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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

Introduction

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.

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