Synaptic plasticity at hippocampal mossy fibre synapses

The dentate gyrus provides the main input to the hippocampus. Information reaches the CA3 region through mossy fibre synapses made by dentate granule cell axons. Synaptic plasticity at the mossy fibre-pyramidal cell synapse is unusual for several reasons, including low basal release probability, pronounced frequency facilitation and a lack of N-methyl-D-aspartate receptor involvement in long-term potentiation. In the past few years, some of the mechanisms underlying the peculiar features of mossy fibre synapses have been elucidated. Here we describe recent work from several laboratories on the various forms of synaptic plasticity at hippocampal mossy fibre synapses. We conclude that these contacts have just begun to reveal their many secrets.     

Long-term potentiation selectively expressed by NMDA receptors at hippocampal mossy fiber synapses

The mossy fiber to CA3 pyramidal cell synapse (mf-CA3) provides a major source of excitation to the hippocampus. Thus far, these glutamatergic synapses are well recognized for showing a presynaptic, NMDA receptor-independent form of LTP that is expressed as a long-lasting increase of transmitter release. Here, we show that in addition to this "classical" LTP, mf-CA3 synapses can undergo a form of LTP characterized by a selective enhancement of NMDA receptor-mediated transmission. This potentiation requires coactivation of NMDA and mGlu5 receptors and a postsynaptic calcium rise. Unlike classical LTP, expression of this mossy fiber LTP is due to a PKC-dependent recruitment of NMDA receptors specifically to the mf-CA3 synapse via a SNARE-dependent process. Having two mechanistically different forms of LTP may allow mf-CA3 synapses to respond with more flexibility to the changing demands of the hippocampal network.     

The maintenance of LTP at hippocampal mossy fiber synapses is independent of sustained presynaptic calcium.

We have examined the role of presynaptic residual calcium in maintaining long-term changes in synaptic efficacy observed at mossy fiber synapses between hippocampal dentate granule cells and CA3 pyramidal cells. Calcium concentrations in individual mossy fiber terminals in hippocampal slice were optically measured with the calcium indicator fura-2 while stimulating the mossy fiber pathway and recording excitatory postsynaptic potentials extracellularly. Short-term synaptic enhancement was accompanied by increased presynaptic residual calcium concentration. A 2-fold enhancement of transmitter release was accompanied by a 10-30 nM increase in residual calcium. Following induction of mossy fiber LTP, transiently elevated presynaptic calcium decayed to prestimulus levels, whereas enhancement of synaptic transmission persisted. Our results demonstrate that, despite an apparent strong sensitivity of synaptic enhancement to presynaptic residual calcium levels, sustained increases in presynaptic residual calcium levels are not responsible for the maintained synaptic enhancement observed during mossy fiber LTP.     

Functional development of hippocampal mossy fiber synapses in rabbits

The course of functional maturation with age of mossy fiber synapses on pyramidal cells in areas CA_3,4 of the dorsal hippocampus was investigated by extracellular recording of focal potentials and single unit responses of the hippocampus to electrical stimulation of the dentate fascia in waking, unimmobilized rabbits aged from 1 to 14 days. After the 4th day of postnatal life focal potentials appeared in response to single stimulation, in the form of a biphasic short-latency wave, characteristic of responses of the mature hippocampus, accompanied by spike discharges with a latent period of 3 to 10 msec and inhibitory responses of the hippocampal neurons. During the next 10 days the amplitude of the focal potentials increased from several hundred millivolts, with the sharpest increase observed from the 4th through the 7th days. In early age periods global and unitary responses were shown to be capable of frequency potentiation and also of short-term after-potentiation.Brain Institute, Academy of Medical Sciences of the USSR, Moscow. Translated from Neirofiziologiya, Vol. 12, No. 3, pp. 246–254, May–June, 1980.     

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.     

Synaptic kainate receptors

Kainate receptors are a family of ionotropic glutamate receptors with poorly understood functions. Recent evidence firmly establishes kainate receptors as postsynaptic mediators of synaptic transmission. A second, presynaptic, modulatory role of kainate receptors has also been suggested, although the mechanism(s) involved remain controversial.     

Synaptic drive at developing synapses: Transient upregulation of kainate receptors

At the onset of a period of intense synaptic refinement initiated by synchronized eye opening (EO), rapid changes in postsynaptic NMDA receptor and AMPA receptor currents (NMDARcs and AMPARcs) occur within the superficial visual layers of the rodent superior colliculus (sSC; Lu and Constantine‐Paton [ 2004 ]: Neuron 43:237–249). Subsequently, evoked non‐NMDARc amplitudes increase, but by 2 weeks after EO (AEO) they decrease significantly. Here, using whole‐cell patch‐clamp recording, we demonstrate that small, slowly desensitizing excitatory kainate receptor currents (KARcs) are responsible for the rise and subsequent fall in non‐NMDARcs. The increase in KAR transmission parallels inhibitory GABA_A responses that plateau at 7 days AEO. By 2 weeks AEO, KARcs are gone. AMPARcs remain unchanged during the appearance and disappearance of the KARcs, despite increases in sSC neuropil activity and continued refinement of inputs to individual sSC neurons. We suggest that in the interval of heightened activity, before SC inhibition matures, many AMPARcs desensitize and are relatively ineffective at relieving the Mg²⁺ block on NMDARs. This transient appearance of slowly desensitizing, long‐duration KARcs may provide increased membrane depolarization necessary for NMDAR function and continuation of synaptic refinement. © 2010 Wiley Periodicals, Inc. Develop Neurobiol 70: 737–750, 2010     

Rapid and differential regulation of AMPA and kainate receptors at hippocampal mossy fibre synapses by PICK1 and GRIP

We identified four PDZ domain-containing proteins, syntenin, PICK1, GRIP, and PSD95, as interactors with the kainate receptor (KAR) subunits GluR5(2b,) GluR5(2c), and GluR6. Of these, we show that both GRIP and PICK1 interactions are required to maintain KAR-mediated synaptic function at mossy fiber-CA3 synapses. In addition, PKC alpha can phosphorylate ct-GluR5(2b) at residues S880 and S886, and PKC activity is required to maintain KAR-mediated synaptic responses. We propose that PICK1 targets PKC alpha to phosphorylate KARs, causing their stabilization at the synapse by an interaction with GRIP. Importantly, this mechanism is not involved in the constitutive recycling of AMPA receptors since blockade of PDZ interactions can simultaneously increase AMPAR- and decrease KAR-mediated synaptic transmission at the same population of synapses.     

Bidirectional regulation of hippocampal mossy fiber filopodial motility by kainate receptors: a two-step model of synaptogenesis

The rapid motility of axonal filopodia and dendritic spines is prevalent throughout the developing CNS, although the function of this motility remains controversial. Using two-photon microscopy, we imaged hippocampal mossy fiber axons in slice cultures and discovered that filopodial extensions are highly motile. Axonal filopodial motility is actin based and is downregulated with development, although it remains in mature cultures. This motility is correlated with free extracellular space yet is inversely correlated with contact with postsynaptic targets, indicating a potential role in synaptogenesis. Filopodial motility is differentially regulated by kainate receptors: synaptic stimulation of kainate receptors enhances motility in younger slices, but it inhibits it in mature slices. We propose that neuronal activity controls filopodial motility in a developmentally regulated manner, in order to establish synaptic contacts in a two-step process. A two-step model of synaptogenesis can also explain the opposite effects of neuronal activity on the motility of dendritic protrusions.     

The actions of synaptically released zinc at hippocampal mossy fiber synapses

Zn2+ is present at high concentrations in the synaptic vesicles of hippocampal mossy fibers. We have used Zn2+ chelators and the mocha mutant mouse to address the physiological role of Zn2+ in this pathway. Zn2+ is not involved in the unique presynaptic plasticities observed at mossy fiber synapses but is coreleased with glutamate from these synapses, both spontaneously and with electrical stimulation, where it exerts a strong modulatory effect on the NMDA receptors. Zn2+ tonically occupies the high-affinity binding site of NMDA receptors at mossy fiber synapses, whereas the lower affinity voltage-dependent Zn2+ binding site is occupied during action potential driven-release. We conclude that Zn2+ is a modulatory neurotransmitter released from mossy fiber synapses and plays an important role in shaping the NMDA receptor response at these synapses.     

A critical role of a facilitatory presynaptic kainate receptor in mossy fiber LTP.

The mechanisms involved in mossy fiber LTP in the hippocampus are not well established. In the present study, we show that the kainate receptor antagonist LY382884 (10 microM) is selective for presynaptic kainate receptors in the CA3 region of the hippocampus. At a concentration at which it blocks mossy fiber LTP, LY382884 selectively blocks the synaptic activation of a presynaptic kainate receptor that facilitates AMPA receptor-mediated synaptic transmission. Following the induction of mossy fiber LTP, there is a complete loss of the presynaptic kainate receptor-mediated facilitation of synaptic transmission. These results identify a central role for the presynaptic kainate receptor in the induction of mossy fiber LTP. In addition, these results suggest that the pathway by which kainate receptors facilitate glutamate release is utilized for the expression of mossy fiber LTP.     

Adenosine A2A receptors are essential for long-term potentiation of NMDA-EPSCs at hippocampal mossy fiber synapses

The physiological conditions under which adenosine A2A receptors modulate synaptic transmission are presently unclear. We show that A2A receptors are localized postsynaptically at synapses between mossy fibers and CA3 pyramidal cells and are essential for a form of long-term potentiation (LTP) of NMDA-EPSCs induced by short bursts of mossy fiber stimulation. This LTP spares AMPA-EPSCs and is likely induced and expressed postsynaptically. It depends on a postsynaptic Ca2+ rise, on G protein activation, and on Src kinase. In addition to A2A receptors, LTP of NMDA-EPSCs requires the activation of NMDA and mGluR5 receptors as potential sources of Ca2+ increase. LTP of NMDA-EPSCs displays a lower threshold for induction as compared with the conventional presynaptic mossy fiber LTP; however, the two forms of LTP can combine with stronger induction protocols. Thus, postsynaptic A2A receptors may potentially affect information processing in CA3 neuronal networks and memory performance.     

Recruitment of release sites underlies chemical presynaptic potentiation at hippocampal mossy fiber boutons

Synaptic plasticity is a cellular model for learning and memory. However, the expression mechanisms underlying presynaptic forms of plasticity are not well understood. Here, we investigate functional and structural correlates of presynaptic potentiation at large hippocampal mossy fiber boutons induced by the adenylyl cyclase activator forskolin. We performed 2-photon imaging of the genetically encoded glutamate sensor iGlu_u that revealed an increase in the surface area used for glutamate release at potentiated terminals. Time-gated stimulated emission depletion microscopy revealed no change in the coupling distance between P/Q-type calcium channels and release sites mapped by Munc13-1 cluster position. Finally, by high-pressure freezing and transmission electron microscopy analysis, we found a fast remodeling of synaptic ultrastructure at potentiated boutons: Synaptic vesicles dispersed in the terminal and accumulated at the active zones, while active zone density and synaptic complexity increased. We suggest that these rapid and early structural rearrangements might enable long-term increase in synaptic strength.

This study uses several high-resolution imaging techniques to investigate the structural correlates of presynaptic potentiation at hippocampal mossy fiber boutons, observing an increase in release sites and in release synchronicity accompanied by synaptic vesicle dispersion in the terminal and accumulation at release sites, but no modulation of the distance between calcium channel and release sites.     

Presynaptic kainate receptors are localized close to release sites in rat hippocampal synapses

The subsynaptic distribution of kainate receptors is still a matter of much debate given its importance to understand the way they influence neuronal communication. Here, we show that, in synapses of the rat hippocampus, presynaptic kainate receptors are localized within the presynaptic active zone close to neurotransmitter release sites. The activation of these receptors with low concentrations of agonists induces the release of [(3)H]glutamate in the absence of a depolarizing stimulus. Furthermore, this modulation of [(3)H]glutamate release by kainate is more efficient when compared with a KCl-evoked depolarization that causes a more than two-fold increase in the intra-terminal calcium concentration but no apparent release of [(3)H]glutamate, suggesting a direct receptor-mediated process. Using a selective synaptic fractionation technique that allows for a highly efficient separation of presynaptic, postsynaptic and non-synaptic proteins we confirmed that, presynaptically, kainate receptors are mainly localized within the active zone of hippocampal synapses where they are expected to be in a privileged position to modulate synaptic phenomena.     

Long-term potentiation of hippocampal mossy fiber synapses is blocked by postsynaptic injection of calcium chelators

The role of intracellular calcium in an APV-insensitive form of long-term potentiation (LTP) has been studied at the hippocampal mossy fiber synapse. Intracellular calcium was buffered by iontophoretic injection of either BAPTA or QUIN-2, into CA3 pyramidal neurons. The slow calcium-dependent after hyperpolarization was used as an indicator of buffering. LTP was elicited in control and in APV-treated cells (6/6 and 4/5 cell, respectively). In contrast, LTP was observed in only 2/9 BAPTA-loaded cells and in 1/4 QUIN-2-loaded cells. The magnitude of LTP for control and APV-treated cells were not significantly different, but both groups showed significantly greater LTP than BAPTA-loaded cells. These results suggest that an increase in postsynaptic calcium is required for the induction of mossy fiber LTP.     

Presynaptic glycine receptors on hippocampal mossy fibers

Presynaptic glycine receptors (GlyRs) have been implicated in the regulation of glutamatergic synaptic transmission. Here, we characterized presynaptic GlyR-mediated currents by patch-clamp recording from mossy fiber boutons (MFBs) in rat hippocampal slices. In MFBs, focal puff-application of glycine-evoked chloride currents that were blocked by the GlyR antagonist strychnine. Their amplitudes declined substantially during postnatal development, from a mean conductance per MFB of ∼600 pS in young to ∼130 pS in adult animals. Single-channel analysis revealed multiple conductance states between ∼20 and ∼120 pS, consistent with expression of both homo- and hetero-oligomeric GlyRs. Accordingly, estimated GlyRs densities varied between 8-17 per young, and 1-3 per adult, MFB. Our results demonstrate that functional presynaptic GlyRs are present on hippocampal mossy fiber terminals and suggest a role of these receptors in the regulation of glutamate release during the development of the mossy fiber - CA3 synapse.     

GABAA receptors at hippocampal mossy fibers

Presynaptic GABAA receptors modulate synaptic transmission in several areas of the CNS but are not known to have this action in the cerebral cortex. We report that GABAA receptor activation reduces hippocampal mossy fibers excitability but has the opposite effect when intracellular Cl- is experimentally elevated. Synaptically released GABA mimics the effect of exogenous agonists. GABAA receptors modulating axonal excitability are tonically active in the absence of evoked GABA release or exogenous agonist application. Presynaptic action potential-dependent Ca2+ transients in individual mossy fiber varicosities exhibit a biphasic dependence on membrane potential and are altered by GABAA receptors. Antibodies against the alpha2 subunit of GABAA receptors stain mossy fibers. Axonal GABAA receptors thus play a potentially important role in tonic and activity-dependent heterosynaptic modulation of information flow to the hippocampus.     

Astrocyte activation of presynaptic metabotropic glutamate receptors modulates hippocampal inhibitory synaptic transmission

In the CNS, fine processes of astrocytes often wrap around dendrites, axons and synapses, which provides an interface where neurons and astrocytes might interact. We have reported previously that selective Ca(2+) elevation in astrocytes, by photolysis of caged Ca(2+) by o-nitrophenyl-EGTA (NP-EGTA), causes a kainite receptor-dependent increase in the frequency of spontaneous inhibitory post-synaptic potentials (sIPSCs) in neighboring interneurons in hippocampal slices. However, tetrodotoxin (TTX), which blocks action potentials, reduces the frequency of miniature IPSCs (mIPSCs) in interneurons during Ca(2+) uncaging by an unknown presynaptic mechanism. In this study we investigate the mechanism underlying the presynaptic inhibition. We show that Ca(2+) uncaging in astrocytes is accompanied by a decrease in the amplitude of evoked IPSCs (eIPSCs) in neighboring interneurons. The decreases in eIPSC amplitude and mIPSC frequency are prevented by CPPG, a group II/III metabotropic glutamate receptor (mGluR) antagonist, but not by the AMPA/kainate and NMDA receptor antagonists CNQX/CPP. Application of either the group II mGluR agonist DCG IV or the group III mGluR agonist L-AP4 decreased the amplitude of eIPSCs by a presynaptic mechanism, and both effects are blocked by CPPG. Thus, activation of mGluRs mediates the effects of Ca(2+) uncaging on mIPSCs and eIPSCs. Our results indicate that Ca(2+)-dependent release of glutamate from astrocytes can activate distinct classes of glutamate receptors and differentially modulate inhibitory synaptic transmission in hippocampal interneurons.     

The two sides of hippocampal mossy fiber plasticity

Two studies in this issue of Neuron (Kwon and Castillo and Rebola et al.) show that the mossy fiber-CA3 pyramidal neuron synapse, a hippocampal synapse well known for its presynaptic plasticity, exhibits a novel form of long-term potentiation of NMDAR-mediated currents, which is induced and expressed postsynaptically.     

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.