into early and late phases, of which the late phase demonstrates longer-lasting depression (Kauderer & Kandel, 2000; Linden, 1996). Both NMDA- and mGluR-dependent forms of late LTD are dependent on protein translation (Huber, Kayser, & Bear, 2000; Huber, Roder, & Bear, 2001; Kauderer & Kandel, 2000; Linden, 1996). Disruption of the cap-binding complex by introducing an artificial cap structure or pharmacological inhibition of TOR or other initiation factors eliminates LTD maintenance (Banko, Hou, Poulin, Sonenberg, & Klann, 2006; Hou & Klann, 2004; Karachot, Shirai, Vigot, Yamamori, & Ito, 2001).

Compared to LTP, the requirement for de novo protein translation in LTD might appear less intuitive, since LTD manifests as reduced synaptic strength and is associated with synapse elimination. One mechanism by which protein translation promotes sustained depression of synaptic efficacy is by changing the subunit stoichiometry of α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors. AMPA receptors containing GluA2 subunits are less permeable to calcium and show reduced single channel conductance compared to non-GluA2 AMPA receptors (S. Cull-Candy, Kelly, & Farrant, 2006; Isaac, Ashby, & McBain, 2007). LTD induction promotes rapid synthesis and incorporation of GluA2 subunits, resulting in reduced synaptic function and dampened postsynaptic calcium influx (Mameli, Balland, Lujan, & Luscher, 2007). LTD also results in marked endocytosis of AMPA receptors (Y. T. Wang & Linden, 2000; Xiao, Zhou, & Nicoll, 2001), and protein translation supports this process by synthesizing components of the endocytic pathway (H. Wang et al., 2016; Waung & Huber, 2009; Waung, Pfeiffer, Nosyreva, Ronesi, & Huber, 2008). Examples include Arc, which enhances endophilin and dynamin mediated endocytosis of AMPA receptors (Chowdhury et al., 2006; Waung et al., 2008); striatal-enriched protein tyrosine phosphatase (STEP), which phosphorylates AMPA receptors to signal endocytosis (Y. Zhang et al., 2008); and microtubule-associated protein 1B (MAP1B), which sequesters factors that stabilize AMPA localization in the membrane (Davidkova & Carroll, 2007). Altogether, it appears that translation pathways are required at multiple levels to allow for persistent LTD.

Homeostatic Plasticity and Protein Translation in the Central Nervous System

Homeostatic mechanisms exist to keep synaptic activity within a tight physiological range, and depending on input, they can tune synaptic strength to maintain a desirable set-point. This is crucial both to keep the feedforward nature of LTP and LTD in check, as well as to maintain the ability of synapses to respond to appropriate inputs in a Hebbian manner (Braegelmann et al., 2017; Davis, 2013; Davis & Bezprozvanny, 2001; Davis & Muller, 2015; Perry et al., 2017; Plomp, 2017; Takamori, 2017; G. Turrigiano, 2012; G. G. Turrigiano, 2017; G. G. Turrigiano & Nelson, 2000, 2004; Vitureira & Goda, 2013; Zenke & Gerstner, 2017). Homeostatic plasticity is widely observed in both the central nervous system and the peripheral nervous system and is highly conserved from invertebrate models to human synapses. (For reviews on homeostatic plasticity, see [Davis, 2013; Davis & Bezprozvanny, 2001; Davis & Muller, 2015; G. G. Turrigiano, 2008]). In general, synaptic homeostasis can be achieved by changes in postsynaptic receptor function, presynaptic neurotransmitter release or neuronal membrane excitability (Garcia-Bereguiain, Gonzalez-Islas, Lindsly, & Wenner, 2016; A. Goel et al., 2006; Hengen, Lambo, Van Hooser, Katz, & Turrigiano, 2013; Keck et al., 2013; Kirov, Goddard, & Harris, 2004; Lissin et al., 1998; Maffei et al., 2004; Maffei & Turrigiano, 2008; O’Brien et al., 1998; Orr, Fetter, & Davis, 2017; Plomp, Morsch, Phillips, & Verschuuren, 2015; Plomp et al., 1995; Pozo & Goda, 2010; Teichert, Liebmann, Hubner, & Bolz, 2017; G. G. Turrigiano, Leslie, Desai, Rutherford, & Nelson, 1998; Tyler, Petzold, Pal, & Murthy, 2007; Vale & Sanes, 2002; W. Zhang & Linden, 2003). Experimental evidence indicates that synapses depend on protein synthesis to engage and maintain homeostatic adjustments of synaptic function. Translational regulation can be adapted to achieve highly diverse effects by fine-tuning the targets of mRNA translation; it is therefore not surprising that both presynaptic and postsynaptic adjustments to synaptic activity can be achieved by increased protein translation activities.

Homeostatic Plasticity in the Vertebrate Central Nervous System: Postsynaptic Compensation

One of the well-characterized examples of homeostatic plasticity, also known as synaptic scaling, occurs at excitatory glutamatergic synapses on hippocampal and cortical neurons. Inhibition of evoked synaptic activity by tetrodotoxin (TTX) treatment in dissociated primary cortical neurons results in a compensatory up-regulation of mEPSC (miniature excitatory postsynaptic current) amplitudes (G. G. Turrigiano et al., 1998). The increase in mEPSCs is a result of increased postsynaptic sensitivity to glutamate, rather than changes in presynaptic neurotransmitter release (G. G. Turrigiano et al., 1998). In fact, TTX application increases GluA1 and GluA2 AMPA receptor insertion into the postsynaptic dendrites (Wierenga, Ibata, & Turrigiano, 2005), a process that can be disrupted with inhibitors of protein synthesis (Schanzenbacher et al., 2016). While this experimental paradigm clearly demonstrates the importance of protein synthesis for postsynaptic homeostatic compensation in response to global activity blockade, it requires a prolonged application of blockers before homeostatic plasticity is observed (>12 hours). An alternative protocol, which includes co-application of the AMPA receptor antagonist CNQX (6-cyano-7-nitroquinoxaline-2,3-dione) and the NMDA receptor antagonist APV ((2R)-amino-5-phosphonovaleric acid), induces homeostatic compensation in the dendrite at a much shorter time scale. Under this inhibitory regime, neurons show homeostatic compensation after 2–3 hours of treatment (Sutton et al., 2006). Inhibition of postsynaptic receptors and hence miniature synaptic activity was shown to induce protein synthesis within the first hour of treatment, increasing de novo synthesis and incorporation of GluA1 containing AMPA receptors (Sutton et al., 2006). As such, inhibition of protein translation eliminates GluA1 synthesis and incorporation, thereby abrogating the homeostatic postsynaptic compensation (Ju et al., 2004; Sutton et al., 2006; Sutton, Taylor, Ito, Pham, & Schuman, 2007; Sutton, Wall, Aakalu, & Schuman, 2004). These findings demonstrate that differential responses of translational mechanisms to different synaptic perturbations can determine the degree and speed of homeostatic compensation in neurons.

A potential mechanism whereby mEPSCs could regulate local protein translation is through modulation of receptor calcium influx. NMDA receptors have been proposed to inhibit local protein translation elongation via phosphorylation of eEF2 (eukaryotic elongation factor 2) (Scheetz, Nairn, & Constantine-Paton, 2000), whose phosphorylation state is regulated by calcium dependent eEF2 kinase (Nairn & Palfrey, 1987). Blocking NMDA receptors is sufficient to dephosphorylate eEF2 and increase protein translation at the elongation level (Sutton et al., 2007). NMDA receptor function has also been tied to TOR pathway activity via SynGAP (Synaptic Ras-GTPase activating protein; C. C. Wang, Held, & Hall, 2013), which colocalizes with NMDA receptors (H. J. Chen, Rojas-Soto, Oguni, & Kennedy, 1998; Kim, Liao, Lau, & Huganir, 1998) and is activated by CaMKII (Ca2+-Calmodulin protein Kinase II) in the presence of calcium (Oh, Manzerra, & Kennedy, 2004). SynGAP functions to limit protein translation via suppression of mTOR under normal conditions, and knockdown of SynGAP or the activation of the TOR pathway is sufficient to increase mEPSC amplitudes in the absence of synaptic activity blockade (C. C. Wang et al., 2013). In addition to synaptic calcium, alteration in calcium release from internal sources can also influence synaptic scaling. Blocking calcium-induced calcium release from internal storage sources triggers synaptic scaling by promoting translation initiation through an eIF2α dependent mechanism (Reese & Kavalali, 2015).

Interestingly, calcium can also specifically control GluA1 synthesis via retinoic acid (RA) signaling. Under basal conditions, calcium inhibits the production of RA, but upon synaptic perturbation, RA synthesis is disinhibited (H. L. Wang, Zhang, Hintze, & Chen, 2011). RA then activates its receptor RARα, an atypical receptor that associates with dendritic RNA granules and promotes the synthesis of GluA1 (Aoto, Nam, Poon, Ting, & Chen, 2008; N. Chen, Onisko, & Napoli, 2008; Maghsoodi et al., 2008). Consistent with a role in synaptic scaling, RA production can be induced by blockade of action potentials along with AMPA receptor blockade (Aoto et al., 2008). Conversely, disruptions in RA production or RARα expression blocks synaptic upscaling in response to activity blockade (Aoto et al., 2008). RA signaling via neuronal calcium acts as another avenue of protein synthesis control that can respond to changes in neuronal activity to induce synaptic homeostasis.

Homeostatic Plasticity in the Vertebrate Central Nervous System: Presynaptic Compensation

In addition to postsynaptic compensation, homeostatic plasticity can be achieved through presynaptic alterations of neurotransmitter release sites or the amount of neurotransmitter release at individual sites. Several lines of evidence have revealed presynaptic changes in neurotransmitter release as part of the homeostatic compensation. In particular, hippocampal neurons exhibit homeostatic plasticity in response to activity blockade not only through enhancement on mEPSC amplitudes, but also through enhancement in mEPSC frequencies (Henry et al., 2012; Henry et al., 2018; Jakawich et al., 2010; Wierenga, Walsh, & Turrigiano, 2006), indicating presynaptic modifications. The changes in mEPSC frequencies are corroborated by morphological alterations in the presynaptic terminal, including increased number of docked vesicles, size of readily releasable pool, and size of vesicles (Murthy, Schikorski, Stevens, & Zhu, 2001). Since presynaptic changes occur in response to postsynaptic activity perturbations, this suggests the presence of a retrograde signaling mechanism that relays the state of postsynaptic activity to the presynaptic neuron. Indeed, experimental evidence points to a critical role for TOR activity in postsynaptic dendrites for the ability of presynaptic terminals to undergo homeostatic compensation: block of TOR activity blocks the compensation, while activation of TOR is sufficient to upregulate presynaptic release (Henry et al., 2012; Henry et al., 2018; Jakawich et al., 2010). It appears that retrograde synaptic compensation in cultured hippocampal neurons requires BDNF, which is released in response to synaptic perturbations. Further, extrinsic application of BDNF is sufficient to induce presynaptic functional increase (Jakawich et al., 2010). In fact, the production of BDNF is eliminated as a result of pharmacological inhibition of TOR, which also eliminates presynaptic homeostatic compensation (Henry et al., 2012; Henry et al., 2018). All in all, protein translation regulation therefore mediates homeostatic plasticity in the presynaptic terminal by promoting the synthesis of retrograde signaling factor(s) during synaptic perturbation.

Homeostatic Plasticity at the Neuromuscular Junction

Like many central synapses, synapses at the neuromuscular junction (NMJ) show robust homeostatic synaptic plasticity: reduced neurotransmitter receptor activity in postsynaptic muscles can induce compensatory increases in presynaptic release, a response that is well conserved from invertebrates to humans (S. G. Cull-Candy, Miledi, & Trautmann, 1979; Frank, Kennedy, Goold, Marek, & Davis, 2006; Katz & Miledi, 1978; Miledi, Molenaar, & Polak, 1978; Petersen, Fetter, Noordermeer, Goodman, & DiAntonio, 1997; Plomp, van Kempen, & Molenaar, 1992; Tian, Prior, Dempster, & Marshall, 1994; X. Wang, Pinter, & Rich, 2016). The ability of the NMJ to homeostatically regulate presynaptic release may be especially critical for patients with myasthenia gravis, an autoimmune disorder that targets acetylcholine receptors or related proteins at the NMJ (Gilhus & Verschuuren, 2015). The affected NMJs often have reduced levels of acetylcholine receptor expression and reduced sensitivity to acetylcholine (Albuquerque, Rash, Mayer, & Satterfield, 1976; Fambrough, Drachman, & Satyamurti, 1973; Tsujihata, Hazama, Ishii, Ide, & Takamori, 1980); however, the motor neurons exhibit a compensatory increase in presynaptic neurotransmitter release, which may be of clinical benefit during early stages of the disease (Albuquerque et al., 1976; Plomp et al., 1995).

Homeostatic enhancement in presynaptic release has been particularly well studied at the Drosophila NMJ, where the genetic removal of GluRIIA, one of the glutamate receptor subunits, causes a strong decrease in single channel mean open time leading to a reduction in mEPSC amplitudes (DiAntonio, Petersen, Heckmann, & Goodman, 1999). This reduction ultimately triggers a retrograde signal that leads to presynaptic enhancement of neurotransmitter release to compensate for the reduced response of neurotransmitter receptors (Petersen et al., 1997). A similar compensatory homeostatic response can also be triggered acutely through pharmacological block of GluRIIA-containing receptors (Frank et al., 2006). As one might expect, this robust synaptic compensation requires the presynaptic machinery to respond to the increased demand at the synapse. As such, many presynaptic components have been identified to be essential elements for the compensatory synaptic enhancement at the NMJ, including calcium channels, active zone components, and signaling molecules (Davis & Muller, 2015; Frank et al., 2006; Frank, Pielage, & Davis, 2009; Goold & Davis, 2007; Marie, Pym, Bergquist, & Davis, 2010; Muller & Davis, 2012; Muller, Liu, Sigrist, & Davis, 2012; Muller, Pym, Tong, & Davis, 2011; Pilgram, Potikanond, van der Plas, Fradkin, & Noordermeer, 2011; Tsurudome et al., 2010; Weyhersmuller, Hallermann, Wagner, & Eilers, 2011; Younger, Muller, Tong, Pym, & Davis, 2013).

For the presynaptic neuron to initiate a compensatory response, postsynaptic components must be engaged to trigger and/or maintain a retrograde signaling cascade downstream from glutamate receptor manipulations in the muscle (Frank et al., 2006; Haghighi et al., 2003; Petersen et al., 1997). Over the past several years, it has become clear that translational mechanisms play a central role in the regulation of this retrograde signaling (Kauwe et al., 2016; Penney et al., 2012; Penney et al., 2016). Here, we will describe these select studies in detail.

Postsynaptic TOR Regulates Presynaptic Homeostatic Plasticity

Propelled by the power of genetics, Drosophila larval NMJs became the first in vivo model for testing the role of translational mechanisms in the retrograde regulation of synaptic homeostasis. Based on the critical role of translation initiation in protein synthesis, limiting initiation either by removing one gene copy of eIF4E or eIF2α was hypothesized to be sufficient to influence the ability of the NMJ to undergo synaptic homeostasis. Normally, GluRIIA mutant larvae show reduced miniature amplitudes but can match the wild-type evoked response. Heterozygosity for eIF4E curtailed this ability, while heterozygosity for eIF2α failed to do so (Penney et al., 2012). This finding pointed to a potential role for TOR as a regulator of eIF4E availability in the regulation of synaptic homeostasis. Indeed, genetic experiments supported a role for TOR: TOR heterozygosity was sufficient to block synaptic homeostasis in GluRIIA mutant larvae. Interestingly, certain hypomorphic homozygous mutant combinations of TOR can live to larval stages, which allowed for a genetic examination of the role of TOR at the synapse in a tissue-specific manner. TOR mutant larvae showed no structural defects at the NMJ but, as the previous experiments would have predicted, failed to exhibit synaptic homeostasis. Rescue experiments were clear but surprising: TOR was needed in postsynaptic muscles rather than in motoneurons to restore synaptic homeostasis. If TOR were required for synaptic compensation, then one would expect pharmacological inhibition of TOR to block synaptic homeostasis at the NMJ. Living and free moving larvae were fed rapamycin in their food prior to dissection and electrophysiological analysis. Interestingly, at least 6–12 hours of feeding on rapamycin-containing food was required before any significant block could be detected in larvae, thus suggesting that the early synaptic homeostatic response was not dependent on de novo protein synthesis, but longer-term maintenance of compensation became critically dependent on de novo translation (Penney et al., 2012). This idea is supported by the fact that acute pharmacological induction of synaptic homeostasis at the larval NMJ can operate within minutes independently of de novo protein synthesis (Cheng, Locke, & Davis, 2011; Frank et al., 2006; P. Goel, Li, & Dickman, 2017). The distinction between acute and chronic forms of synaptic homeostasis is reminiscent of the early versus late forms of LTP and LTD; the synapse is well equipped to adjust synaptic activity in an acute manner, but persistent changes require protein synthesis. Together with evidence from mammalian culture systems (Henry et al., 2012; Henry et al., 2018; Sutton et al., 2006; Sutton et al., 2007; Sutton et al., 2004; C. C. Wang et al., 2013), these findings clearly demonstrate a role for postsynaptic TOR-dependent translation in maintaining synaptic homeostasis and highlight the importance of retrograde signaling in this process.

Postsynaptic 4E-BP Links Nutrient Availability to Presynaptic Homeostatic Plasticity

TOR acts to integrate a number of intracellular and extracellular signals, but perhaps its most prominent role is to link nutrient signaling to protein synthesis and cell growth (Barbet et al., 1996; Hara et al., 1998; for reviews, see Loewith & Hall, 2011; Wullschleger, Loewith, & Hall, 2006). Thus, it would be expected that nutrient scarcity could suppress TOR activity and thereby suppress retrograde synaptic homeostasis. Interestingly, however, although these predictions were supported by experimental data, the picture was more complicated than expected. Wild-type larvae moved to vials with or without food for 3–6 hours showed no apparent difference in synaptic structure or the amount of neurotransmitter release at the NMJ, but GluRIIA mutant larvae showed great sensitivity to food: acute starvation completely blocked their ability to show synaptic compensation (Kauwe et al., 2016). Indeed, the level of S6K phosphorylation (an index of TOR activity) was reduced in these larvae, so it appeared that the culprit had been identified. However, a surprising experiment suggested otherwise. Transgenic expression of a constitutively active form of S6K, which can function independently of TOR, failed to rescue synaptic homeostasis during starvation. This finding suggested that TOR independent pathways might be responsible for failure of GluRIIA mutants to exhibit synaptic homeostasis during acute starvation. In addition to inhibiting TOR activity, starvation has been shown to influence the transcription of 4E-BP through the action of the Forkhead-box-O transcription factor (Foxo); Foxo is normally under the negative control of insulin signaling under nutrient rich conditions, but starvation removes this inhibition and activates Foxo, which then can activate 4E-BP transcription as one of its target genes (Demontis & Perrimon, 2010; Junger et al., 2003; Puig, Marr, Ruhf, & Tjian, 2003; Teleman, Chen, & Cohen, 2005). Confirming this scenario, heterozygosity for 4E-BP was sufficient to maintain the ability of the NMJ to undergo synaptic homeostasis even under starvation conditions. Similarly, genetic knockdown of Foxo in muscle blocked the increase in 4E-BP transcription in postsynaptic muscles in response to acute starvation and restored synaptic homeostasis (Kauwe et al., 2016). These findings not only add to the complexity of the translational regulation of synaptic homeostasis, but they also show that the state of nutrient availability can have a significant influence on synaptic homeostasis.

Translation, Synaptic Homeostasis, and Implications for Disease

The requirement for TOR activity in postsynaptic muscles for the retrograde compensatory enhancement of presynaptic release in GluRIIA mutants (Penney et al., 2012) raised the question of whether increased postsynaptic TOR activity in an otherwise wild-type animal could hijack this retrograde pathway and abnormally enhance presynaptic release. Indeed, experimental data indicated that increased postsynaptic TOR activity was sufficient to induce a retrograde enhancement in presynaptic release (Penney et al., 2012); in other words, increased TOR activity appeared to have pitched the set point of synaptic strength higher. This abnormal increase in synaptic activity could potentially explain some aspects of disease in tuberous sclerosis complex (TSC), a multi-system disorder characterized by non-malignant tumors, and often accompanied by major neurological effects (Tsai & Sahin, 2011). About 90% of TSC patients exhibit seizures, about half meet the criteria for mental retardation, and about one-third exhibit autistic behaviors (Kwiatkowski & Manning, 2005). TSC is caused by mutation of either the TSC1 or TSC2 genes, whose products form a protein complex that negatively regulates TOR activity. The TSC protein complex is a GAP (GTPase activating protein) for the small GTPase Rheb (Ras homolog enriched in the brain), whose activity is required for activation of TOR. Mutation of either TSC1or TSC2 leads to disruption of the complex, abnormal activation of TOR and deregulation of the pathway (Hoeffer & Klann, 2010). It is conceivable that the enhanced TOR activity in the absence of TSC can lead to an abnormal increase in neurotransmission, which can in turn destabilize circuit function and lead to epileptic seizures. Indeed, rodent TSC models exhibit numerous learning and memory defects, as well as alterations in both short-term and long-term plasticity, many of which can be rescued by short-term rapamycin treatment during adulthood (Ehninger et al., 2008; Goorden, van Woerden, van der Weerd, Cheadle, & Elgersma, 2007; von der Brelie, Waltereit, Zhang, Beck, & Kirschstein, 2006). These findings further highlight the critical importance of translational mechanisms in the regulation of higher brain functions and reveal the instrumental role these mechanisms play in nervous system diseases.

Leucine Rich Repeat Kinase 2 Is a Modulator of Cap-Dependent Translation and a Regulator of Synaptic Homeostasis

Another disease related gene that has been suggested to influence cap-dependent translation is leucine-rich repeat kinase 2 (LRRK2). Mutations in the gene encoding LRRK2 were originally identified in linkage studies of familial Parkinson’s disease (Funayama et al., 2002; Paisan-Ruiz et al., 2004; Zimprich et al., 2004). Today, LRRK2 mutations are considered the single most common cause of inherited Parkinson’s disease (Greggio & Cookson, 2009). LRRK2 is a large protein with multiple functional domains including a kinase domain (Martin, Dawson, & Dawson, 2011; Mata, Wedemeyer, Farrer, Taylor, & Gallo, 2006). Interestingly, the most common familial mutations in LRRK2 appear to lead to an increase in autophosphorylation and kinase activity (Greggio & Cookson, 2009; Martin et al., 2011); therefore, it is plausible to assume that some aspects of the disease may be related to dysregulated and/or elevated levels of kinase activity. There has been a widespread interest in identifying LRRK2’s phosphorylation substrates, and several potential candidates have been identified, including Rab GTPases (Alessi & Sammler, 2018; Imai et al., 2008; Jaleel et al., 2007). The Drosophila genome contains a single homologous gene to LRRK2, which we will call dLRRK to distinguish it from the human protein hLRRK2. Several studies have used transgenic hLRRK2 in Drosophila to study its gain-of-function in vivo (Liu et al., 2008; Ng et al., 2009; Venderova et al., 2009). A loss of function allele of dLRRK has also been generated, which has enabled insight into the endogenous function of LRRK2 in the nervous system (Imai et al., 2008; S. B. Lee, Kim, Lee, & Chung, 2007). Moreover, the Drosophila model has allowed for genetic interaction experiments that have linked LRRK2 to other Parkinson’s related genes, including Parkin, DJ-1, and PINK-1 (Ng et al., 2009; Tain et al., 2009; Venderova et al., 2009). Although the precise mechanism through which LRRK2 influences translational mechanisms remains unclear, there is strong evidence that LRRK2 can enhance cap-dependent translation both in Drosophila and in mammalian cells (Imai et al., 2008; S. Lee, Liu, Lin, Guo, & Lu, 2010; Penney et al., 2016; Tain et al., 2009). Genetic knockdown of LRRK2 in muscle blocks synaptic homeostasis at the NMJ, while its overexpression in muscle leads to a retrograde enhancement in presynaptic neurotransmitter release (Penney et al., 2016). Further, all gain-of-function effects of LRRK2 at the NMJ could be countered by feeding larvae rapamycin or cycloheximide or by genetic manipulation of translation initiation, indicating that this synaptic function of LRRK2 depends on its ability to enhance translation (Penney et al., 2016). The ability of pathogenic LRRK2 mutations to disrupt synaptic homeostasis and enhance synaptic release, reminiscent of TOR gain-of-function, is potentially relevant to the pathogenesis of Parkinson’s disease and suggest that perhaps synaptic dysfunction precedes the pathological manifestations of the disease. These results open new avenues of research into the biological function of LRRK2, and its dysfunction during disease may point to alternative approaches toward tackling Parkinson’s disease.

Future Directions

The experimental evidence accumulated over the last two decades has built a strong and conclusive case for the essential role of translational mechanisms in the regulation of synaptic plasticity in general and synaptic homeostasis in particular. The inevitable future challenge will be to identify synapse-specific translational targets and understand the details of how specificity is achieved. With growing evidence implicating translational mechanisms in age-dependent neurodegenerative diseases (Beckelman et al., 2016; Cestra, Rossi, Di Salvio, & Cozzolino, 2017; T. Ma et al., 2013; Moon, Sonenberg, & Parker, 2018; Shih & Hsueh, 2018; Taymans, Nkiliza, & Chartier-Harlin, 2015; Zheng et al., 2016), identifying synapse-specific translational targets will open new avenues for designing novel therapeutics aimed at tackling these devastating diseases.


Abbott, L. F., & Nelson, S. B. (2000). Synaptic plasticity: Taming the beast. Nature Neuroscience, 3 Suppl, 1178–1183. doi:10.1038/81453Find this resource:

Albuquerque, E. X., Rash, J. E., Mayer, R. F., & Satterfield, J. R. (1976). An electrophysiological and morphological study of the neuromuscular junction in patients with myasthenia gravis. Experimental Neurology, 51(3), 536–563.Find this resource:

Alessi, D. R., & Sammler, E. (2018). LRRK2 kinase in Parkinson’s disease. Science, 360(6384), 36–37. doi:10.1126/science.aar5683Find this resource:

Andersen, N., Krauth, N., & Nabavi, S. (2017). Hebbian plasticity in vivo: Relevance and induction. Current Opinion in Neurobiology, 45, 188–192. doi:10.1016/j.conb.2017.06.001Find this resource:

Aoto, J., Nam, C. I., Poon, M. M., Ting, P., & Chen, L. (2008). Synaptic signaling by all-trans retinoic acid in homeostatic synaptic plasticity. Neuron, 60(2), 308–320. doi:10.1016/j.neuron.2008.08.012Find this resource:

Asano, K., Clayton, J., Shalev, A., & Hinnebusch, A. G. (2000). A multifactor complex of eukaryotic initiation factors, eIF1, eIF2, eIF3, eIF5, and initiator tRNA(Met) is an important translation initiation intermediate in vivo. Genes & Development, 14(19), 2534–2546.Find this resource:

Banko, J. L., Hou, L., Poulin, F., Sonenberg, N., & Klann, E. (2006). Regulation of eukaryotic initiation factor 4E by converging signaling pathways during metabotropic glutamate receptor-dependent long-term depression. Journal of Neuroscience, 26(8), 2167–2173. doi:10.1523/JNEUROSCI.5196–05.2006Find this resource:

Banko, J. L., Poulin, F., Hou, L., DeMaria, C. T., Sonenberg, N., & Klann, E. (2005). The translation repressor 4E-BP2 is critical for eIF4F complex formation, synaptic plasticity, and memory in the hippocampus. Journal of Neuroscience, 25(42), 9581–9590. doi:10.1523/JNEUROSCI.2423–05.2005Find this resource:

Barbet, N. C., Schneider, U., Helliwell, S. B., Stansfield, I., Tuite, M. F., & Hall, M. N. (1996). TOR controls translation initiation and early G1 progression in yeast. Molecular Biology of the Cell, 7(1), 25–42.Find this resource:

Beckelman, B. C., Day, S., Zhou, X., Donohue, M., Gouras, G. K., Klann, E., … Ma, T. (2016). Dysregulation of Elongation Factor 1A Expression is Correlated with Synaptic Plasticity Impairments in Alzheimer’s Disease. Journal of Alzheimers Disease, 54(2), 669–678. doi:10.3233/JAD-160036Find this resource:

Bliss, T. V., & Collingridge, G. L. (1993). A synaptic model of memory: Long-term potentiation in the hippocampus. Nature, 361(6407), 31–39. doi:10.1038/361031a0Find this resource:

Bosch, M., Castro, J., Saneyoshi, T., Matsuno, H., Sur, M., & Hayashi, Y. (2014). Structural and molecular remodeling of dendritic spine substructures during long-term potentiation. Neuron, 82(2), 444–459. doi:10.1016/j.neuron.2014.03.021Find this resource:

Braegelmann, K. M., Streeter, K. A., Fields, D. P., & Baker, T. L. (2017). Plasticity in respiratory motor neurons in response to reduced synaptic inputs: A form of homeostatic plasticity in respiratory control? Experimental Neurology, 287(Pt 2), 225–234. doi:10.1016/j.expneurol.2016.07.012Find this resource:

Buckmaster, P. S., Ingram, E. A., & Wen, X. (2009). Inhibition of the mammalian target of rapamycin signaling pathway suppresses dentate granule cell axon sprouting in a rodent model of temporal lobe epilepsy. Journal Neuroscience, 29(25), 8259–8269. doi:10.1523/JNEUROSCI.4179–08.2009Find this resource:

Cestra, G., Rossi, S., Di Salvio, M., & Cozzolino, M. (2017). Control of mRNA translation in ALS proteinopathy. Frontiers in Molecular Neuroscience, 10, 85. doi:10.3389/fnmol.2017.00085Find this resource:

Chen, H. J., Rojas-Soto, M., Oguni, A., & Kennedy, M. B. (1998). A synaptic Ras-GTPase activating protein (p135 SynGAP) inhibited by CaM kinase II. Neuron, 20(5), 895–904.Find this resource:

Chen, J. J., Pal, J. K., Petryshyn, R., Kuo, I., Yang, J. M., Throop, M. S., … London, I. M. (1991). Amino acid microsequencing of internal tryptic peptides of heme-regulated eukaryotic initiation factor 2 alpha subunit kinase: homology to protein kinases. Proceedings of the National Academy of Sciences of the United States of America, 88(2), 315–319.Find this resource:

Chen, N., Onisko, B., & Napoli, J. L. (2008). The nuclear transcription factor RARalpha associates with neuronal RNA granules and suppresses translation. Journal of Biological Chemistry, 283(30), 20841–20847. doi:10.1074/jbc.M802314200Find this resource:

Cheng, L., Locke, C., & Davis, G. W. (2011). S6 kinase localizes to the presynaptic active zone and functions with PDK1 to control synapse development. Journal of Cell Biology, 194(6), 921–935. doi:10.1083/jcb.201101042Find this resource:

Chowdhury, S., Shepherd, J. D., Okuno, H., Lyford, G., Petralia, R. S., Plath, N., … Worley, P. F. (2006). Arc/Arg3.1 interacts with the endocytic machinery to regulate AMPA receptor trafficking. Neuron, 52(3), 445–459. doi:10.1016/j.neuron.2006.08.033Find this resource:

Clemens, M. J. (1994). Regulation of eukaryotic protein synthesis by protein kinases that phosphorylate initiation factor eIF-2. Molecular Biology Reports, 19(3), 201–210.Find this resource:

Collingridge, G. L., Peineau, S., Howland, J. G., & Wang, Y. T. (2010). Long-term depression in the CNS. Nature Reviews Neuroscience, 11(7), 459–473. doi:10.1038/nrn2867Find this resource:

Costa-Mattioli, M., Gobert, D., Harding, H., Herdy, B., Azzi, M., Bruno, M., … Sonenberg, N. (2005). Translational control of hippocampal synaptic plasticity and memory by the eIF2alpha kinase GCN2. Nature, 436(7054), 1166–1173. doi:10.1038/nature03897Find this resource:

Costa-Mattioli, M., Gobert, D., Stern, E., Gamache, K., Colina, R., Cuello, C., … Sonenberg, N. (2007). eIF2alpha phosphorylation bidirectionally regulates the switch from short- to long-term synaptic plasticity and memory. Cell, 129(1), 195–206. doi:10.1016/j.cell.2007.01.050Find this resource:

Costa-Mattioli, M., Sossin, W. S., Klann, E., & Sonenberg, N. (2009). Translational control of long-lasting synaptic plasticity and memory. Neuron, 61(1), 10–26. doi:10.1016/j.neuron.2008.10.055Find this resource:

Cull-Candy, S., Kelly, L., & Farrant, M. (2006). Regulation of Ca2+-permeable AMPA receptors: Synaptic plasticity and beyond. Current Opinion in Neurobiology, 16(3), 288–297. doi:10.1016/j.conb.2006.05.012Find this resource:

Cull-Candy, S. G., Miledi, R., & Trautmann, A. (1979). End-plate currents and acetylcholine noise at normal and myasthenic human end-plates. Journal of Physiology, 287, 247–265.Find this resource:

Davidkova, G., & Carroll, R. C. (2007). Characterization of the role of microtubule-associated protein 1B in metabotropic glutamate receptor-mediated endocytosis of AMPA receptors in hippocampus. Journal of Neuroscience, 27(48), 13273–13278. doi:10.1523/JNEUROSCI.3334–07.2007Find this resource:

Davis, G. W. (2013). Homeostatic signaling and the stabilization of neural function. Neuron, 80(3), 718–728. doi:10.1016/j.neuron.2013.09.044Find this resource:

Davis, G. W., & Bezprozvanny, I. (2001). Maintaining the stability of neural function: A homeostatic hypothesis. Annual Review of Physiology, 63, 847–869. doi:10.1146/annurev.physiol.63.1.847Find this resource:

Davis, G. W., & Muller, M. (2015). Homeostatic control of presynaptic neurotransmitter release. Annual Review of Physiology, 77, 251–270. doi:10.1146/annurev-physiol-021014-071740Find this resource:

Demontis, F., & Perrimon, N. (2010). FOXO/4E-BP signaling in Drosophila muscles regulates organism-wide proteostasis during aging. Cell, 143(5), 813–825. doi:10.1016/j.cell.2010.10.007Find this resource:

Dever, T. E., Dar, A. C., & Sicheri, F. (2007). The eIF2alpha kinases. Cold Spring Harbor Monograph Series, 48, 319.Find this resource:

Dever, T. E., Feng, L., Wek, R. C., Cigan, A. M., Donahue, T. F., & Hinnebusch, A. G. (1992). Phosphorylation of initiation factor 2 alpha by protein kinase GCN2 mediates gene-specific translational control of GCN4 in yeast. Cell, 68(3), 585–596.Find this resource:

DiAntonio, A., Petersen, S. A., Heckmann, M., & Goodman, C. S. (1999). Glutamate receptor expression regulates quantal size and quantal content at the Drosophila neuromuscular junction. Journal of Neuroscience, 19(8), 3023–3032.Find this resource:

Dorrello, N. V., Peschiaroli, A., Guardavaccaro, D., Colburn, N. H., Sherman, N. E., & Pagano, M. (2006). S6K1- and betaTRCP-mediated degradation of PDCD4 promotes protein translation and cell growth. Science, 314(5798), 467–471. doi:10.1126/science.1130276Find this resource:

Dudek, S. M., & Bear, M. F. (1992). Homosynaptic long-term depression in area CA1 of hippocampus and effects of N-methyl-D-aspartate receptor blockade. Proceedings of the National Academy of Sciences of the United States of America, 89(10), 4363–4367.Find this resource:

Ehninger, D., Han, S., Shilyansky, C., Zhou, Y., Li, W., Kwiatkowski, D. J., … Silva, A. J. (2008). Reversal of learning deficits in a Tsc2+/- mouse model of tuberous sclerosis. Nature Medicine, 14(8), 843–848. doi:10.1038/nm1788Find this resource:

Fambrough, D. M., Drachman, D. B., & Satyamurti, S. (1973). Neuromuscular junction in myasthenia gravis: decreased acetylcholine receptors. Science, 182(4109), 293–295.Find this resource:

Flexner, J. B., Flexner, L. B., & Stellar, E. (1963). Memory in mice as affected by intracerebral puromycin. Science, 141(3575), 57–59.Find this resource:

Flexner, J. B., Flexner, L. B., Stellar, E., De La Haba, G., & Roberts, R. B. (1962). Inhibition of protein synthesis in brain and learning and memory following puromycin. Journal of Neurochemistry, 9, 595–605.Find this resource:

Frank, C. A., Kennedy, M. J., Goold, C. P., Marek, K. W., & Davis, G. W. (2006). Mechanisms underlying the rapid induction and sustained expression of synaptic homeostasis. Neuron, 52(4), 663–677. doi:10.1016/j.neuron.2006.09.029Find this resource:

Frank, C. A., Pielage, J., & Davis, G. W. (2009). A presynaptic homeostatic signaling system composed of the Eph receptor, ephexin, Cdc42, and CaV2.1 calcium channels. Neuron, 61(4), 556–569. doi:10.1016/j.neuron.2008.12.028Find this resource:

Frey, U., Huang, Y. Y., & Kandel, E. R. (1993). Effects of cAMP simulate a late stage of LTP in hippocampal CA1 neurons. Science, 260(5114), 1661–1664.Find this resource:

Funayama, M., Hasegawa, K., Kowa, H., Saito, M., Tsuji, S., & Obata, F. (2002). A new locus for Parkinson’s disease (PARK8) maps to chromosome 12p11.2-q13.1. Annals of Neurology, 51(3), 296–301. doi:10.1002/ana.10113Find this resource:

Garcia-Bereguiain, M. A., Gonzalez-Islas, C., Lindsly, C., & Wenner, P. (2016). Spontaneous Release Regulates Synaptic Scaling in the Embryonic Spinal Network In Vivo. Journal of Neuroscience, 36(27), 7268–7282. doi:10.1523/JNEUROSCI.4066–15.2016Find this resource:

Gilhus, N. E., & Verschuuren, J. J. (2015). Myasthenia gravis: Subgroup classification and therapeutic strategies. Lancet Neurology, 14(10), 1023–1036. doi:10.1016/S1474-4422(15)00145-3Find this resource:

Goel, A., Jiang, B., Xu, L. W., Song, L., Kirkwood, A., & Lee, H. K. (2006). Cross-modal regulation of synaptic AMPA receptors in primary sensory cortices by visual experience. Nature Neuroscience, 9(8), 1001–1003. doi:10.1038/nn1725Find this resource:

Goel, A., & Lee, H. K. (2007). Persistence of experience-induced homeostatic synaptic plasticity through adulthood in superficial layers of mouse visual cortex. Journal of Neuroscience, 27(25), 6692–6700. doi:10.1523/JNEUROSCI.5038–06.2007Find this resource:

Goel, P., Li, X., & Dickman, D. (2017). Disparate postsynaptic induction mechanisms ultimately converge to drive the retrograde enhancement of presynaptic efficacy. Cell Reports, 21(9), 2339–2347. doi:10.1016/j.celrep.2017.10.116Find this resource:

Goold, C. P., & Davis, G. W. (2007). The BMP ligand Gbb gates the expression of synaptic homeostasis independent of synaptic growth control. Neuron, 56(1), 109–123. doi:10.1016/j.neuron.2007.08.006Find this resource:

Goorden, S. M., van Woerden, G. M., van der Weerd, L., Cheadle, J. P., & Elgersma, Y. (2007). Cognitive deficits in Tsc1+/– mice in the absence of cerebral lesions and seizures. Annals of Neurology, 62(6), 648–655. doi:10.1002/ana.21317Find this resource:

Grecksch, G., & Matthies, H. (1980). Two sensitive periods for the amnesic effect of anisomycin. Pharmacology, Biochemistry, and Behavior, 12(5), 663–665.Find this resource:

Greggio, E., & Cookson, M. R. (2009). Leucine-rich repeat kinase 2 mutations and Parkinson’s disease: Three questions. ASN Neuro, 1(1). doi:10.1042/AN20090007Find this resource:

Haghighi, A. P., McCabe, B. D., Fetter, R. D., Palmer, J. E., Hom, S., & Goodman, C. S. (2003). Retrograde control of synaptic transmission by postsynaptic CaMKII at the Drosophila neuromuscular junction. Neuron, 39(2), 255–267.Find this resource:

Hara, K., Yonezawa, K., Weng, Q. P., Kozlowski, M. T., Belham, C., & Avruch, J. (1998). Amino acid sufficiency and mTOR regulate p70 S6 kinase and eIF-4E BP1 through a common effector mechanism. Journal of Biological Chemistry, 273(23), 14484–14494.Find this resource:

Hay, N., & Sonenberg, N. (2004). Upstream and downstream of mTOR. Genes and Development, 18(16), 1926–1945. doi:10.1101/gad.1212704Find this resource:

Hebb, D. O. (1949). The organization of behavior: a neuropsychological theory. New York, NY: Wiley.Find this resource:

Hengen, K. B., Lambo, M. E., Van Hooser, S. D., Katz, D. B., & Turrigiano, G. G. (2013). Firing rate homeostasis in visual cortex of freely behaving rodents. Neuron, 80(2), 335–342. doi:10.1016/j.neuron.2013.08.038Find this resource:

Henry, F. E., Hockeimer, W., Chen, A., Mysore, S. P., & Sutton, M. A. (2017). Mechanistic target of rapamycin is necessary for changes in dendritic spine morphology associated with long-term potentiation. Molecular Brain, 10(1), 50. doi:10.1186/s13041-017-0330-yFind this resource:

Henry, F. E., McCartney, A. J., Neely, R., Perez, A. S., Carruthers, C. J., Stuenkel, E. L., … Sutton, M. A. (2012). Retrograde changes in presynaptic function driven by dendritic mTORC1. Journal of Neuroscience, 32(48), 17128–17142. doi:10.1523/JNEUROSCI.2149–12.2012Find this resource:

Henry, F. E., Wang, X., Serrano, D., Perez, A. S., Carruthers, C. J. L., Stuenkel, E. L., & Sutton, M. A. (2018). A unique homeostatic signaling pathway links synaptic inactivity to postsynaptic mTORC1. Journal of Neuroscience, 38(9), 2207–2225. doi:10.1523/JNEUROSCI.1843–17.2017Find this resource:

Hoeffer, C. A., & Klann, E. (2004). mTOR signaling: At the crossroads of plasticity, memory and disease. Trends in Neuroscience, 33(2), 67–75. doi:10.1016/j.tins.2009.11.003Find this resource:

Hoeffer, C. A., & Klann, E. (2010). mTOR signaling: At the crossroads of plasticity, memory and disease. Trends in Neuroscience, 33(2), 67–75. doi:10.1016/j.tins.2009.11.003Find this resource:

Hou, L., & Klann, E. (2004). Activation of the phosphoinositide 3-kinase-Akt-mammalian target of rapamycin signaling pathway is required for metabotropic glutamate receptor-dependent long-term depression. Journal of Neuroscience, 24(28), 6352–6361. doi:10.1523/JNEUROSCI.0995–04.2004Find this resource:

Huber, K. M., Kayser, M. S., & Bear, M. F. (2000). Role for rapid dendritic protein synthesis in hippocampal mGluR-dependent long-term depression. Science, 288(5469), 1254–1257.Find this resource:

Huber, K. M., Roder, J. C., & Bear, M. F. (2001). Chemical induction of mGluR5- and protein synthesis—dependent long-term depression in hippocampal area CA1. Journal of Neurophysiology, 86(1), 321–325. doi:10.1152/jn.2001.86.1.321Find this resource:

Imai, Y., Gehrke, S., Wang, H. Q., Takahashi, R., Hasegawa, K., Oota, E., & Lu, B. (2008). Phosphorylation of 4E-BP by LRRK2 affects the maintenance of dopaminergic neurons in Drosophila. EMBO Journal, 27(18), 2432–2443. doi:10.1038/emboj.2008.163Find this resource:

Isaac, J. T., Ashby, M. C., & McBain, C. J. (2007). The role of the GluR2 subunit in AMPA receptor function and synaptic plasticity. Neuron, 54(6), 859–871. doi:10.1016/j.neuron.2007.06.001Find this resource:

Jakawich, S. K., Nasser, H. B., Strong, M. J., McCartney, A. J., Perez, A. S., Rakesh, N., … Sutton, M. A. (2010). Local presynaptic activity gates homeostatic changes in presynaptic function driven by dendritic BDNF synthesis. Neuron, 68(6), 1143–1158. doi:10.1016/j.neuron.2010.11.034Find this resource:

Jaleel, M., Nichols, R. J., Deak, M., Campbell, D. G., Gillardon, F., Knebel, A., & Alessi, D. R. (2007). LRRK2 phosphorylates moesin at threonine-558: characterization of how Parkinson’s disease mutants affect kinase activity. Biochemistry Journal, 405(2), 307–317. doi:10.1042/BJ20070209Find this resource:

Jian, M., Luo, Y. X., Xue, Y. X., Han, Y., Shi, H. S., Liu, J. F., … Lu, L. (2014). eIF2alpha dephosphorylation in basolateral amygdala mediates reconsolidation of drug memory. Journal of Neuroscience, 34(30), 10010–10021. doi:10.1523/JNEUROSCI.0934–14.2014Find this resource:

Ju, W., Morishita, W., Tsui, J., Gaietta, G., Deerinck, T. J., Adams, S. R., … Malenka, R. C. (2004). Activity-dependent regulation of dendritic synthesis and trafficking of AMPA receptors. Nature Neuroscience, 7(3), 244–253. doi:10.1038/nn1189Find this resource:

Junger, M. A., Rintelen, F., Stocker, H., Wasserman, J. D., Vegh, M., Radimerski, T., … Hafen, E. (2003). The Drosophila forkhead transcription factor FOXO mediates the reduction in cell number associated with reduced insulin signaling. Journal of Biology, 2(3), 20. doi:10.1186/1475-4924-2-20Find this resource:

Kang, H., & Schuman, E. M. (1996). A requirement for local protein synthesis in neurotrophin-induced hippocampal synaptic plasticity. Science, 273(5280), 1402–1406.Find this resource:

Karachot, L., Shirai, Y., Vigot, R., Yamamori, T., & Ito, M. (2001). Induction of long-term depression in cerebellar Purkinje cells requires a rapidly turned over protein. Journal of Neurophysiology, 86(1), 280–289. doi:10.1152/jn.2001.86.1.280Find this resource:

Katz, B., & Miledi, R. (1978). A re-examination of curare action at the motor endplate. Proceedings of the Royal Society of London B: Biological Sciences, 203(1151), 119–133.Find this resource:

Kauderer, B. S., & Kandel, E. R. (2000). Capture of a protein synthesis-dependent component of long-term depression. Proceedings of the National Academy of Sciences of the United States of America, 97(24), 13342–13347. doi:10.1073/pnas.97.24.13342Find this resource:

Kaufman, R. J., Davies, M. V., Pathak, V. K., & Hershey, J. W. (1989). The phosphorylation state of eucaryotic initiation factor 2 alters translational efficiency of specific mRNAs. Molecular and Cellular Biology, 9(3), 946–958.Find this resource:

Kauwe, G., Tsurudome, K., Penney, J., Mori, M., Gray, L., Calderon, M. R., … Haghighi, A. P. (2016). Acute Fasting Regulates Retrograde Synaptic Enhancement through a 4E-BP-Dependent Mechanism. Neuron, 92(6), 1204–1212. doi:10.1016/j.neuron.2016.10.063Find this resource:

Keck, T., Keller, G. B., Jacobsen, R. I., Eysel, U. T., Bonhoeffer, T., & Hubener, M. (2013). Synaptic scaling and homeostatic plasticity in the mouse visual cortex in vivo. Neuron, 80(2), 327–334. doi:10.1016/j.neuron.2013.08.018Find this resource:

Kelleher, R. J., 3rd, Govindarajan, A., Jung, H. Y., Kang, H., & Tonegawa, S. (2004). Translational control by MAPK signaling in long-term synaptic plasticity and memory. Cell, 116(3), 467–479.Find this resource:

Kelleher, R. J., 3rd, Govindarajan, A., & Tonegawa, S. (2004). Translational regulatory mechanisms in persistent forms of synaptic plasticity. Neuron, 44(1), 59–73. doi:10.1016/j.neuron.2004.09.013Find this resource:

Kim, J. H., Liao, D., Lau, L. F., & Huganir, R. L. (1998). SynGAP: a synaptic RasGAP that associates with the PSD-95/SAP90 protein family. Neuron, 20(4), 683–691.Find this resource:

Kirov, S. A., Goddard, C. A., & Harris, K. M. (2004). Age-dependence in the homeostatic upregulation of hippocampal dendritic spine number during blocked synaptic transmission. Neuropharmacology, 47(5), 640–648. doi:10.1016/j.neuropharm.2004.07.039Find this resource:

Kwiatkowski, D. J., & Manning, B. D. (2005). Tuberous sclerosis: a GAP at the crossroads of multiple signaling pathways. Human Molecular Genetics, 14 Spec. No. 2, R251–258. doi:10.1093/hmg/ddi260Find this resource:

Lee, S. B., Kim, W., Lee, S., & Chung, J. (2007). Loss of LRRK2/PARK8 induces degeneration of dopaminergic neurons in Drosophila. Biochemical and Biophysical Research Communications, 358(2), 534–539. doi:10.1016/j.bbrc.2007.04.156Find this resource:

Lee, S., Liu, H. P., Lin, W. Y., Guo, H., & Lu, B. (2010). LRRK2 kinase regulates synaptic morphology through distinct substrates at the presynaptic and postsynaptic compartments of the Drosophila neuromuscular junction. Journal of Neuroscience, 30(50), 16959–16969. doi:10.1523/JNEUROSCI.1807–10.2010Find this resource:

Linden, D. J. (1996). A protein synthesis-dependent late phase of cerebellar long-term depression. Neuron, 17(3), 483–490.Find this resource:

Lisman, J., Grace, A. A., & Duzel, E. (2011). A neoHebbian framework for episodic memory; role of dopamine-dependent late LTP. Trends in Neuroscience, 34(10), 536–547. doi:10.1016/j.tins.2011.07.006Find this resource:

Lissin, D. V., Gomperts, S. N., Carroll, R. C., Christine, C. W., Kalman, D., Kitamura, M., … von Zastrow, M. (1998). Activity differentially regulates the surface expression of synaptic AMPA and NMDA glutamate receptors. Proceedings of the National Academy of Sciences of the United States of America, 95(12), 7097–7102.Find this resource:

Liu, Z., Wang, X., Yu, Y., Li, X., Wang, T., Jiang, H., … Smith, W. W. (2008). A Drosophila model for LRRK2-linked parkinsonism. Proceedings of the National Academy of Sciences of the United States of America, 105(7), 2693–2698. doi:10.1073/pnas.0708452105Find this resource:

Loewith, R., & Hall, M. N. (2011). Target of rapamycin (TOR) in nutrient signaling and growth control. Genetics, 189(4), 1177–1201. doi:10.1534/genetics.111.133363Find this resource:

Luscher, C., & Malenka, R. C. (2012). NMDA receptor-dependent long-term potentiation and long-term depression (LTP/LTD). Cold Spring Harbor Perspectives in Biology, 4(6). doi:10.1101/cshperspect.a005710Find this resource:

Lynch, M. A. (2004). Long-term potentiation and memory. Physiology Review, 84(1), 87–136. doi:10.1152/physrev.00014.2003Find this resource:

Ma, T., Trinh, M. A., Wexler, A. J., Bourbon, C., Gatti, E., Pierre, P., … Klann, E. (2013). Suppression of eIF2alpha kinases alleviates Alzheimer’s disease-related plasticity and memory deficits. Nature Neuroscience, 16(9), 1299–1305. doi:10.1038/nn.3486Find this resource:

Ma, X. M., & Blenis, J. (2009). Molecular mechanisms of mTOR-mediated translational control. Nature Reviews: Molecular Cell Biology, 10(5), 307–318. doi:10.1038/nrm2672Find this resource:

Maffei, A., Nelson, S. B., & Turrigiano, G. G. (2004). Selective reconfiguration of layer 4 visual cortical circuitry by visual deprivation. Nature Neuroscience, 7(12), 1353–1359. doi:10.1038/nn1351Find this resource:

Maffei, A., & Turrigiano, G. G. (2008). Multiple modes of network homeostasis in visual cortical layer 2/3. Journal of Neuroscience, 28(17), 4377–4384. doi:10.1523/JNEUROSCI.5298–07.2008Find this resource:

Maghsoodi, B., Poon, M. M., Nam, C. I., Aoto, J., Ting, P., & Chen, L. (2008). Retinoic acid regulates RARalpha-mediated control of translation in dendritic RNA granules during homeostatic synaptic plasticity. Proceedings of the National Academy of Sciences of the United States of America, 105(41), 16015–16020. doi:10.1073/pnas.0804801105Find this resource:

Malenka, R. C., & Bear, M. F. (2004). LTP and LTD: An embarrassment of riches. Neuron, 44(1), 5–21. doi:10.1016/j.neuron.2004.09.012Find this resource:

Mameli, M., Balland, B., Lujan, R., & Luscher, C. (2007). Rapid synthesis and synaptic insertion of GluR2 for mGluR-LTD in the ventral tegmental area. Science, 317(5837), 530–533. doi:10.1126/science.1142365Find this resource:

Marie, B., Pym, E., Bergquist, S., & Davis, G. W. (2010). Synaptic homeostasis is consolidated by the cell fate gene gooseberry, a Drosophila pax3/7 homolog. Journal of Neuroscience, 30(24), 8071–8082. doi:10.1523/JNEUROSCI.5467–09.2010Find this resource:

Martin, I., Dawson, V. L., & Dawson, T. M. (2011). Recent advances in the genetics of Parkinson’s disease. Annual Review of Genomics and Human Genetics, 12, 301–325. doi:10.1146/annurev-genom-082410-101440Find this resource:

Massey, P. V., & Bashir, Z. I. (2007). Long-term depression: Multiple forms and implications for brain function. Trends in Neuroscience, 30(4), 176–184. doi:10.1016/j.tins.2007.02.005Find this resource:

Mata, I. F., Wedemeyer, W. J., Farrer, M. J., Taylor, J. P., & Gallo, K. A. (2006). LRRK2 in Parkinson’s disease: protein domains and functional insights. Trends in Neuroscience, 29(5), 286–293. doi:10.1016/j.tins.2006.03.006Find this resource:

Miledi, R., Molenaar, P. C., & Polak, R. L. (1978). Alpha-Bungarotoxin enhances transmitter “released” at the neuromuscular junction. Nature, 272(5654), 641–643.Find this resource:

Montarolo, P. G., Goelet, P., Castellucci, V. F., Morgan, J., Kandel, E. R., & Schacher, S. (1986). A critical period for macromolecular synthesis in long-term heterosynaptic facilitation in Aplysia. Science, 234(4781), 1249–1254.Find this resource:

Moon, S. L., Sonenberg, N., & Parker, R. (2018). Neuronal regulation of eIF2alpha function in health and neurological disorders. Trends in Molecular Medicine. doi:10.1016/j.molmed.2018.04.001Find this resource:

Muller, M., & Davis, G. W. (2012). Transsynaptic control of presynaptic Ca(2)(+) influx achieves homeostatic potentiation of neurotransmitter release. Current Biology, 22(12), 1102–1108. doi:10.1016/j.cub.2012.04.018Find this resource:

Muller, M., Liu, K. S., Sigrist, S. J., & Davis, G. W. (2012). RIM controls homeostatic plasticity through modulation of the readily-releasable vesicle pool. Journal of Neuroscience, 32(47), 16574–16585. doi:10.1523/JNEUROSCI.0981–12.2012Find this resource:

Muller, M., Pym, E. C., Tong, A., & Davis, G. W. (2011). Rab3-GAP controls the progression of synaptic homeostasis at a late stage of vesicle release. Neuron, 69(4), 749–762. doi:10.1016/j.neuron.2011.01.025Find this resource:

Murthy, V. N., Schikorski, T., Stevens, C. F., & Zhu, Y. (2001). Inactivity produces increases in neurotransmitter release and synapse size. Neuron, 32(4), 673–682.Find this resource:

Nabavi, S., Fox, R., Proulx, C. D., Lin, J. Y., Tsien, R. Y., & Malinow, R. (2014). Engineering a memory with LTD and LTP. Nature, 511(7509), 348–352. doi:10.1038/nature13294Find this resource:

Nairn, A. C., & Palfrey, H. C. (1987). Identification of the major Mr 100,000 substrate for calmodulin-dependent protein kinase III in mammalian cells as elongation factor-2. Journal of Biological Chemistry, 262(36), 17299–17303.Find this resource:

Ng, C. H., Mok, S. Z., Koh, C., Ouyang, X., Fivaz, M. L., Tan, E. K., … Lim, K. L. (2009). Parkin protects against LRRK2 G2019S mutant-induced dopaminergic neurodegeneration in Drosophila. Journal of Neuroscience, 29(36), 11257–11262. doi:10.1523/JNEUROSCI.2375–09.2009Find this resource:

Nguyen, P. V., & Kandel, E. R. (1997). Brief theta-burst stimulation induces a transcription-dependent late phase of LTP requiring cAMP in area CA1 of the mouse hippocampus. Learning and Memory, 4(2), 230–243.Find this resource:

O’Brien, R. J., Kamboj, S., Ehlers, M. D., Rosen, K. R., Fischbach, G. D., & Huganir, R. L. (1998). Activity-dependent modulation of synaptic AMPA receptor accumulation. Neuron, 21(5), 1067–1078.Find this resource:

Oh, J. S., Manzerra, P., & Kennedy, M. B. (2004). Regulation of the neuron-specific Ras GTPase-activating protein, synGAP, by Ca2+/calmodulin-dependent protein kinase II. Journal of Biological Chemistry, 279(17), 17980–17988. doi:10.1074/jbc.M314109200Find this resource:

Orr, B. O., Fetter, R. D., & Davis, G. W. (2017). Retrograde semaphorin-plexin signalling drives homeostatic synaptic plasticity. Nature, 550(7674), 109–113. doi:10.1038/nature24017Find this resource:

Paisan-Ruiz, C., Jain, S., Evans, E. W., Gilks, W. P., Simon, J., van der Brug, M., … Singleton, A. B. (2004). Cloning of the gene containing mutations that cause PARK8-linked Parkinson’s disease. Neuron, 44(4), 595–600. doi:10.1016/j.neuron.2004.10.023Find this resource:

Pavitt, G. D., Ramaiah, K. V., Kimball, S. R., & Hinnebusch, A. G. (1998). eIF2 independently binds two distinct eIF2B subcomplexes that catalyze and regulate guanine-nucleotide exchange. Genes and Development, 12(4), 514–526.Find this resource:

Pelletier, J., & Sonenberg, N. (1988). Internal initiation of translation of eukaryotic mRNA directed by a sequence derived from poliovirus RNA. Nature, 334(6180), 320–325. doi:10.1038/334320a0Find this resource:

Penney, J., Tsurudome, K., Liao, E. H., Elazzouzi, F., Livingstone, M., Gonzalez, M., … Haghighi, A. P. (2012). TOR is required for the retrograde regulation of synaptic homeostasis at the Drosophila neuromuscular junction. Neuron, 74(1), 166–178. doi:10.1016/j.neuron.2012.01.030Find this resource:

Penney, J., Tsurudome, K., Liao, E. H., Kauwe, G., Gray, L., Yanagiya, A., … Haghighi, A. P. (2016). LRRK2 regulates retrograde synaptic compensation at the Drosophila neuromuscular junction. Nature Communications, 7, 12188. doi:10.1038/ncomms12188Find this resource:

Perry, S., Han, Y., Das, A., & Dickman, D. (2017). Homeostatic plasticity can be induced and expressed to restore synaptic strength at neuromuscular junctions undergoing ALS-related degeneration. Human Molecular Genetics, 26(21), 4153–4167. doi:10.1093/hmg/ddx304Find this resource:

Petersen, S. A., Fetter, R. D., Noordermeer, J. N., Goodman, C. S., & DiAntonio, A. (1997). Genetic analysis of glutamate receptors in Drosophila reveals a retrograde signal regulating presynaptic transmitter release. Neuron, 19(6), 1237–1248. doi:10.1016/S0896-6273(00)80415-8Find this resource:

Pilgram, G. S., Potikanond, S., van der Plas, M. C., Fradkin, L. G., & Noordermeer, J. N. (2011). The RhoGAP crossveinless-c interacts with Dystrophin and is required for synaptic homeostasis at the Drosophila neuromuscular junction. Journal of Neuroscience, 31(2), 492–500. doi:10.1523/JNEUROSCI.4732–10.2011Find this resource:

Plomp, J. J. (2017). Trans-synaptic homeostasis at the myasthenic neuromuscular junction. Frontiers in Bioscience, Landmark, 22, 1033–1051.Find this resource:

Plomp, J. J., Morsch, M., Phillips, W. D., & Verschuuren, J. J. (2015). Electrophysiological analysis of neuromuscular synaptic function in myasthenia gravis patients and animal models. Experimental Neurology, 270, 41–54. doi:10.1016/j.expneurol.2015.01.007Find this resource:

Plomp, J. J., Van Kempen, G. T., De Baets, M. B., Graus, Y. M., Kuks, J. B., & Molenaar, P. C. (1995). Acetylcholine release in myasthenia gravis: Regulation at single end-plate level. Annals of Neurology, 37(5), 627–636. doi:10.1002/ana.410370513Find this resource:

Plomp, J. J., van Kempen, G. T., & Molenaar, P. C. (1992). Adaptation of quantal content to decreased postsynaptic sensitivity at single endplates in alpha-bungarotoxin-treated rats. Journal of Physiology, 458, 487–499.Find this resource:

Pozo, K., & Goda, Y. (2010). Unraveling mechanisms of homeostatic synaptic plasticity. Neuron, 66(3), 337–351. doi:10.1016/j.neuron.2010.04.028Find this resource:

Puig, O., Marr, M. T., Ruhf, M. L., & Tjian, R. (2003). Control of cell number by Drosophila FOXO: Downstream and feedback regulation of the insulin receptor pathway. Genes and Development, 17(16), 2006–2020. doi:10.1101/gad.1098703Find this resource:

Reese, A. L., & Kavalali, E. T. (2015). Spontaneous neurotransmission signals through store-driven Ca(2+) transients to maintain synaptic homeostasis. Elife, 4. doi:10.7554/eLife.09262Find this resource:

Schanzenbacher, C. T., Sambandan, S., Langer, J. D., & Schuman, E. M. (2016). Nascent proteome remodeling following homeostatic scaling at hippocampal synapses. Neuron, 92(2), 358–371. doi:10.1016/j.neuron.2016.09.058Find this resource:

Scheetz, A. J., Nairn, A. C., & Constantine-Paton, M. (2000). NMDA receptor-mediated control of protein synthesis at developing synapses. Nature Neuroscience, 3(3), 211–216. doi:10.1038/72915Find this resource:

Shahbazian, D., Parsyan, A., Petroulakis, E., Topisirovic, I., Martineau, Y., Gibbs, B. F., … Sonenberg, N. (2010). Control of cell survival and proliferation by mammalian eukaryotic initiation factor 4B. Molecular and Cellular Biology, 30(6), 1478–1485. doi:10.1128/MCB.01218–09Find this resource:

Sharma, A., Hoeffer, C. A., Takayasu, Y., Miyawaki, T., McBride, S. M., Klann, E., & Zukin, R. S. (2010). Dysregulation of mTOR signaling in fragile X syndrome. Journal of Neuroscience, 30(2), 694–702. doi:10.1523/JNEUROSCI.3696–09.2010Find this resource:

Shih, Y. T., & Hsueh, Y. P. (2018). The involvement of endoplasmic reticulum formation and protein synthesis efficiency in VCP- and ATL1-related neurological disorders. Journal of Biomedical Science, 25(1), 2. doi:10.1186/s12929-017-0403-3Find this resource:

Sonenberg, N., & Hinnebusch, A. G. (2009). Regulation of translation initiation in eukaryotes: Mechanisms and biological targets. Cell, 136(4), 731–745. doi:10.1016/j.cell.2009.01.042Find this resource:

Squire, L. R., & Davis, H. P. (1981). The pharmacology of memory: A neurobiological perspective. Annual Review of Pharmacology and Toxicology, 21, 323–356. doi:10.1146/ this resource:

Sutton, M. A., Ito, H. T., Cressy, P., Kempf, C., Woo, J. C., & Schuman, E. M. (2006). Miniature neurotransmission stabilizes synaptic function via tonic suppression of local dendritic protein synthesis. Cell, 125(4), 785–799. doi:10.1016/j.cell.2006.03.040Find this resource:

Sutton, M. A., & Schuman, E. M. (2006). Dendritic protein synthesis, synaptic plasticity, and memory. Cell, 127(1), 49–58. doi:10.1016/j.cell.2006.09.014Find this resource:

Sutton, M. A., Taylor, A. M., Ito, H. T., Pham, A., & Schuman, E. M. (2007). Postsynaptic decoding of neural activity: eEF2 as a biochemical sensor coupling miniature synaptic transmission to local protein synthesis. Neuron, 55(4), 648–661. doi:10.1016/j.neuron.2007.07.030Find this resource:

Sutton, M. A., Wall, N. R., Aakalu, G. N., & Schuman, E. M. (2004). Regulation of dendritic protein synthesis by miniature synaptic events. Science, 304(5679), 1979–1983. doi:10.1126/science.1096202Find this resource:

Swiech, L., Perycz, M., Malik, A., & Jaworski, J. (2008). Role of mTOR in physiology and pathology of the nervous system. Biochimica et Biophysica Acta, 1784(1), 116–132. doi:10.1016/j.bbapap.2007.08.015Find this resource:

Tain, L. S., Mortiboys, H., Tao, R. N., Ziviani, E., Bandmann, O., & Whitworth, A. J. (2009). Rapamycin activation of 4E-BP prevents parkinsonian dopaminergic neuron loss. Nature Neuroscience, 12(9), 1129–1135. doi:10.1038/nn.2372Find this resource:

Takamori, M. (2017). Synaptic homeostasis and its immunological disturbance in neuromuscular junction disorders. International Journal of Molecular Science, 18(4). doi:10.3390/ijms18040896Find this resource:

Tang, S. J., Reis, G., Kang, H., Gingras, A. C., Sonenberg, N., & Schuman, E. M. (2002). A rapamycin-sensitive signaling pathway contributes to long-term synaptic plasticity in the hippocampus. Proceedings of the National Academy of Sciences of the United States of America, 99(1), 467–472. doi:10.1073/pnas.012605299Find this resource:

Taymans, J. M., Nkiliza, A., & Chartier-Harlin, M. C. (2015). Deregulation of protein translation control, a potential game-changing hypothesis for Parkinson’s disease pathogenesis. Trends in Molecular Medicine, 21(8), 466–472. doi:10.1016/j.molmed.2015.05.004Find this resource:

Teichert, M., Liebmann, L., Hubner, C. A., & Bolz, J. (2017). Homeostatic plasticity and synaptic scaling in the adult mouse auditory cortex. Science Reports, 7(1), 17423. doi:10.1038/s41598-017-17711-5Find this resource:

Teleman, A. A., Chen, Y. W., & Cohen, S. M. (2005). 4E-BP functions as a metabolic brake used under stress conditions but not during normal growth. Genes and Development, 19(16), 1844–1848. doi:10.1101/gad.341505Find this resource:

Tian, L., Prior, C., Dempster, J., & Marshall, I. G. (1994). Nicotinic antagonist-produced frequency-dependent changes in acetylcholine release from rat motor nerve terminals. Journal of Physiology, 476(3), 517–529.Find this resource:

Tsai, P., & Sahin, M. (2011). Mechanisms of neurocognitive dysfunction and therapeutic considerations in tuberous sclerosis complex. Current Opinion in Neurology, 24(2), 106–113. doi:10.1097/WCO.0b013e32834451c4Find this resource:

Tsujihata, M., Hazama, R., Ishii, N., Ide, Y., & Takamori, M. (1980). Ultrastructural localization of acetylcholine receptor at the motor endplate: myasthenia gravis and other neuromuscular diseases. Neurology, 30(11), 1203–1211.Find this resource:

Tsurudome, K., Tsang, K., Liao, E. H., Ball, R., Penney, J., Yang, J. S., … Haghighi, A. P. (2010). The Drosophila miR-310 cluster negatively regulates synaptic strength at the neuromuscular junction. Neuron, 68(5), 879–893. doi:10.1016/j.neuron.2010.11.016Find this resource:

Turrigiano, G. (2012). Homeostatic synaptic plasticity: local and global mechanisms for stabilizing neuronal function. Cold Spring Harbor Perspectives in Biology, 4(1), a005736. doi:10.1101/cshperspect.a005736Find this resource:

Turrigiano, G. G. (2008). The self-tuning neuron: Synaptic scaling of excitatory synapses. Cell, 135(3), 422–435. doi:10.1016/j.cell.2008.10.008Find this resource:

Turrigiano, G. G. (2017). The dialectic of Hebb and homeostasis. Proceedings of the Royal Society of London B: Biological Sciences, 372(1715). doi:10.1098/rstb.2016.0258Find this resource:

Turrigiano, G. G., Leslie, K. R., Desai, N. S., Rutherford, L. C., & Nelson, S. B. (1998). Activity-dependent scaling of quantal amplitude in neocortical neurons. Nature, 391(6670), 892–896. doi:10.1038/36103Find this resource:

Turrigiano, G. G., & Nelson, S. B. (2000). Hebb and homeostasis in neuronal plasticity. Current Biochim Biophys Acta Opinion in Neurobiology, 10(3), 358–364.Find this resource:

Turrigiano, G. G., & Nelson, S. B. (2004). Homeostatic plasticity in the developing nervous system. Nature Reviews. Neuroscience, 5(2), 97–107. doi:10.1038/nrn1327Find this resource:

Tyler, W. J., Petzold, G. C., Pal, S. K., & Murthy, V. N. (2007). Experience-dependent modification of primary sensory synapses in the mammalian olfactory bulb. Journal of Neuroscience, 27(35), 9427–9438. doi:10.1523/JNEUROSCI.0664–07.2007Find this resource:

Vale, C., & Sanes, D. H. (2002). The effect of bilateral deafness on excitatory and inhibitory synaptic strength in the inferior colliculus. European Journal of Neuroscience, 16(12), 2394–2404.Find this resource:

Venderova, K., Kabbach, G., Abdel-Messih, E., Zhang, Y., Parks, R. J., Imai, Y., … Park, D. S. (2009). Leucine-Rich Repeat Kinase 2 interacts with Parkin, DJ-1 and PINK-1 in a Drosophila melanogaster model of Parkinson’s disease. Human Molecular Genetics, 18(22), 4390–4404. doi:10.1093/hmg/ddp394Find this resource:

Vitureira, N., & Goda, Y. (2013). Cell biology in neuroscience: The interplay between Hebbian and homeostatic synaptic plasticity. Journal of Cellular Biology, 203(2), 175–186. doi:10.1083/jcb.201306030Find this resource:

von der Brelie, C., Waltereit, R., Zhang, L., Beck, H., & Kirschstein, T. (2006). Impaired synaptic plasticity in a rat model of tuberous sclerosis. European Journal Neuroscience, 23(3), 686–692. doi:10.1111/j.1460–9568.2006.04594.xFind this resource:

Wang, C. C., Held, R. G., & Hall, B. J. (2013). SynGAP regulates protein synthesis and homeostatic synaptic plasticity in developing cortical networks. PLoS One, 8(12), e83941. doi:10.1371/journal.pone.0083941Find this resource:

Wang, H., Ardiles, A. O., Yang, S., Tran, T., Posada-Duque, R., Valdivia, G., … Kirkwood, A. (2016). Metabotropic glutamate receptors induce a form of LTP controlled by translation and arc signaling in the hippocampus. Journal of Neuroscience, 36(5), 1723–1729. doi:10.1523/JNEUROSCI.0878–15.2016Find this resource:

Wang, H. L., Zhang, Z., Hintze, M., & Chen, L. (2011). Decrease in calcium concentration triggers neuronal retinoic acid synthesis during homeostatic synaptic plasticity. Journal of Neuroscience, 31(49), 17764–17771. doi:10.1523/JNEUROSCI.3964–11.2011Find this resource:

Wang, X., Pinter, M. J., & Rich, M. M. (2016). Reversible recruitment of a homeostatic reserve pool of synaptic vesicles underlies rapid homeostatic plasticity of quantal content. Journal of Neuroscience, 36(3), 828–836. doi:10.1523/JNEUROSCI.3786–15.2016Find this resource:

Wang, Y. T., & Linden, D. J. (2000). Expression of cerebellar long-term depression requires postsynaptic clathrin-mediated endocytosis. Neuron, 25(3), 635–647.Find this resource:

Waung, M. W., & Huber, K. M. (2009). Protein translation in synaptic plasticity: mGluR-LTD, Fragile X. Current Opinion in Neurobiology, 19(3), 319–326. doi:10.1016/j.conb.2009.03.011Find this resource:

Waung, M. W., Pfeiffer, B. E., Nosyreva, E. D., Ronesi, J. A., & Huber, K. M. (2008). Rapid translation of Arc/Arg3.1 selectively mediates mGluR-dependent LTD through persistent increases in AMPAR endocytosis rate. Neuron, 59(1), 84–97. doi:10.1016/j.neuron.2008.05.014Find this resource:

Weyhersmuller, A., Hallermann, S., Wagner, N., & Eilers, J. (2011). Rapid active zone remodeling during synaptic plasticity. Journal of Neuroscience, 31(16), 6041–6052. doi:10.1523/JNEUROSCI.6698–10.2011Find this resource:

Wierenga, C. J., Ibata, K., & Turrigiano, G. G. (2005). Postsynaptic expression of homeostatic plasticity at neocortical synapses. Journal of Neuroscience, 25(11), 2895–2905. doi:10.1523/JNEUROSCI.5217–04.2005Find this resource:

Wierenga, C. J., Walsh, M. F., & Turrigiano, G. G. (2006). Temporal regulation of the expression locus of homeostatic plasticity. Journal of Neurophysiology, 96(4), 2127–2133. doi:10.1152/jn.00107.2006Find this resource:

Wullschleger, S., Loewith, R., & Hall, M. N. (2006). TOR signaling in growth and metabolism. Cell, 124(3), 471–484. doi:10.1016/j.cell.2006.01.016Find this resource:

Xiao, M. Y., Zhou, Q., & Nicoll, R. A. (2001). Metabotropic glutamate receptor activation causes a rapid redistribution of AMPA receptors. Neuropharmacology, 41(6), 664–671.Find this resource:

Younger, M. A., Muller, M., Tong, A., Pym, E. C., & Davis, G. W. (2013). A presynaptic ENaC channel drives homeostatic plasticity. Neuron, 79(6), 1183–1196. doi:10.1016/j.neuron.2013.06.048Find this resource:

Zenke, F., & Gerstner, W. (2017). Hebbian plasticity requires compensatory processes on multiple timescales. Proceedings of the Royal Society of London B: Biological Sciences, 372(1715). doi:10.1098/rstb.2016.0259Find this resource:

Zhang, W., & Linden, D. J. (2003). The other side of the engram: Experience-driven changes in neuronal intrinsic excitability. Nature Reviews. Neuroscience, 4(11), 885–900. doi:10.1038/nrn1248Find this resource:

Zhang, Y., Venkitaramani, D. V., Gladding, C. M., Zhang, Y., Kurup, P., Molnar, E., … Lombroso, P. J. (2008). The tyrosine phosphatase STEP mediates AMPA receptor endocytosis after metabotropic glutamate receptor stimulation. Journal of Neuroscience, 28(42), 10561–10566. doi:10.1523/JNEUROSCI.2666–08.2008Find this resource:

Zheng, X., Boyer, L., Jin, M., Kim, Y., Fan, W., Bardy, C., … Hunter, T. (2016). Alleviation of neuronal energy deficiency by mTOR inhibition as a treatment for mitochondria-related neurodegeneration. Elife, 5. doi:10.7554/eLife.13378Find this resource:

Zimprich, A., Muller-Myhsok, B., Farrer, M., Leitner, P., Sharma, M., Hulihan, M., … Gasser, T. (2004). The PARK8 locus in autosomal dominant parkinsonism: confirmation of linkage and further delineation of the disease-containing interval. American Journal of Human Genetics, 74(1), 11–19. doi:10.1086/380647Find this resource: