Protein Synthesis and Synapse Specificity in Functional Plasticity
Abstract and Keywords
This chapter discusses the role of protein synthesis in the maintenance of long-term potentiation (LTP) and its associative properties, synaptic tagging and capture, which are cellular correlates of long-term memory. Starting from a brief overview of the early and late phases of LTP, the chapter discusses various existing models for synaptic activity-induced protein synthesis and its roles in late-LTP. The synaptic tagging and capture and cross-tagging theories are given emphasis, along with the elucidation of local dendritic protein synthesis and its significance in the maintenance of LTP. Inverse synaptic tagging, synaptic competition for plasticity-related proteins, and metaplasticity are also covered. The importance of the balance between proteasomal degradation and synthesis of plasticity-related proteins in persistent potentiation is briefly discussed. This chapter touches upon the physiological implications of epigenetic regulation in the control of neuronal functions and the molecular mechanisms within the neurons that translate epigenetic changes into long-lasting responses.
Synaptic plasticity, wherein synapses are weakened or strengthened in response to different input stimulation intensities and frequencies, is considered the cellular correlate of learning and memory (Bear, 1996). Long-term potentiation (LTP) is a form of synaptic plasticity whereby the synaptic strength is increased in response to strong input stimulation. A persistent potentiation of synaptic strength, termed late-LTP (L-LTP), lasting for at least eight hours in vitro (E. P. Huang, 1998; Ostroff, Fiala, Allwardt, & Harris, 2002), is protein-synthesis dependent. Plasticity-related products (PRPs) synthesized in response to the signaling cascades triggered by the L-LTP inducing stimuli, lead to the persistence of potentiation, which translates as the long-term preservation of memories. However, several theories/models exist for the protein-synthesis dependence of L-LTP. The synaptic tagging and capture model, as well as the synaptic cross-tagging model, discusses the role of tagging of active synapses in being able to capture PRPs and thereby enable the persistence of synaptic potentiation at specific synapses (Frey & Morris, 1998b; Sajikumar, Navakkode, Sacktor, & Frey, 2005). In addition, local dendritic protein synthesis, and a possible cooperation between dendritically and somatically synthesized proteins are suggested to be involved in the maintenance of LTP (Sherff & Carew, 1999; Sutton & Schuman, 2006). However, protein synthesis in the absence of a balance by proteasomal degradation of PRPs does not result in L-LTP. The balance between synthesis and degradation of PRPs is thus critical in LTP maintenance (Fonseca, Vabulas, Hartl, Bonhoeffer, & Nagerl, 2006). Epigenetic mechanisms activated during memory consolidation may poise genes for reactivation at a later point in time.
Protein synthesis in memory: Role in consolidation of LTP
LTP is the persistent strengthening of synapses that explains the cellular and molecular processes that underlie learning and memory formation (Lynch, 2004; Whitlock, Heynen, Shuler, & Bear, 2006). It was imperative to understand the role of protein synthesis in hippocampal LTP, given the hippocampal role in various memory processes (Milner, 1972; O’Keefe & Nadel, 1978; Penfield & Milner, 1958; Teyler & DiScenna, 1986; Thompson, 1986). Studies have demonstrated that the induction and maintenance of LTP is governed by pre-synaptic and post-synaptic mechanisms (Buzsáki, 1985; Frey, Krug, Reymann, & Matthies, 1988; Desmond & Levy, 1986; Dolphin, Errington, & Bliss, 1982; Krug, Brodemann, & Ott, 1982). Studies previously have shown how presynaptic mechanisms leading to an increase in transmitter release are involved at least in early-phase of LTP (E-LTP) in the dentate area while the post-synaptic changes of the membrane structure and second messenger systems engender the long-lasting maintenance of LTP (Akers & Routtenberg, 1985; T. V. Bliss, Errington, Lynch, & Williams, 1990; Dolphin et al., 1982; Reymann, Frey, Jork, & Matthies, 1988). Nevertheless, several recent studies suggest that expression of LTP involves the reinforcement of both pre and post synaptic function and is not confined to a single neuron (Lisman & Raghavachari, 2006). The requirement of protein synthesis in LTP maintenance was established by the observation that anisomycin, a protein synthesis inhibitor, completely abolished the late phase of LTP (Krug, Lossner, & Ott, 1984). The dependence of late phase LTP on intact protein synthesis has been corroborated by findings from Frey et al. (Frey et al., 1988). Further evidence for protein synthesis dependency of long-lasting plasticity was shown in Aplysia where protein synthesis blockers blocked long-term heterosynaptic facilitation which correlates to learning, but not short-lasting forms of facilitation (Montarolo et al., 1986).The requirement of protein synthesis for both LTP and memory is consistent with a role for LTP in the formation of memories.
The continued expression of LTP depends on activation of gene transcription and protein synthesis (Roberson, English, & Sweatt, 1996). Post-synaptic calcium influx in response to strong synaptic stimulation activates intracellular signaling cascades leading to an increase in cAMP concentration and activation of protein kinase A (PKA; Lynch, 2004). PKA catalytic subunit translocates to the nucleus and phosphorylates and activates the transcription factor cAMP response element-binding protein (CREB; Kandel, 2012). CREB can also be activated by mitogen-activated protein kinases/extracellular signal regulated kinases (MAPK/ERKs) and Ca2+/calmodulin kinases (CaMKs; Kandel, 2012). Phosphorylated CREB aids in transcription of plasticity-related genes and is thereby a central component of memory storage (Bourtchuladze et al., 1994; Kida, 2012). Studies have shown that a constitutively active form of CREB, VP16-CREB, lowers the threshold for L-LTP in hippocampal CA1 neurons at Schaffer collateral synapses (Barco, Alarcon, & Kandel, 2002). cAMP response element (CRE)-driven gene products result in a cell-wide priming for LTP and synaptic capture of CRE-driven gene products enable LTP consolidation at tagged active synapses that are only weakly stimulated (Barco et al., 2002). Extracellular signal regulated kinase ERK1/2 has an important role in regulating CREB-mediated gene transcription and long-term memory (Giese & Mizuno, 2013). CaMKIV, a Ca2+/calmodulin kinase found exclusively in the nucleus, is another crucial component in the regulation of CRE-dependent transcription and the sustenance of hippocampal L-LTP and memory consolidation (Kang et al., 2001). Interestingly, CREB has been proposed to be involved in neuronal memory allocation, wherein neurons with higher levels of CREB are more excitable and therefore has a higher probability to fire in response to sensory input and be represented to a greater extent in the memory trace (Zhou et al., 2009).
Studies have investigated how LTP can be reversed. One of the studies from (Hardt, Nader, & Wang, 2014) showed that the E-LTP decay is caused by homeostatic downscaling while the decay of late phase LTP is mediated by the regulators of metaplasticity phenomenon such as the NMDA receptors with their subunit composition, wherein both E-LTP and L-LTP processes mandate the activity-dependent removal of post-synaptic GluA2-containing α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptors (AMPARs). The number and composition of AMPARs dictate the stability and formation of LTP where N-methyl-D-aspartate receptor (NMDAR) is a core regulating element. In addition, it is well known that NMDAR activation leads to an intracellular increase in calcium which in turn triggers downstream signaling processes involving Ca2+/calmodulin-dependent protein kinase II
(CaMKII), protein kinase C (PKC), transcription factors such as CREB/C/EBP, translation initiation factors (e.g., eIF4E) and growth factors such as brain-derived neurotrophic factor (BDNF; Rampon et al., 2000; Tsien, Huerta, & Tonegawa, 1996). Research over the years has established that the atypical PKC isoform M-zeta (PKMζ) is involved in the late phase of LTP and in the consolidation processes (Sacktor, 2011, 2012; Shema et al., 2011). The PKMζ protein is known to promote its own synthesis leading to PKMζ mediated late-LTP (Shema et al., 2011; Whitlock et al., 2006).
AMPAR with GluA2 subunits are pivotal for long-term memory formation (Collingridge, Peineau, Howland, & Wang, 2010; C. H. Kim, Chung, Lee, & Huganir, 2001; Scholz et al., 2010; Y. T. Wang & Linden, 2000). There have been findings highlighting the involvement of PKMζ with the mechanisms that regulate AMPAR/GluA2 expression. PKMζ infusions have been shown to increase the AMPAR currents and the post-synaptic insertion of AMPAR/GluA2s as well as preventing the activity-dependent endocytosis of GluA2/AMPARs (Hardt et al., 2014). These studies, thus engendered the idea that synaptic efficacy and the long-lasting changes concomitant with it, require incessant maintenance for the memory to not be perished. It has been suggested that LTP decay is a direct consequence of the effects of protein turnover (Genoux et al., 2002; C. C. Huang, Liang, & Hsu, 2001; E. P. Huang, 1998). Alternatively, some studies have brought out the significance of NMDAR activation in LTP decay and this LTP decay may have an overlap in the signaling pathways of LTD, showing decreased AMPAR levels at the post-synaptic sites on depotentiation and LTD (Cazakoff & Howland, 2011; Dalton, Wang, Floresco, & Phillips, 2008; J. Kim et al., 2007; H. K. Lee & Kirkwood, 2011; Park, Lee, Kim, & Choi, 2012; Villarreal, Do, Haddad, & Derrick, 2002). LTP decay may be mediated by both depotentiation and LTD that results in the decrease of synaptic potentiation. Recent studies have demonstrated a role for AMPAR surface diffusion in facilitating hippocampal LTP and contextual learning and that, this diffusion is governed by protein-protein interactions which are anticipated to be a fundamental trafficking mechanism for LTP (Penn et al., 2017).
In view of the critical requirement for protein synthesis in maintaining synaptic plasticity, two models for activity-induced protein synthesis in postsynaptic neurons will be discussed in detail:
1. Somatic protein synthesis and synaptic tagging and capture: Activated synapses are marked by synaptic tags which capture the somatically synthesized plasticity-related products synthesized from translation of plasticity-related mRNAs in the cell body in response to strong synaptic activation.
2. Local dendritic protein synthesis: Plasticity-related mRNAs are translated locally in neuronal dendrites and the proteins thus synthesized are used at the activated synapses to sustain LTP.
Synaptic tagging and capture
Synaptic tagging and capture is a cellular correlate of associative plasticity/memory where plasticity/memories triggered by weakly stimulating events are converted to long-term memories by means of associating the short-lasting memories with strong memories. A strong synaptic stimulation that results in protein-synthesis dependent late-LTP in synapse S1 helps transform a short-lasting E-LTP at another input S2 to the same neuron to long lasting late-LTP by virtue of this capture of PRPs synthesized in response to strong synaptic stimulation at S1. This is possible by means of the synaptic tags set at the weakly stimulated synapse S2 that capture PRPs.
The process of tagging and capture should occur within the time frame of decay of PRPs synthesized as a result of the strong stimulation at S1. Therefore, the time window between the two synaptic stimulations is crucial. PRPs are either synthesized in the soma or in the dendrites and thereafter distributed diffusely throughout the dendritic tree. The synaptic tag helps sequester these proteins and prevents the requirement for extensive protein trafficking (Frey & Morris, 1998a) and also helps facilitate input specificity. The requirements for the synthesis and trafficking of PRPs in this process demonstrates the need for protein synthesis in associative plasticity. Figure 1 demonstrates the protein synthesis dependence of the synaptic tagging hypothesis. Strong tetanization (STET) at synapse S1 resulting in L-LTP followed by STET at S2 in presence of anisomycin still results in L-LTP at S2, indicating that PRPs resulting from L-LTP at S1 were captured by the tag set at S2.
PKMζ is a critical LTP-specific PRP required for synaptic tagging. This has been proven from studies where the persistent potentiation at the tagged synapses by virtue of L-LTP at neighboring synapses, was blocked when inhibitors of PKMζ were applied after tetanization (see Figure 2; Sajikumar et al., 2005). Although the specificity of the inhibitor ZIP has been questioned (Glanzman, 2013) and even the role of PKMζ itself in the maintenance of memories (A. M. Lee et al., 2013; Volk, Bachman, Johnson, Yu, & Huganir, 2013), subsequent studies have demonstrated compensatory mechanisms via PKCι/λ that enable the maintenance of LTP and long-term memories in PKMζ-null mice (Tsokas et al., 2016). Thus, while PKMζ is essential for LTP in wild-type mice, compensatory mechanisms enable LTP maintenance and long-term memories in PKMζ-null mice (Tsokas et al., 2016).
The lifetime of the tagged state is considered to be approximately 90 minutes in brain slice experiments (Frey & Morris, 1998b), and PRPs arriving after tag decay cannot be added to the PSD of dendritic spines, and thus is unable to transform E-LTP to L-LTP beyond the 90 minutes tagging lifetime window. Not only is the associative maintenance of LTP dependent on the half-life of the synaptic tags, but also on the half-life of PRPs. Therefore, the interaction between the tag and the PRPs must take place within the time window dictated by their individual half-lives (Sajikumar, Navakkode, & Frey, 2007). The dependence on half-life of PRPs for the associative plasticity mechanism can be demonstrated by employing a strong-before-weak tetanization paradigm in in vitro slice electrophysiology experiments. The E-LTP to L-LTP transformation by virtue of capture of PRPs synthesized in response to the STET depends on how temporally spaced the WTET is from the STET. The more spaced the two tetanizations, the PRPs are subject to decay and hence cannot facilitate the associative transformation of E-LTP to L-LTP at the weakly tetanized synapses.
The STC hypothesis has been revised over the years. The current view of the nature of the synaptic tag is that it is not a single molecule, but a state of the synapse, wherein tagging should be viewed as a temporary structural state of the synapse involving interaction between several proteins rendering an “unlocking” of the synapse for stabilization of synaptic plasticity (Redondo & Morris, 2011). Tagging possibly involves an alteration of the dendritic spine architecture rendering remodeling of the postsynaptic density (PSD). A tagged synapse has the potential to transform its potentiated state to persistent long-lasting plasticity if it receives PRPs that will stabilize the functional and structural alterations of the synapse, within the time window of decay of the tagged state. For example, autophosphorylated CaMKII that moves into the PSD of activated spines in LTP (Shen & Meyer, 1999), and although less accessible to inactivation by phosphatases (Bayer et al., 2006; Bayer, De Koninck, Leonard, Hell, & Schulman, 2001), can still be inactivated over time and released from the PSD (Redondo & Morris, 2011; Strack, Choi, Lovinger, & Colbran, 1997) unless there is a PRP capture process that stabilizes the tagged state. The structural scaffold at the tagged synapse will revert to a “locked” state and over time the kinases responsible for the tagged state of the synapse become inactivated and the synapse returns to an untagged state (Redondo & Morris, 2011). The capture of PRPs culminates in spine remodeling, addition of PSD slots or scaffolding molecules available for AMPARs (Bosch et al., 2014; Luscher, Nicoll, Malenka, & Muller, 2000) and presynaptic modifications that include changes in synaptic vesicle release sites (Lisman & Raghavachari, 2006). AMPAR trafficking into and out of the PSD slots continues in a dynamic fashion and the final state of the tagged and PRP-captured synapse leads to the persistence of LTP (Redondo & Morris, 2011).
Availability of plasticity proteins decides synaptic cooperation and competition
Synaptic tagging and capture offers a blueprint to understand the interaction between different groups of synapses and the possible mechanisms that account for memory maintenance and establishment. Associative learning is an unceasing process that can impact how information is processed amongst the activated synapses resulting in the modulation of the ability to induce and maintain LTP and LTD (Etkin et al., 2006; Govindarajan, Israely, Huang, & Tonegawa, 2011). These dynamic interactions among synapses can result in either synaptic cooperation or synaptic competition. The synaptic tagging and capture model (STC) was successful in establishing the cooperation phenomenon by demonstrating that synapses share the PRPs (Frey & Morris, 1998a). It was shown by studies from (Redondo et al., 2010; Sajikumar et al., 2005, 2007) that “tag setting” and LTP maintenance are processes that occur separately in time and in an independent manner. Synaptic cooperation among the synapses is space-restricted. This space constraint brings about a bias for correlated neurons even at the developmental phase for establishing connections (Turney & Lichtman, 2012). Close-knit dendritic branches have a higher probability of summation and thus the induction of LTP and formation of synaptic tags. By corollary, this also increases the chances of the same being involved in synaptic competition where PRPs may be inadequately available. The occurrence of limited PRPs in the presence of multiple inputs results in these PRPs being distributed competitively among all activated synapses. During such a situation, parameters such as the tag strength, distance between activated synapse and translational initiation site and the time between the two events have a bearing, on which synapse is to be stabilized. Studies from (Sajikumar & Frey, 2004; Sajikumar, Morris, & Korte, 2014) have elucidated the significance of synaptic competition in the formation of long lasting memory. These studies showed that the potentiation of a third pathway around the same time that the synaptic potentiation is enabled on a specific pathway, given the availability of PRPs from another earlier or later event, may result in the blockade of potentiation at all the pathways. Shetty et al. (Shivarama Shetty, Gopinadhan, & Sajikumar, 2016) showed that D1/D5 receptor mediated potentiation in a dose dependent manner aids in the fine tuning of associativity processes for long-term memory formation. This study also elucidated ERK1/2 as the molecular pathway involved in the synaptic associativity process in the differential regulation of synaptic cooperation and competition (Figure 3 a, b).
Metaplasticity prolongs associative plasticity and rescues synaptic competition
The term metaplasticity coined by Abraham and Bear in 1996 (Abraham & Bear, 1996) dictates the threshold levels at which the tags can operate. In addition, the time window during which these tags are functional is also altered. The normal time window of a synaptic tag and capture phenomenon is confined to an E-LTP duration of 60 minutes (Frey & Morris, 1998a, 1998b; Redondo & Morris, 2011) which is mediated by CaMKII (Sajikumar et al., 2007). As a result, the information from various synapses is stipulated to be integrated within this restricted time period (Q. Li et al., 2014). There are evidences from studies showing that RyR (Ryanodine receptors) activation before the induction of LTP can prolong the duration of tags from normal 1 hour to more than 5 hours offering more leeway for associative interaction for an extended period of time (Q. Li et al., 2014). By virtue of switching synaptic tags from the short-lived CaMKII tag to a longer-lived tag, this process is mediated by PKMζ, wherein, a metaplasticity-enabled synaptic tagging and capture process (primed-STC) enables the primed synapses to capture PRPs across a prolonged duration of 4-5 hours (Q. Li et al., 2014). This is mediated through an extended half-life of PKMζ and is a longer-lasting tag setting process which facilitates the extended time window for both the sets of synapses to associate. It is noteworthy that this study brought out the facets of PKMζ as a molecule that can mediate synaptic tags aside being able to function as a PRP (Figure 4).
The metaplasticity-enabled recalibration of threshold levels is believed to facilitate learning and establish homeostasis. Studies from Li et al. (Q. Li et al., 2017) demonstrated that L-LTP and STC and cross tagging and capture are impaired in the APP/PS1 mouse model of Alzheimer’s disease and could be rescued by priming synapses with activation of RyRs through metaplastic mechanisms. Some cognitive impairment in neurodegenerative and neurological disorders stems from aberrant metaplasticity-mediated mechanisms. Hence exploring these mechanisms could offer insights on understanding behavioral outcomes and harnessing clinical benefits. Activation of metabotropic glutamate receptors mGluRs is one of the widely studied forms of homosynaptic metaplasticity (Tim V. P. Bliss, Collingridge, Morris, & Reymann). mGluRs trigger the cell signaling pathways inclusive of the activation of PKC (group 1) as well as inhibition of cAMP (groups II and III). This offered the incentive to investigate the effects of mGluRs in the induction of LTP by using mGluR antagonist (Behnisch, Fjodorow, & Reymann, 1991). Collingridge, Watkins, and Jane then confirmed similar findings by developing a selective mGluR antagonist (+)-α-methyl-4-carboxyphenylglycine (MCPG) (Bortolotto et al., 1995). Studies from (Sajikumar et al., 2014) have shown how priming of mGluRs acts to prevent synaptic competition. This was shown in a three input model, where L-LTP was originally induced in one of the synaptic inputs followed by E-LTP (strong before weak paradigm) at 30 and 45 minutes in other synaptic inputs S2 and S3, respectively. Synaptic competition was observed in these synaptic clusters, in which all the synapses compete for scarce plasticity related proteins, thus preventing all forms of plasticity. Competition was prevented with the metaplastic activation of mGluR prior to the induction of L-LTP in the three input model. Synaptic competition can be overcome by increasing PRP availability over time by promoting transcriptional activation and increased PRP synthesis by metaplastic stimulation (Sajikumar et al., 2014). Metaplasticity-mediated rescue of synaptic competition is depicted in Figure 5. Thus, a combination of synaptic tag switching and increased PRP synthesis possibly facilitates the strengthening of synapses, prolonged associativity and rescue of synaptic competition, thereby contributing to robust forms of memory.
The behavioral tagging (BT) hypothesis postulates that a learning experience triggers the setting of a tag along with the induction of PRPs. Thus the behavioral tagging requires the integration of these two processes at common neural substrates within a critical time window. This was proven by studies from (Ballarini, Moncada, Martinez, Alen, & Viola, 2009) wherein a taste recognition task that induces activation of insular cortex and a spatial learning task that activates hippocampus failed to integrate the formation of CTA-LTM (conditioned taste aversion–long-term memory) using the exposure to a novel environment; and reciprocally, the taste recognition task failed to integrate consolidation of SOR-LTM (spatial object recognition–long-term memory). These results corroborate the importance of spatial coexistence of both tags and PRPs to facilitate a long lasting memory. BT processes also exhibit input specificity wherein PRPs are captured only by the tagged sites reinforcing only the tagged sites and not every single input of a network. It has been established that novelty induces LTP reinforcement in the BT (behavioral tagging) processes and that this phenomenon depends on D1/D5 dopaminergic receptors functionality (S. Li, Cullen, Anwyl, & Rowan, 2003). Further to this evidence, there are studies supporting that these receptors may have a crucial role in triggering the synthesis of PRPs. Direct administration of SKF-38393 and adrenergic (dobutamine) agonists could replace novel experience to promote IA-LTM consolidation. Inhibitory avoidance task is a widely used behavioral task which allows investigating and manipulating the accuracy of memory in the study of fear learning and memory mechanisms in rodents. In the behavioral tagging hypothesis, wIA task which helps set the tags utilizes the PRPs induced as a result of novel open field resulting in the IA-LTM consolidation. The injection of these drugs failed to promote IA memory 180 minutes prior to weak IA training, unlike the case wherein drugs injected 70 minutes prior to the wIA training showed IA-LTM consolidation. This proves that the strong event is effective when occurring within a critical time window around the weak one and thereby the time scale of the agonists proves consistency with novelty being used as memory promoter. Activation of D1/D5 dopaminergic and beta-adrenergic receptors in the hippocampus during strong IA training is specifically involved in mediating the synthesis of PRPs imperative for the memory consolidation (Moncada, Ballarini, Martinez, Frey, & Viola, 2011).
Cross-tagging and capture: Early LTP to late LTP conversion by virtue of late-LTD at neighboring synapses
Associative plasticity is not solely limited to early and late forms LTD or LTP acting in isolation. It also involves interactions between LTP and LTD at different synaptic inputs to the same neuron, in a process called “cross-tagging.” Similar to synaptic tagging and capture, synaptic “cross-tagging” is also a conceptual cellular correlate of associative memory, wherein L-LTD/L-LTP at one synaptic input S1 to a neuron helps transform an early form of the opposite plasticity event viz. E-LTP/E-LTD at another synaptic input S2 to the same neuron to its long-lasting late form (Sajikumar & Frey, 2004). In terms of E-LTP to L-LTP transformation at a synaptic input S2 by virtue of L-LTD at a separate synaptic input S1 to the same neuron, “cross-tagging” involves capture of PRPs synthesized as a result of the late plasticity event (here L-LTD) at synaptic input S1. The L-LTD at S1 leads to synthesis of a pool of PRPs- both LTD and LTP-specific. E-LTP inducing weak stimulation at S2 sets synaptic tags at S2 that are able to capture process-specific PRPs such as PKMζ (Sajikumar et al., 2005) and thereby help transform E-LTP at S2 to L-LTP. It has been shown that PKMζ inhibitors were able to block this E-LTP to L-LTP transformation of the weakly tetanized cross-tagged synapses (S2) although the L-LTD maintenance at S1 was unaffected by inhibiting PKMζ, showing that PKMζ is an LTP-specific PRP that is necessary for the persistent potentiation demonstrated at the cross-tagged synapses (Figure 6).
CaMKIIβ and Arc/Arg3.1 interaction in inverse synaptic tagging
“Inverse synaptic tagging” is an inactivity-dependent redistribution of synaptic weights (Okuno, Minatohara, & Bito, 2018). Similar to proteins that tag active synapses in the STC model enabling capture of PRPs and in turn maintenance of synaptic potentiation, an “inverse synaptic tag” marks inactive synapses for synaptic weakening. Such differential tagging allows the activity-dependent maintenance of the contrast between strong and weak synapses. CaMKIIβ has been suggested to be an “inverse synaptic tag” that marks inactive synapses (Okuno et al., 2012). A dynamic interaction between the immediate early gene product Arc/Arg3.1 and CaMKIIβ has been shown to facilitate the inverse tagging process (Okuno et al., 2012). The inactive, calmodulin-unbound form of CaMKIIβ has a much higher affinity for Arc/Arg3.1 than the active form of CaMKIIβ (Okuno et al., 2012). It has been proposed that synaptic tagging and inverse synaptic tagging coexist and thereby enable redistribution of synaptic weights and enhance the contrast between potentiated and non-potentiated synapses (Okuno et al., 2018), thereby possibly playing a homeostatic role. A similar mechanism has been shown to be brought about by recent studies on G9a/GLP complex through its properties as a bidirectional switch that regulates mGluR-dependent plasticity. Studies from (Sharma & Sajikumar, 2018) has demonstrated the involvement of this epigenetic mechanism in facilitating the expression of mGluR-LTD when turned on and in promoting the expression of long-term potentiation when turned off and as a result, indicating a homeostatic role of the G9a/GLP complex in bringing about a delicate balance between the strong and the weak synapses during the course of long term synaptic plasticity.
The inverse tagging model involving Arc/Arg3.1 and CaMKIIβ interaction is shown in Figure 7.
Protein synthesis for LTP maintenance and associative plasticity in hippocampal area CA2: Role of PKMζ and CaMKIV
The hippocampal subfield CA2, a small area sandwiched between the more well studied CA1 and CA3 subfield, has gained importance with findings indicating its role in social memory (Hitti & Siegelbaum, 2014). CA2 functional plasticity is unique in comparison to the other CA subfields in that the Schaffer collateral-CA2 (SC-CA2) synapses are resistant to activity-dependent LTP whereas the entorhinal cortical synapses onto CA2 (EC-CA2) express robust LTP (Chevaleyre & Siegelbaum, 2010; Dudek, Alexander, & Farris, 2016). However, neuromodulators have shown to induce LTP at the otherwise plasticity-resistant SC-CA2 synapses (Dudek et al., 2016). Substance P (SP) released from the supramammillary nucleus terminals synapsing at CA2 induces a slow-onset LTP at SC-CA2 and EC-CA2 synapses which is protein-synthesis dependent (Dasgupta et al., 2017). Moreover, the SP-induced lasting potentiation at SC-CA2 is capable of mediating associative plasticity in that it enables transformation of an E-LTP to L-LTP at EC-CA2 in a synaptic tagging and capture-dependent manner and hence dependent on protein synthesis (Dasgupta et al., 2017). PKMζ and CaMKIV, which have been shown to play an important role in maintenance of plasticity and STC in CA1 (Redondo et al., 2010; Sajikumar et al., 2005, 2007) were also identified as key PRPs for SP-induced LTP and associative plasticity at synapses in CA2 (Dasgupta et al., 2017).
Local dendritic protein synthesis in memory maintenance
Protein synthesis has been shown to be critical for the formation of long term memories. Recent studies have demonstrated the translation of proteins in neuronal dendrites, meaning local protein synthesis (Aakalu, Smith, Nguyen, Jiang, & Schuman, 2001) and studies suggest a role for local dendritic protein synthesis in memory (Sutton & Schuman, 2006). It has been reported from studies in “isolated” hippocampal slices where dendritic and cell body regions were isolated by a microsurgical cut, that high frequency stimulation-induced NMDA receptor dependent L-LTP, lasting up to 5 hours, is expressed in the “isolated” slices devoid of cell body (Vickers, Dickson, & Wyllie, 2005). Vickers et al. report that the magnitude of the fEPSPs in these isolated dendritic preparations was similar to the fEPSPs recorded in intact slices and that the late-LTP in isolated slices was blocked upon incubating the slices with mRNA translation inhibitor. However, incubation of the isolated slices with mRNA transcription inhibitor did not affect the late-LTP in the isolated slices. The results suggested that the maintenance of L-LTP in the isolated dendritic preparations was facilitated by protein synthesis from dendritically localized pre-existing mRNAs and point to a postsynaptic dendritic locus for the protein synthesis requirement of L-LTP expression. The idea of dendritic protein synthesis from translation of dendritically localized mRNAs is further supported from other studies that have identified numerous dendritically localized mRNAs and translation machinery (Jiang & Schuman, 2002; Steward & Schuman, 2003; Vickers et al., 2005). Moreover, translocation of ribosomes to active synaptic sites upon giving LTP-inducing have been reported by (Ostroff et al., 2002) further supporting local dendritic protein synthesis.
Protein synthesis inhibitors applied to local dendritic regions have been shown to decrease tetanically induced L-LTP (Bradshaw, Emptage, & Bliss, 2003). Moreover, this study showed that the protein synthesis inhibitor emetine when applied locally to the apical dendritic field of hippocampal CA1 pyramidal neurons, impaired L-LTP at only apical but not basal dendrites. Similarly, emetine when applied to basal dendrites, impaired L-LTP at only basal but not apical dendrites. Thus, the complete expression of late-LTP requires local dendritic protein synthesis (Bradshaw et al., 2003) but this does not preclude the role for somatic protein synthesis in L-LTP and perhaps requires cooperation of both somatically and dendritically synthesized proteins (Casadio et al., 1999; Sherff & Carew, 1999).
The signaling cascades that occur in conjunction with synaptic activation and local dendritic protein synthesis remain notoriously elusive. Studies have investigated the role of glutamate receptors and mTOR signaling pathways in the regulation of local dendritic protein synthesis in live neurons. It highlighted the importance of NMDAR and mTOR signaling for synaptic activity induced dendritic protein synthesis in hippocampal neurons by showing the lack of αCaMKII and MAP2 proteins through high frequency stimulations in the hippocampal slices when mTOR kinase was inhibited (Gong, Park, Abbassi, & Tang, 2006).
The idea of activity-dependent local dendritic protein synthesis supports synapse specificity that is characteristic of NMDA-receptor dependent plasticity. It could be that a cooperation of both synaptic tagging and capture of somatically synthesized proteins and activity-dependent local dendritic protein synthesis processes are required (H. Wang & Tiedge, 2004). Dendritic protein synthesis, by virtue of regulation of actin cytoskeletal dynamics, controls stabilization and long-term maintenance of both structural and functional synaptic plasticity (Bramham, 2008). The actin network can itself be considered as part of the LTP tag machinery that facilitates interaction of tagging complexes at activated synapses with PRPs, and thereby contribute to L-LTP (Ramachandran & Frey, 2009).
Balance between proteasomal degradation and synthesis of plasticity-related proteins
Studies have shown that protein synthesis is pivotal for late phase LTP. This stems from the fact that different experimental settings have demonstrated how the inhibitors have affected late phase LTP yet retaining the early phase of LTP. A balance between degradation and synthesis of proteins is essential for the sustenance of late-phase LTP (Fonseca et al., 2006). When protein synthesis alone is blocked, meaning translation of both positive and negative proteins is inhibited, LTP is diminished as the degradation of pre-existing positive proteins overwhelms the degradation of pre-existing negative proteins. The blockade of proteasome-dependent degradation of proteins also brings about a decrease in LTP as the pool of negative proteins that persist, counteracts the effects of positive proteins. When both degradation and synthesis is disrupted, L-LTP is sustained by the abundance of the pre-existing positive proteins over the pre-existing negative proteins. This leads to the surprising conclusion that de novo protein synthesis is not an absolute requirement for the late maintenance of LTP. Protein synthesis is required for the sustenance of LTP when protein degradation is functional. Thus, a dynamic balance between synthesis and degradation of positive plasticity proteins and negative proteins is critical for the maintenance of LTP (Fonseca et al., 2006). The possibility that tagging of activated synapses enables selective stabilization of the synapse by delaying degradation of PRPs and thereby enabling maintenance of LTP could be a mechanism for partial explanation of these results.
Role of epigenetics in the maintenance of LTP
Long-term contextual memory formation demands for transcription within the hippocampus wherein histone acetylation is known to be involved along with other mechanisms that initiate and maintain this transcription process. HDAC inhibitors, which increase histone acetylation have shown to increase long term memory when injected into the hippocampus during memory consolidation. Investigating the genes that regulate this process was believed to offer insights into the necessary parameters of the memory consolidation. Phosphorylated CREB and histone acetyltransferase CREB-binding protein (CBP) interaction is mandatory for long term memory.
CREB as an important transcription factor in hippocampus for memory formation and storage
Several studies have focused on the molecular mechanisms behind the contextual fear memory storage in hippocampus and amygdala. There happens to be two time windows in these brain regions post learning, with an increase in the phosphorylation of CREB, which is the cAMP-response element binding protein (Stanciu, Radulovic, & Spiess, 2001). There is a striking coincidence with the two time windows, 0–30 minutes and 3–6 hours post training, with that of the time windows during which inhibition of transcription or translation which impairs memory storage happens (Bourtchouladze et al., 1998; Igaz, Vianna, Medina, & Izquierdo, 2002). Despite CREB being one of the pivotal transcription factors for the formation of long-term memory, CREB phosphorylation alone is insufficient, stipulating the requirement of additional other co-activators of CREB for the expression of target genes.
The significance of histone acetyltransferases in long-term memory
Many proteins such as HATs, including CBP, p300 and p300/CBP associated factor (PCAF) interact with phosphorylated CREB. Portelli (Portelli, 1975) first proposed the concept that DNA-histone complexes regulate memory formation. These HATs have been believed to be important regulators of the transcription necessary for long-term memory wherein each HAT serves a role in a specific type of long term memory. A truncated form of p300 or conditional p300 deletion causes only a selective long-term memory deficits in both contextual fear conditioning and object recognition memory (Oliveira, Hawk, Abel, & Havekes, 2010) suggesting that memory deficits in p300 mutant mice is effected due to a possible transcriptional effects in brain regions outside hippocampus. Histone methylation is the transfer of one, two or three methyl groups from S-adenosyl-L—methionine to lysine or arginine residues of histone proteins by histone methyltransferases (HMTs) and they regulate DNA methylation through chromatin dependent transcriptional repression or activation. G9a/GLP is a histone lysine methyltransferase complex that has been shown to be critical for brain development and goal directed learning. Some of the findings from (Sharma, Dierkes, & Sajikumar, 2017) from our lab have highlighted the key role for G9a/GLP in the maintenance and the homeostasis of neuronal transcription. The study demonstrated that the inhibition of this G9a/GLP complex reverses the amyloid-b oligomer induced deficits in late-LTP and synaptic tagging and capture and is achieved by the capture of BDNF by the weakly activated synapses. This evidence for plasticity and associativity in conditions such as Alzheimer’s disease has highlighted its significance as a possible target to prevent amyloid-b oligomer-induced plasticity deficits in hippocampal neurons.
Acetylation in memory consolidation
Acetylation of particular lysine residues have been believed to control the transcription for long-term memory. Studies showed that acetylation of lysine 14 on H3 increased in bulk histone extracts post one hour of contextual learning (Levenson et al., 2004). An efficient way of fishing out acetylation marks owing to memory formation is to investigate proteins required for memory consolidation such as CBP which gets affected by histone acetyltransferases. In vitro and more in specific, some of the in-vivo works have suggested HATs role in the regulation of acetylation of specific lysine residues (Barrett et al., 2011; Jin et al., 2011). Exploring the genes that are regulated by acetylation during the memory consolidation helps unfold the targets that are important for long-term memory formation and thereby novel therapeutics that may help facilitate the formation of memory.
Histone deacetylase inhibitors increase long-term memory
Increased levels of histone acetylation during memory consolidation has suggested that unnaturally increasing histone acetylation could augment long-term memory. A delicate balance of HATs such as CBP that add acetyl groups to specific lysine residues on histone Tails and HDACs that remove acetyl groups from these lysines governs the histone acetylation as shown in Figure 8.
Either enhancing HAT activity or abating HDAC activity results in an increase in the histone acetylation. HDAC inhibitors enhance long term memory when administered during memory consolidation. Work from Vecsey et al. (Vecsey et al., 2007) has shown the enhancement of memory by HDAC inhibitor trichostatin A (TSA) which requires CREB-CBP interaction, suggesting the stipulation of CREB target genes for memory enhancement. Studies have shown that chronic treatment of broad spectrum HDAC inhibitors such as TSA causes synaptic dysfunction (Nelson, Kavalali, & Monteggia, 2006). Therefore, targeting only specific HDAC proteins that dampen memory formation may enable the application of selective therapeutics with a reduced side effect profiles in comparison to the broad spectrum HDAC inhibitors.
DNA methylation in long-term memory formation
For memory to persist, there must be a continual replacement of that proteins that were originally responsible for its formation. It was a speculation even decades ago by Francis Crick and Robin Holliday that DNA methylation might be a self-perpetuating mechanism involved in the storage of long-term memories. The chromatin-regulating mechanism, DNA methylation, is a dynamic process that controls long-lasting changes in synaptic function and behavior. This mechanism was proposed since DNA methyltransferase inhibitors (DNMTi) applied acutely into the adult CNS alters the methylation of genes like BDNF, PP1 and reelin and blocks long-term potentiation (LTP) induction in the hippocampal slice preparation through the following studies (Lubin, Roth, & Sweatt, 2008; Miller & Sweatt, 2007). DNA methylation is capable of self-regeneration and self-perpetuation which are salient features for a stable molecular mark and these processes are accomplished partly by DNA methyltransferases (DNMTs). DNMTs can acknowledge the presence of hemi-methylated C-G dinucleotide and can convert the complementary C-G on the opposite strand into a methylated C-G. As a result, DNA can be methylated perpetually in a manner that is similar to the self-perpetuating auto-phosphorylation of activated CaMKII that had been identified originally as a candidate for the molecular mechanism for memory storage (Roberson & Sweatt, 1999). DNA methylation has been associated both with transcriptional silencing and with activating roles (Chahrour et al., 2008). There have been results demonstrating that application of different types of DNMT inhibitors results in deficits in hippocampal LTP and deficits in memory consolidation (Levenson et al., 2006). Several such studies through biochemical evidence have also come to a similar conclusion that long-term memory consolidation is associated with altered DNA methylation in the hippocampus (Lubin et al., 2008; Miller & Sweatt, 2007). Having established that changes in transcription such as DNA methylation and histone modifications are important for learning, it is now an active question whether these transcriptional marks are required for the memory to be maintained (Miller et al., 2010). Demonstrations from the Glanzman’s lab has shown that even after the loss of long-term synaptic changes, transcriptional marks allow for memories to be relearned more easily(Chen et al., 2014). Some have argued that this shows that memories are not stored at synapses (Poo et al., 2016; Trettenbrein, 2016). Recent arguments from Sossin (2018) state that long-term transcriptional marks encode changes that may aid in mechanisms for the storage of specific weights locally at synapses. It also highlights that the transcription marks will need to know the specificity of the synaptic connections that require strengthening in order for these marks to elicit these changes.
Conclusion and future directions
Remarkable progress has been made in understanding the regulation of proteins in bringing about long lasting molecular changes in a neuron which will partake in future plasticity. The finding that simultaneous inhibition of both protein synthesis as well as degradation did not interfere with either the induction or the maintenance of the LTP suggests the possibility of protein synthesis-independent synaptic plasticity or metaplasticity that could last for long duration of time the preponderance of evidence suggests an important role for protein synthesis in the production of PRPs. Synaptic plasticity is a pivotal learning mechanism in the brain wherein many aspects of tagging needs to be understood yet. The three models of activity induced protein synthesis in the post-synaptic neurons is discussed elaborately viz., synaptic targeting, synaptic tagging and capture and local dendritic protein synthesis. It has been discussed how dendritic protein synthesis has a role to play in the maintenance of long term memories of both structural and functional synaptic plasticity. This has helped in the conjecture that actin network could be a part of the tagging machinery that helps set tags in both early and late forms of LTP. One of the important emerging avenues in understanding the molecular mechanisms of long-term memory storage is tapping into the epigenetic control of brain function. Several studies already showing pharmacological manipulations of epigenetic markers reinstating learning and restoring remote memory after neurodegeneration provides hope in terms of clinical implications for the reversal of memory deficits.
S.S. is supported by National Medical Research Council Collaborative Research Grant (NMRC/CBRG/0099/2015 and NMRC-OFIRG-0037-2017) and NUS-Strategic and Aspiration Research Funds. R.R and A.B is supported by President Graduate Fellowship, National University of Singapore.
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