Postsynaptic Kainate Receptor Recycling and Surface Expression Are Regulated by Metabotropic Autoreceptor Signalling

Kainate receptors (KARs) play fundamentally important roles in controlling synaptic function and regulating neuronal excitability. Postsynaptic KARs contribute to excitatory neurotransmission but the molecular mechanisms underlying their activity‐dependent surface expression are not well understood. Strong activation of KARs in cultured hippocampal neurons leads to the downregulation of postsynaptic KARs via endocytosis and degradation. In contrast, low‐level activation augments postsynaptic KAR surface expression. Here, we show that this increase in KARs is due to enhanced recycling via the recruitment of Rab11‐dependent, transferrin‐positive endosomes into spines. Dominant‐negative Rab11 or the recycling inhibitor primaquine prevents the kainate‐evoked increase in surface KARs. Moreover, we show that the increase in surface expression is mediated via a metabotropic KAR signalling pathway, which is blocked by the protein kinase C inhibitor chelerythrine, the calcium chelator BAPTA and the G‐protein inhibitor pertussis toxin. Thus, we report a previously uncharacterized positive feedback system that increases postsynaptic KARs in response to low‐ or moderate‐level agonist activation and can provide additional flexibility to synaptic regulation.      

Presynaptic kainate receptor-mediated bidirectional modulatory actions: Mechanisms

Kainate receptors (KARs) are members of the glutamate receptor family, which also includes two other ionotropic subtypes, i.e. NMDA- and AMPA-type receptors, and types I, II and III metabotropic glutamate receptors. KARs mediate synaptic transmission postynaptically through their ionotropic capacity, while presynaptically, they modulate the release of both GABA and glutamate through operationally diverse modus operandi. At hippocampal mossy fiber (MF)-CA3 synapses, KARs have a biphasic effect on glutamate release, such that, depending on the extent of their activation, a facilitation or depression of glutamate release can be observed. This modulation is posited to contribute to important roles of KARs in short- and long-term plasticity. Elucidation of the modes of action of KARs in their depression and facilitation of glutamate release is beginning to gather impetus. Here we will focus on the cellular mechanisms involved in the modulation of glutamate release by presynaptic KAR activation at MF-CA3 synapses, a field that has seen significant progress in recent years.     

Subunit composition of kainate receptors in hippocampal interneurons

Kainate receptor activation affects GABAergic inhibition in the hippocampus by mechanisms that are thought to involve the GluR5 subunit. We report that disruption of the GluR5 subunit gene does not cause the loss of functional KARs in CA1 interneurons, nor does it prevent kainate-induced inhibition of evoked GABAergic synaptic transmission onto CA1 pyramidal cells. However, KAR function is abolished in mice lacking both GluR5 and GluR6 subunits, indicating that KARs in CA1 stratum radiatum interneurons are heteromeric receptors composed of both subunits. In addition, we show the presence of presynaptic KARs comprising the GluR6 but not the GluR5 subunit that modulate synaptic transmission between inhibitory interneurons. The existence of two separate populations of KARs in hippocampal interneurons adds to the complexity of KAR localization and function.     

Morphogenic Signaling in Neurons Via Neurotransmitter Receptors and Small GTPases

Several neurotransmitters including serotonin and glutamate have been shown to be involved in many aspects of neural development, such as neurite outgrowth, regulation of neuronal morphology, growth cone motility and dendritic spine shape and density, in addition to their well-established role in neuronal communication. This review focuses on recent advances in our understanding of the molecular mechanisms underlying neurotransmitter-induced changes in neuronal morphology. In the first part of the review, we introduce the roles of small GTPases of the Rho family in morphogenic signaling in neurons and discuss signaling pathways, which may link serotonin, operating as a soluble guidance factor, and the Rho GTPase machinery, controlling neuronal morphology and motility. In the second part of the review, we focus on glutamate-induced neuroplasticity and discuss the evidence on involvement of Rho and Ras GTPases in functional and structural synaptic plasticity triggered by the activation of glutamate receptors.     

Finding functions of phase separation in the presynapse

Synapses are the basic units of neuronal communication. Understanding how synapses assemble and function is therefore essential to understanding nervous systems. Decades of study have identified many molecular components and functional mechanisms of synapses. Recently, an additional level of synaptic protein organization has been identified: phase separation. In the presynapse, components of the central active zone and a synaptic vesicle-clustering factor have been shown to form liquid–liquid phase-separated condensates or hydrogels. New in vivo functional studies have directly tested how phase separation impacts both synapse formation and function. Here, we review this emerging evidence for in vivo functional roles of phase separation at the presynapse and discuss future functional studies necessary to understand its complexity.     

Recent advances in using Drosophila to model neurodegenerative diseases

Neurodegenerative diseases are progressive disorders of the nervous system that affect the function and maintenance of specific neuronal populations. Most disease cases are sporadic with no known cause. The identification of genes associated with familial cases of these diseases has enabled the development of animal models to study disease mechanisms. The model organism Drosophila has been successfully used to study pathogenic mechanisms of a wide range of neurodegenerative diseases. Recent genetic studies in the Drosophila models have provided new insights into disease mechanisms, emphasizing the roles played by mitochondrial dynamics, RNA (including miRNA) function, protein translation, and synaptic plasticity and differentiation. It is anticipated that Drosophila models will further our understanding of mechanisms of neurodegeneration and facilitate the development of novel and rational treatments for these debilitating neurodegenerative diseases.     

Differential trafficking of GluR7 kainate receptor subunit splice variants

Kainate receptors (KARs) are heteromeric ionotropic glutamate receptors that play a variety of roles in the regulation of synaptic network activity. The function of glutamate receptors (GluRs) is highly dependent on their surface density in specific neuronal domains. Alternative splicing is known to regulate surface expression of GluR5 and GluR6 subunits. The KAR subunit GluR7 exists under different splice variant isoforms in the C-terminal domain (GluR7a and GluR7b). Here we have studied the trafficking of GluR7 splice variants in cultured hippocampal neurons from wild-type and KAR mutant mice. We have found that alternative splicing regulates surface expression of GluR7-containing KARs. GluR7a and GluR7b differentially traffic from the ER to the plasma membrane. GluR7a is highly expressed at the plasma membrane, and its trafficking is dependent on a stretch of positively charged amino acids also found in GluR6a. In contrast, GluR7b is detected at the plasma membrane at a low level and retained mostly in the endoplasmic reticulum (ER). The RXR motif of GluR7b does not act as an ER retention motif, at variance with other receptors and ion channels, but might be involved during the assembly process. Like GluR6a, GluR7a promotes surface expression of ER-retained subunit splice variants when assembled in heteromeric KARs. However, our results also suggest that this positive regulation of KAR trafficking is limited by the ability of different combinations of subunits to form heteromeric receptor assemblies. These data further define the complex rules that govern membrane delivery and subcellular distribution of KARs.     

Wiring and firing neuronal networks: endocannabinoids take center stage

Endocannabinoids (eCBs) function as retrograde messengers at both excitatory and inhibitory synapses, and control various forms of synaptic plasticity in the adult brain. The molecular machinery required for specific eCB functions during synaptic plasticity is well established. However, eCB signaling plays surprisingly fundamental roles in controlling the acquisition of neuronal identity during CNS development. Recent work suggests that selective recruitment of regulatory signaling networks to CB1 cannabinoid receptors dictates neuronal state-change decisions. In addition, the spatial localization and temporal precision of eCB actions emerges as a novel organizer in developing neuronal networks. Current challenges include fitting novel molecular candidates into regulatory eCB signaling pathways, and defining the temporal dynamics of context-dependent signaling mechanisms underpinning particular neuronal specification events.     

Kainate receptors and RNA editing in cholinergic neurons

Parasympathetic ganglia are considered simple relay systems that have cholinergic input and output, with modulation occurring centrally. Greater complexity is suggested, however, by our showing here that avian ciliary ganglion (CG) neurons also express a different excitatory receptor type--ionotropic glutamate receptors of the kainate subtype (KARs). This is the first report of glutamate receptor expression in the CG and KAR expression in any cholinergic neuron. We show that KARs form functional channels on CG neurons. KARs localize to CG neuron axons and somata as well as axons and terminals of pre-synaptic inputs to the CG. Glutamate transporters are expressed on Schwann cells that surround synapses on neuronal somata, and may provide a local source of glutamate. CG neurons express multiple KAR subunit mRNAs (GluR5, GluR7, and KA1), and their relative levels change dramatically during axon outgrowth and synaptic differentiation. The developmental role for KARs may depend upon their calcium permeability, a property regulated by mRNA editing. We show GluR5 editing increases predominantly at the time CG axons contact peripheral targets. Our data suggest that glutamatergic signaling may function as a local circuit mechanism to modulate excitability and calcium signaling during synapse formation and maturation in the CG in vivo.     

The modulation of calcium currents by the activation of mGluRs

Glutamatergic transmission in the central nervous system (CNS) is mediated by ionotropic, ligand-gated receptors (iGluRs), and metabotropic receptors (mGluRs). mGluRs are coupled to GTP-binding regulatory proteins (G-proteins) and modulate different second messenger pathways. Multiple effects have been described following their activation; among others, regulation of fast synaptic transmission, changes in synaptic plasticity, and modification of the threshold for seizure generation. Some of the major roles played by the activation of mGluRs might depend on the modulation of high-voltage-activated (HVA) calcium (Ca²⁺) currents. Some HVA Ca²⁺ channels (N-, P-, and Q-type channels) are signaling components at most presynaptic active zones. Their mGluR-mediated inhibition reduces synaptic transmission. The interference, by agonists at mGluRs, on L-type channels might affect the repetitive neuronal firing behavior and the integration of complex events at the somatic level. In addition, the mGluR-mediated effects on voltagegated Ca²⁺ signals have been suggested to strongly influence neurotoxicity. Rather different coupling mechanisms underlie the relation between mGluRs and Ca²⁺ currents: Together with a fast, membrane-delimited mechanism of action, much slower responses, involving intracellular second messengers, have also been postulated. In the recent past, the relative paucity of selective agonists and antagonists for the different subclasses of mGluRs had hampered the clear definition of the roles of mGluRs in brain function. However, the recent availability of new pharmacological tools is promising to provide a better understanding of the neuronal functions related to different mGluR subtypes. The analysis of the mGluR-mediated modulation of Ca²⁺ conductances will probably offer new insights into the characterization of synaptic transmission and the development of neuroprotective agents.     

Wnt Signaling in the Vertebrate Central Nervous System: From Axon Guidance to Synaptic Function

Regulation of cell signaling by Wnt proteins is critical for the formation of neuronal circuits. Wnts modulate axon pathfinding, dendritic development, and synaptic assembly. Through different receptors, Wnts activate diverse signaling pathways that lead to local changes on the cytoskeleton or global cellular changes involving nuclear function. Recently, a link between neuronal activity, essential for the formation and refinement of neuronal connections, and Wnt signaling has been uncovered. Indeed, neuronal activity regulates the release of Wnt and the localization of their receptors. Wnts mediate synaptic structural changes induced by neuronal activity or experience. New emerging evidence suggests that dysfunction in Wnt signaling contributes to neurological disorders. In this article, the attention is focused on the function of Wnt signaling in the formation of neuronal circuits in the vertebrate central nervous system.The formation of neuronal connections requires the navigation of axons to their appropriate synaptic targets, the formation of terminal branches, and the assembly of functional synapses. These processes greatly depend on the proper dialogue between axons and their environment as they navigate to their target, and between axons and their postsynaptic dendrites during synapse assembly. A combination of secreted molecules and transmembrane proteins modulates these processes. Studies over the last 10 years have revealed an essential role for Wnt signaling in axon pathfinding, dendritic development, and synapse assembly in both central and peripheral nervous systems. Wnts also modulate basal synaptic transmission and the structural and functional plasticity of synapses in the central nervous system. Studies of Wnts in the nervous system have significantly contributed to our current understanding of the molecular mechanisms that control neuronal circuit assembly. These studies have also shed light into fundamental aspects of cell signaling such as novel mechanisms of protein secretion (Korkut et al. 2009) and receptor dynamics (Sahores et al. 2010). Here I review the mechanisms by which Wnts modulate axon guidance and synapse formation in the vertebrate central nervous system. I also discuss the increasing evidence in support for a role of Wnts in basal synaptic transmission, synaptic plasticity, and neurological disorders.     

Lateral thinking: CaMKII uncouples kainate receptors from mossy fibre synapses

EMBO J (2013) 32: 496–510 doi:10.1038/emboj.2012.334; published online January042013Alteration of the efficacy of excitatory synaptic transmission between neurons is a critical element in the processes of learning, memory, and behaviour. Despite decades of research aimed at elucidating basic cellular mechanisms underlying synaptic plasticity, new pathways and permutations continue to be discovered. Carta et al (2013) now show that activation of the calcium/calmodulin dependent kinase II (CaMKII) induces an unusual postsynaptic form of long-term depression (LTD) at the hippocampal mossy fibre synapse by promoting lateral diffusion of kainate receptors (KARs), a family of ionotropic glutamate receptors (iGluRs) that influence pyramidal neuron excitability. This report therefore reveals a new and mechanistically unique way of fine-tuning synaptic plasticity at this central synapse in the hippocampus.Information transfer within the nervous system is regulated at the synaptic level by diverse cellular mechanisms. Synaptic efficacy is not static (i.e., it is ‘plastic''), and the capacity to adjust the strength of communication between neurons in a network has been shown to be a critical component of diverse aspects of brain function that include many forms of behavioural learning (Martin et al, 2000). The complex means by which neurons adjust their synaptic properties in response to changes in local and global activity in the central nervous system has been the subject of intensive investigation spanning multiple decades (Malenka and Bear, 2004; Feldman, 2009). Nonetheless, new mechanisms underlying plasticity of excitatory and inhibitory synaptic transmission continue to be elucidated; these can vary depending on the experimental parameters for induction of plasticity, the particular type of synapse under investigation, and even the prior history of activation at the synapse. Long-term potentiation (LTP) and LTD of excitatory synaptic transmission are two well-known phenomena in which efficacy is increased or decreased, respectively, and at many synapses in the CNS occur through concomitant alterations in the number of postsynaptic iGluRs. The movement of excitatory receptors in and out of synapses, and more generally to and from the neuronal plasma membrane, is dictated by their association with a wide variety of scaffolding and chaperone proteins, whose interactions are often controlled by various protein kinases (Anggono and Huganir, 2012).It is generally appreciated now that long-term synaptic plasticity can be elicited by a variety of mechanisms even within a single type of synaptic connection. In addition to postsynaptic alterations in receptor content, for example, synaptic efficacy can also be tuned by regulated alterations in the probability of vesicular release of the neurotransmitter. Until recently, this presynaptic form of plasticity was thought to be the exclusive mechanism for altering excitatory synaptic strength at a morphologically unusual synapse in the hippocampus formed between large bouton-like presynaptic terminals arising from granule cell axons, or mossy fibres, and proximal dendrites on CA3 pyramidal neurons (Nicoll and Schmitz, 2005). These synaptic connections allow for single dentate granule cells to profoundly influence the likelihood of action potential firing in CA3 pyramidal neurons in a frequency-dependent manner, and for that reason have been referred to as ‘conditional detonator'' synapses (Henze et al, 2002). The precise mechanisms that lead to increased vesicular release probability following LTP-inducing stimulation of mossy fibre axons, including a potential role for retrograde signalling, remain the subject of debate, although there is general consensus that activation of presynaptic protein kinase A (PKA) is a key step in this form of synaptic plasticity (Figure 1A). Enhancing release probability impacts signalling through all three types of iGluRs present at mossy fibre synapses—AMPA, NMDA, and KARs. Recently, however, novel postsynaptic forms of mossy fibre plasticity were discovered in which induction protocols specifically increased the number of NMDA receptors (Kwon and Castillo, 2008; Rebola et al, 2008) or decreased the number of KARs (Selak et al, 2009), expanding the mechanistic repertoire at this historical site of focus of research on presynaptic LTP. Alterations in the synaptic content of particular iGluRs could serve as an additional means to fine-tune synaptic integration at the mossy fibre—CA3 synapse and therefore have important consequences for hippocampal network excitability.Open in a separate windowFigure 1Kainate receptor-dependent plasticity mechanisms at the hippocampal mossy fibre–CA3 synapse. (A) Activation of presynaptic receptors enhances glutamate release from the mossy fibre terminals. (B) A spike-timing-dependent plasticity protocol known to activate postsynaptic CaMKII results in long-term synaptic depression. CaMKII phosphorylates the GluK5 kainate receptor subunit, which uncouples the receptor from PSD-95 in the postsynaptic density. This leads to an increase in receptor mobility and diffusion away from the synapse. (C) Low-frequency stimulation of mossy fibres and activation of postsynaptic group 1 mGluRs leads to activation of PKC, which promotes the association of SNAP-25 to the GluK5 kainate receptor subunit and the subsequent endocytosis of synaptic receptors.In this issue, Carta et al (2013) identify a new postsynaptic mechanism for shaping mossy fibre plasticity that is specific to synaptic KARs, which serve to influence temporal integration of synaptic input as well as pyramidal neuron excitability through modulation of intrinsic ion channels. The authors paired postsynaptic depolarization of CA3 pyramidal neurons with a precisely timed presynaptic release of glutamate in a pattern that is known to produce LTP at many central synapses (Feldman, 2012). At mossy fibre synapses, however, this form of spike-timing-dependent plasticity (STDP) instead caused LTD of KAR-mediated excitatory synaptic potentials (KAR-LTD) while leaving AMPA receptor function unaltered (Figure 1B) (Carta et al, 2013). Using a series of genetic and pharmacological manipulations, Carta et al (2013) found that KAR-LTD was dependent upon the activation of postsynaptic KARs themselves, a rise in postsynaptic Ca²⁺, and CaMKII phosphorylation of a specific protein component of synaptic KARs, the GluK5 subunit. Unlike other mechanisms of postsynaptic mossy fibre plasticity, KAR-LTD was independent of NMDA or metabotropic glutamate receptor activation. Most surprisingly, KAR-LTD did not require receptor endocytosis from the plasma membrane, as is the case with most other forms of postsynaptic depression of excitatory transmission, including a distinct form of KAR-LTD reported previously (Selak et al, 2009) (Figure 1C). Instead, CaMKII-mediated phosphorylation of GluK5 subunits likely uncoupled receptors from the postsynaptic scaffolding protein PSD-95, which then led to enhanced lateral diffusion of KARs out of mossy fibre synapses. As KAR endocytosis was not altered in mossy fibre STDP, the activity-dependent reduction in KAR signalling was effectively limited to those receptors in the synapse. A molecular replacement strategy was employed using biolistic-based expression of mutant KARs in cultured hippocampal slices prepared from KAR knockout mice, which allowed Carta et al (2013) to corroborate their detailed biochemical studies by showing that reconstituted KAR currents in CA3 neurons expressing recombinant GluK5 phosphorylation site substitutions were unable to express KAR-LTD. In summary, KAR-mediated activation of CaMKII leads to phosphorylation of the GluK5 subunit and subsequent KAR-LTD through enhanced lateral mobility of synaptic receptors (Figure 1B).These findings are intriguing for several reasons. Most notably, they stand in stark contrast to studies in which CaMKII activation primarily triggers potentiation, rather than depression, of excitatory synaptic transmission at other synapses (Lisman et al, 2012). CaMKII recently was shown to cause diffusional trapping of AMPA receptor complexes within the postsynaptic density following phosphorylation of a closely associated auxiliary subunit, stargazin (Opazo et al, 2010), which is precisely the opposite of the effects of activation of the enzyme on KAR mobility at mossy fibre synapses. Further, these divergent consequences are both dependent upon carboxy-terminal PDZ interactions with scaffolding proteins, although in each case further research is needed to dissect out the relevant binding partners that control lateral mobility. It is of interest that KAR-LTD required synaptic activation of KARs to initiate signalling via CaMKII, which implies a tight coupling exists between KARs and the holoenzyme in the mossy fibre postsynaptic density. This observation also raises the possibility that activated CaMKII could phosphorylate other targets to effect other, yet-to-be-discovered, changes in synaptic function. Finally, the report by Carta et al expands our understanding of how excitatory synaptic transmission is fine-tuned at an important central synapse and underscores the fact that even well-trod ground (or synapses) continue to yield surprises that inform our understanding of the remarkable mechanistic diversity underlying synaptic plasticity in the CNS.     

Unraveling the neuroprotective mechanisms of PrPC in excitotoxicity

Knowledge of the natural roles of cellular prion protein (PrP^C) is essential to an understanding of the molecular basis of prion pathologies. This GPI-anchored protein has been described in synaptic contacts, and loss of its synaptic function in complex systems may contribute to the synaptic loss and neuronal degeneration observed in prionopathy. In addition, Prnp knockout mice show enhanced susceptibility to several excitotoxic insults, GABA_A receptor-mediated fast inhibition was weakened, LTP was modified and cellular stress increased. Although little is known about how PrP^C exerts its function at the synapse or the downstream events leading to PrP^C-mediated neuroprotection against excitotoxic insults, PrP^C has recently been reported to interact with two glutamate receptor subunits (NR2D and GluR6/7). In both cases the presence of PrP^C blocks the neurotoxicity induced by NMDA and Kainate respectively. Furthermore, signals for seizure and neuronal cell death in response to Kainate in Prnp knockout mouse are associated with JNK3 activity, through enhancing the interaction of GluR6 with PSD-95. In combination with previous data, these results shed light on the molecular mechanisms behind the role of PrP^C in excitotoxicity. Future experimental approaches are suggested and discussed.     

Unraveling the neuroprotective mechanisms of PrPC in excitotoxicity

Knowledge of the natural roles of cellular prion protein (PrP^C) is essential to an understanding of the molecular basis of prion pathologies. This GPI-anchored protein has been described in synaptic contacts, and loss of its synaptic function in complex systems may contribute to the synaptic loss and neuronal degeneration observed in prionopathy. In addition, Prnp knockout mice show enhanced susceptibility to several excitotoxic insults, GABA_A receptor-mediated fast inhibition was weakened, LTP was modified and cellular stress increased. Although little is known about how PrP^C exerts its function at the synapse or the downstream events leading to PrP^C-mediated neuroprotection against excitotoxic insults, PrP^C has recently been reported to interact with two glutamate receptor subunits (NR2D and GluR6/7). In both cases the presence of PrP^C blocks the neurotoxicity induced by NMDA and Kainate respectively. Furthermore, signals for seizure and neuronal cell death in response to Kainate in Prnp knockout mouse are associated with JNK3 activity, through enhancing the interaction of GluR6 with PSD-95. In combination with previous data, these results shed light on the molecular mechanisms behind the role of PrP^C in excitotoxicity. Future experimental approaches are suggested and discussed.     

Neto2 Interacts with the Scaffolding Protein GRIP and Regulates Synaptic Abundance of Kainate Receptors

Kainate receptors (KARs) are a class of ionotropic glutamate receptors that are expressed throughout the central nervous system. The function and subcellular localization of KARs are tightly regulated by accessory proteins. We have previously identified the single-pass transmembrane proteins, Neto1 and Neto2, to be associated with native KARs. In the hippocampus, Neto1, but not Neto2, controls the abundance and modulates the kinetics of postsynaptic KARs. Here we evaluated whether Neto2 regulates synaptic KAR levels in the cerebellum where Neto1 expression is limited to the deep cerebellar nuclei. In the cerebellum, where Neto2 is present abundantly, we found a ∼40% decrease in GluK2-KARs at the postsynaptic density (PSD) of Neto2-null mice. No change, however, was observed in total level of GluK2-KARs, thereby suggesting a critical role of Neto2 on the synaptic localization of cerebellar KARs. The presence of a putative class II PDZ binding motif on Neto2 led us to also investigate whether it interacts with PDZ domain-containing proteins previously implicated in regulating synaptic abundance of KARs. We identified a PDZ-dependent interaction between Neto2 and the scaffolding protein GRIP. Furthermore, coexpression of Neto2 significantly increased the amount of GRIP associated with GluK2, suggesting that Neto2 may promote and/or stabilize GluK2:GRIP interactions. Our results demonstrate that Neto2, like Neto1, is an important auxiliary protein for modulating the synaptic levels of KARs. Moreover, we propose that the interactions of Neto1/2 with various scaffolding proteins is a critical mechanism by which KARs are stabilized at diverse synapses.     

LTP mechanisms: from silence to four-lane traffic

Brief periods of strong neuronal activity induce long-lasting changes in synaptic function. This synaptic plasticity is thought to play important roles in learning and memory. One example--long-term potentation in the CA1 region of the hippocampus--has been studied extensively, and conflicting views regarding the underlying mechanisms have emerged. Recent findings, regarding basic properties of synaptic transmission, appear to reconcile these diverging views.     

Regulation and function of local protein synthesis in neuronal dendrites

It has long been shown that protein synthesis can occur in neuronal dendrites, but its significance remained unclear until relatively recently. Studies suggest that local protein synthesis has crucial roles in synaptic plasticity, the change in neuronal communication efficiency that is probably a cellular basis of learning and memory. Induced by neuronal activity, local protein synthesis provides key factors for the modification of activated synapses. In this review, we summarize the evidence for local protein synthesis and its functions in synaptic plasticity. We also discuss the molecular mechanisms by which neuronal activity induces the synthesis of proteins that allow for changes in synaptic function.     

Transsynaptic Coordination of Synaptic Growth,Function, and Stability by the L1-Type CAM Neuroglian

The precise control of synaptic connectivity is essential for the development and function of neuronal circuits. While there have been significant advances in our understanding how cell adhesion molecules mediate axon guidance and synapse formation, the mechanisms controlling synapse maintenance or plasticity in vivo remain largely uncharacterized. In an unbiased RNAi screen we identified the Drosophila L1-type CAM Neuroglian (Nrg) as a central coordinator of synapse growth, function, and stability. We demonstrate that the extracellular Ig-domains and the intracellular Ankyrin-interaction motif are essential for synapse development and stability. Nrg binds to Ankyrin2 in vivo and mutations reducing the binding affinities to Ankyrin2 cause an increase in Nrg mobility in motoneurons. We then demonstrate that the Nrg–Ank2 interaction controls the balance of synapse growth and stability at the neuromuscular junction. In contrast, at a central synapse, transsynaptic interactions of pre- and postsynaptic Nrg require a dynamic, temporal and spatial, regulation of the intracellular Ankyrin-binding motif to coordinate pre- and postsynaptic development. Our study at two complementary model synapses identifies the regulation of the interaction between the L1-type CAM and Ankyrin as an important novel module enabling local control of synaptic connectivity and function while maintaining general neuronal circuit architecture.     

Long-term depression of kainate receptor-mediated synaptic transmission

Kainate receptors (KARs) have been shown to be involved in hippocampal mossy fiber long-term potentiation (LTP); however, it is not known if KARs are involved in the induction or expression of long-term depression (LTD), the other major form of long-term synaptic plasticity. Here we describe LTD of KAR-mediated synaptic transmission (EPSC(KA) LTD) in perirhinal cortex layer II/III neurons that is distinct from LTD of AMPAR-mediated transmission, which also coexists at the same synapses. Induction of EPSC(KA) LTD requires a rise in postsynaptic Ca(2+) but is independent of NMDARs or T-type voltage-gated Ca(2+) channels; however, it requires synaptic activation of inwardly rectifying KARs and release of Ca(2+) from stores. The synaptic KARs are regulated by tonically activated mGluR5, and expression of EPSC(KA) LTD occurs via a mechanism involving mGluR5, PKC, and PICK1 PDZ domain interactions. Thus, we describe the induction and expression mechanism of a form of synaptic plasticity, EPSC(KA) LTD.