Metabotropic Glutamate Receptor-dependent Long-term Depression Research Articles

Hippocampal long-term depression is enhanced, depotentiation is inhibited and long-term potentiation is unaffected by the application of a selective c-Jun N-terminal kinase inhibitor to freely behaving rats

Synaptic plasticity is regarded as the major candidate mechanism for synaptic information storage and memory formation in the hippocampus. Mitogen-activated protein kinases have recently emerged as an important regulatory factor in many forms of synaptic plasticity and memory. As one of the subfamilies of mitogen-activated protein kinases, extracellular-regulated kinase is involved in the in vitro induction of long-term potentiation (LTP), whereas p38 mediates metabotropic glutamate receptor-dependent long-term depression (LTD) in vitro. Although c-Jun N-terminal kinase (JNK) has also been implicated in synaptic plasticity, the in vivo relevance of JNK activity to different forms of synaptic plasticity remains to be further explored. We investigated the effect of inhibition of JNK on different forms of synaptic plasticity in the dentate gyrus of freely behaving adult rats. Intracereboventricular application of c-Jun N-terminal protein kinase-inhibiting peptide (D-JNKI) (96 ng), a highly selective JNK inhibitor peptide, did not affect basal synaptic transmission but reduced neuronal excitability with a higher dose (192 ng). Application of D-JNKI, at a concentration that did not affect basal synaptic transmission, resulted in reduced specific phosphorylation of the JNK substrates postsynaptic density 95kD protein (PSD 95) and c-Jun, a significant enhancement of LTD and a facilitation of short-term depression into LTD. Both LTP and short-term potentiation were unaffected. An inhibition of depotentiation (recovery of LTP) occurred. These data suggest that suppression of JNK-dependent signalling may serve to enhance synaptic depression, and indirectly promote LTP through impairment of depotentiation.

GluA2 (GluR2) Regulates Metabotropic Glutamate Receptor-Dependent Long-Term Depression through N-Cadherin-Dependent and Cofilin-Mediated Actin Reorganization

The GluA2 (GluR2) subunit is critical for the regulation of AMPA receptor properties and synaptic plasticity, but the underlying mechanisms remain unclear. Here, we demonstrate that GluA2 regulates metabotropic glutamate receptor-dependent long-term depression (mGluR-LTD) through a previously unknown mechanism involving N-cadherin-dependent and cofilin-mediated actin reorganization. We show that GluA2 is indispensable for mGluR-LTD in the hippocampus, and surprisingly this action of GluA2 is mediated by its extracellular domain interaction with N-cadherin. Accordingly, we show that the function of N-cadherin is regulated by and required for mGluR-LTD. Furthermore, we show that the regulatory effect of GluA2/N-cadherin is mediated through activation of Rho GTPase Rac1 and its downstream actin regulator cofilin, and, importantly, the requirement for GluA2/N-cadherin can be overcome by manipulating cofilin. These results provide compelling evidence that the extracellular domain of GluA2 regulates long-lasting synaptic plasticity through a signaling mechanism that is distinct from those used by the other domains of the receptor subunit.

Calcium Binding to PICK1 Is Essential for the Intracellular Retention of AMPA Receptors Underlying Long-Term Depression

NMDA receptor (NMDAR)-dependent long-term depression (LTD) in the hippocampus is mediated primarily by the calcium-dependent removal of AMPA receptors (AMPARs) from the postsynaptic density. The AMPAR-binding, PDZ (PSD-95/Dlg/ZO1) and BAR (Bin/amphiphysin/Rvs) domain-containing protein PICK1 has been implicated in the regulation of AMPAR trafficking underlying several forms of synaptic plasticity. Using a strategy involving small hairpin RNA-mediated knockdown of PICK1 and its replacement with recombinant PICK1, we performed a detailed structure-function analysis of the role of PICK1 in hippocampal synaptic plasticity and the underlying NMDAR-induced AMPAR trafficking. We found that PICK1 is not necessary for maintenance of the basal synaptic complement of AMPARs or expression of either metabotropic glutamate receptor-dependent LTD or NMDAR-dependent LTP. Rather, PICK1 function is specific to NMDAR-dependent LTD and the underlying AMPAR trafficking. Furthermore, although PICK1 does not regulate the initial phase of NMDAR-induced AMPAR endocytosis, it is required for intracellular retention of internalized AMPARs. Detailed biophysical analysis of an N-terminal acidic motif indicated that it is involved in intramolecular electrostatic interactions that are disrupted by calcium. Mutations that interfered with the calcium-induced structural changes in PICK1 precluded LTD and the underlying NMDAR-induced intracellular retention of AMPARs. These findings support a model whereby calcium-induced modification of PICK1 structure is critical for its function in the retention of internalized AMPARs that underlies the expression of hippocampal NMDAR-dependent LTD.

DGKι regulates presynaptic release during mGluR-dependent LTD

Diacylglycerol (DAG) is an important lipid second messenger. DAG signalling is terminated by conversion of DAG to phosphatidic acid (PA) by diacylglycerol kinases (DGKs). The neuronal synapse is a major site of DAG production and action; however, how DGKs are targeted to subcellular sites of DAG generation is largely unknown. We report here that postsynaptic density (PSD)-95 family proteins interact with and promote synaptic localization of DGKι. In addition, we establish that DGKι acts presynaptically, a function that contrasts with the known postsynaptic function of DGKζ, a close relative of DGKι. Deficiency of DGKι in mice does not affect dendritic spines, but leads to a small increase in presynaptic release probability. In addition, DGKι-/- synapses show a reduction in metabotropic glutamate receptor-dependent long-term depression (mGluR-LTD) at neonatal (∼2 weeks) stages that involve suppression of a decrease in presynaptic release probability. Inhibition of protein kinase C normalizes presynaptic release probability and mGluR-LTD at DGKι-/- synapses. These results suggest that DGKι requires PSD-95 family proteins for synaptic localization and regulates presynaptic DAG signalling and neurotransmitter release during mGluR-LTD.

PTEN is recruited to the postsynaptic terminal for NMDA receptor-dependent long-term depression

Phosphatase and tensin homolog deleted on chromosome ten (PTEN) is an important regulator of phosphatidylinositol-(3,4,5,)-trisphosphate signalling, which controls cell growth and differentiation. However, PTEN is also highly expressed in the adult brain, in which it can be found in dendritic spines in hippocampus and other brain regions. Here, we have investigated specific functions of PTEN in the regulation of synaptic function in excitatory hippocampal synapses. We found that NMDA receptor activation triggers a PDZ-dependent association between PTEN and the synaptic scaffolding molecule PSD-95. This association is accompanied by PTEN localization at the postsynaptic density and anchoring within the spine. On the other hand, enhancement of PTEN lipid phosphatase activity is able to drive depression of AMPA receptor-mediated synaptic responses. This activity is specifically required for NMDA receptor-dependent long-term depression (LTD), but not for LTP or metabotropic glutamate receptor-dependent LTD. Therefore, these results reveal PTEN as a regulated signalling molecule at the synapse, which is recruited to the postsynaptic membrane upon NMDA receptor activation, and is required for the modulation of synaptic activity during plasticity.

Activation Conditions for the Induction of Metabotropic Glutamate Receptor-Dependent Long-Term Depression in Hippocampal CA1 Pyramidal Cells

Two forms of homosynaptic long-term depression (LTD) are distinguished in hippocampal CA1 pyramidal cells, one which is NMDA receptor dependent and the other metabotropic glutamate receptor (mGluR) dependent. Although the molecular processes involved in mGluR-LTD are well characterized, the conditions of circuit activation required for its induction remain unclear. We show that mGluR-LTD cannot be induced in synaptically coupled CA3-CA1 pyramidal cell pairs. Experiments to address the underlying mechanisms indicate that, even when glutamate transporters are blocked, one presynaptic cell releases insufficient glutamate to evoke an mGluR-mediated current in a connected CA1 cell. These findings imply that extrasynaptic diffusion is not a limiting factor and are consistent with a sparse distribution of functional mGluRs in the dendritic tree of pyramidal cells. Thus, the discharge of multiple Schaffer collaterals to a targeted cell is necessary for mGluR-LTD. Our experiments indicate that approximately eight CA3 inputs to a CA1 pyramidal cell must be activated to induce mGluR-LTD.

Altered Hippocampal Synaptic Plasticity in the Fmr1 Gene Family Knockout Mouse Models

Fragile X syndrome (FXS) is the most common form of inherited mental retardation. The syndrome results from the absence of the fragile X mental retardation protein (FMRP), which is encoded by the fragile X mental retardation 1 (FMR1) gene. FMR1 and its two paralogs, fragile X-related genes 1 and 2 (FXR1 and -2), form the Fmr1 gene family. Here, we examined long-lasting synaptic plasticity in Fmr1 knockout, Fxr2 knockout, and Fmr1/Fxr2 double knockout mice. We found that metabotropic glutamate receptor-dependent long-term depression (mGluR-LTD) in the hippocampus was affected in Fmr1 knockout, Fxr2 knockout, and Fmr1/Fxr2 double knockout mice at young ages (4-6 wk old). In addition, Fmr1/Fxr2 double knockout mice showed significant deficiencies relative to either Fmr1 or Fxr2 knockout mice in baseline synaptic transmission and short-term presynaptic plasticity, suggesting FMRP and FXR2P may contribute in a cooperative manner to pathways regulating presynaptic plasticity. However, compared with wild-type littermates, late-phase long-term potentiation (L-LTP) was unaltered in all knockout mice at 4-6 mo of age. Interestingly, although Fmr1/Fxr2 double knockout mice exhibited a more robust enhancement in mGluR-LTD compared with that in Fmr1 knockout mice, Fxr2 knockout mice exhibited reduced mGluR-LTD. Furthermore, unlike Fmr1 knockout mice, mGluR-LTD in Fxr2 knockout mice required new protein synthesis, whereas mGluR-LTD in Fmr1/Fxr2 double knockout mice was partially dependent on protein synthesis. These results indicated that both FMRP and FXR2P function in synaptic plasticity and that they likely operate in related but independent pathways.

Regulation of microRNA Expression by Induction of Bidirectional Synaptic Plasticity

Activity-induced protein synthesis is critical for long-lasting synaptic plasticity and subject to tight controls. MicroRNAs (miRNAs) are negative regulators of mRNA translation, but their role during synaptic plasticity is not clear. In this study, we have investigated how induction of long-term potentiation (LTP) and long-term depression (LTD) regulates the expression of miRNAs. Using miRNA arrays, we determined the temporal expression profiles of 62 hippocampal miRNAs following induction of chemical LTP (C-LTP) and metabotropic glutamate receptor-dependent LTD (mGluR-LTD). Several striking features were observed. First, C-LTP or mGluR-LTD induction changed the expression levels of most hippocampal miRNAs. Second, the majority of miRNAs regulated by C-LTP or mGluR-LTD induction followed a similar temporal expression profile. Third, most miRNAs were regulated by both C-LTP and mGluR-LTD induction, but displayed distinct expression dynamics. Fourth, many miRNAs were upregulated at specific time points C-LTP and mGluR-LTD induction, suggesting that C-LTP and mGluR-LTD induction elicits miRNA-mediated suppression of mRNA translation. We propose that the upregulated miRNA expression provides a mechanism to prevent excess protein synthesis during the expression of synaptic plasticity. The extensive regulation of miRNA expression by C-LTP and mGluR-LTD induction suggests a critical role of miRNAs in synaptic plasticity.

Neuronal Pentraxins Modulate Cocaine-Induced Neuroadaptations

Neuronal pentraxins (NPs) function in the extracellular matrix to bind alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors. Three NPs have been described, neuronal activity-regulated pentraxin (Narp), which is regulated as an immediate early gene, NP1, and neuronal pentraxin receptor (NPR). Narp and NP1 enhance synaptogenesis and glutamate signaling by clustering AMPA receptors, whereas NPR contributes to removing AMPA receptors during group I metabotropic glutamate receptor-dependent long-term depression. Here, we examine mice with genetic deletions [knockout (KO)] of each NP to assess their contributions to cocaine-induced neuroplasticity. Consistent with a shared AMPA receptor clustering function for Narp and NP1, deletion of either NP caused similar behavioral alterations. Thus, although both Narp and NP1 deletion promoted cocaine-induced place preference, NPR deletion was without effect. In addition, although Narp and NP1 KO showed reduced time in the center of a novel environment, NPR KO mice spent more time in the center. Finally, although Narp and NP1 KO mice showed blunted locomotion after AMPA microinjection into the accumbens 3 weeks after discontinuing repeated cocaine injections, the AMPA response was augmented in NPR KO. Likewise, endogenous glutamate release elicited less motor activity in Narp KO mice. Consistent with reduced AMPA responsiveness after chronic cocaine in Narp KO mice, glutamate receptor 1 was reduced in the PSD fraction of Narp KO mice withdrawn from cocaine. These data indicate that NPs differentially contribute to cocaine-induced plasticity in a manner that parallels their actions in synaptic plasticity.

Local facilitation of hippocampal metabotropic glutamate receptor-dependent long-term depression by corticosterone and dexamethasone

Long-term potentiation and long-term depression (LTD) of synaptic efficacy, two major forms of synaptic plasticity, are believed to underlie learning processes and memory storage. We have recently shown that acute stress, through corticosterone release and stimulation of glucocorticoid receptors (GRs), facilitates the LTD elicited by the group 1 metabotropic glutamate receptor (mGluR) agonist (R,S)-3,5-dihydroxyphenylglycine (DHPG) in hippocampal CA1 neurons. However, it is unknown whether sustained corticosterone release, per se, is also able to facilitate DHPG-elicited LTD in control (i.e. unstressed) conditions, and if so, whether it acts on local (i.e. hippocampal) or distant GRs. Here, we show that a brief application of 100 nM corticosterone to rat hippocampal slices lowers the threshold for DHPG-elicited LTD, an effect mimicked by the local application of the GR agonist dexamethasone. These results show that high corticosterone release facilitates hippocampal CA1 mGluR-dependent LTD, and does so through local GRs.

The Ups and Downs of Hippocampal Metabotropic Glutamate Receptors: Ramifications for Epileptogenesis and Cognitive Impairment following Status Epilepticus

Loss of Metabotropic Glutamate Receptor-Dependent Long-Term Depression via Downregulation of mGluR5 after Status Epilepticus. Kirschstein T, Bauer M, Müller L, Rüschenschmidt C, Reitze M, Becker AJ, Schoch S, Beck H. J Neurosci 2007;27(29):7696–7704. Synaptic plasticity is thought to be a key mechanism of information storage in the CNS. Different forms of synaptic long-term potentiation have been shown to be impaired in neurological disorders. Here, we show that metabotropic glutamate receptor (mGluR)-dependent long-term depression (LTD), but not NMDA receptor-dependent LTD at Schaffer collateral–CA1 synapses, is profoundly impaired after status epilepticus. Brief application of the group I mGluR agonist ( R, S)-3,5-dihydroxyphenylglycine (100 μM; 5 min) induced mGluR LTD in control, but not in pilocarpine-treated rats. Experiments in the presence of selective inhibitors of either mGluR5 [2-methyl-6-(phenylethynyl)-pyridine] or mGluR1 [7-(hydroxyimino)cyclopropachromen-carboxylate ethyl ester and ( S)-(+)–amino-4-carboxy-2-methylbenzeneacetic acid] demonstrate that loss of mGluR LTD is most likely attributable to a loss of mGluR5 function. Quantitative real-time reverse transcription PCR revealed a specific downregulation of mGluR5 mRNA, but not of mGluR1 mRNA in the CA1 region. Furthermore, we detected a strong reduction in mGluR5 protein expression by immunofluorescence and quantitative immunoblotting. Additionally, the scaffolding protein Homer that mediates coupling of mGluR5 to downstream signaling cascades was downregulated. Thus, we conclude that the reduction of mGluR LTD after pilocarpine-induced status epilepticus is the result of the subtype-specific downregulation of mGluR5 and associated downstream signaling components. Functional Role of mGluR1 and mGluR4 in Pilocarpine-Induced Temporal Lobe Epilepsy. Pitsch J, Schoch S, Gueler N, Flor PJ, van der Putten H, Becker AJ. Neurobiol Dis 2007;26(3):623–633. Altered expression and distribution of neurotransmitter receptors, including metabotropic glutamate receptors (mGluRs), constitute key aspects in epileptogenesis, impaired hippocampal excitability and neuronal degeneration. mGluR1 mediates predominantly excitatory effects, whereas mGluR4 acts as inhibitory presynaptic receptor. Increased hippocampal expression of mGluR1 and mGluR4 has been observed in human temporal lobe epilepsy (TLE). In this study, we address whether genetic mGluR1 upregulation and mGluR4 knock-down influence seizure susceptibility and/or vulnerability of hippocampal neurons by analyzing transgenic animals in the pilocarpine TLE model. Therefore, we generated transgenic mice expressing mGluR1-enhanced green fluorescent protein (EGFP) fusion protein under control of the human cytomegalovirus (CMV) immediate early promoter. Status epilepticus (SE) was induced in 1) mice overexpressing mGluR1-EGFP and 2) mice deficient for mGluR4 (mGluR4 KO) as well as littermate controls. In the acute epileptic stage after pilocarpine application, mGluR4 KO mice showed a significant increase of severe seizure activity, in contrast to mGluR1 transgenics. Analysis of both transgenic mouse lines in the chronic epileptic phase, using a telemetric EEG-/video-monitoring system, revealed a significant increase in seizure frequency only in mGluR1-EGFP mice. In contrast, enhanced neuronal cell loss was only present in the hippocampus of epileptic mGluR4 KO mice. Our results suggest a role for mGluR1 in promoting seizure susceptibility as well as for mGluR4 to counteract excitatory activity and seizure-associated vulnerability of hippocampal neurons. Therefore, our data strongly recommend both mGluRs as potential drug targets to interfere with the development of hippocampal damage and seizure activity in TLE.

Correcting Cocaine-Induced Plasticity

It has been proposed that metabotropic glutamate receptor-dependent long-term depression (mGluR-LTD) can reverse cocaine-evoked synaptic plasticity in the ventral tegmental area (VTA). Mameli et al . have now unraveled the expression mechanism of mGluR-LTD in the VTA of mice exposed to a single dose of cocaine. LTD in this system is not due to the simple removal of AMPA receptors (AMPARs) from the synapse. Instead, AMPARs are replaced by new ones that contain newly synthesized GluR2 subunits. The synapse thus expresses LTD not because there are fewer receptors but because the conductance of the new GluR2-containing AMPARs is reduced. M. Mameli, B. Balland, R. Luján, C. Lüscher, Rapid synthesis and synaptic insertion of GluR2 for mGluR-LTD in the ventral tegmental area. Science 317 , 530-533 (2007). [Abstract] [Full Text]

Regulation of Eukaryotic Initiation Factor 4E by Converging Signaling Pathways during Metabotropic Glutamate Receptor-Dependent Long-Term Depression

Long-term depression (LTD) is an activity-dependent decrease in synaptic efficacy that can be induced in hippocampal area CA1 by pharmacological application of the selective group I metabotropic glutamate receptor (mGluR) agonist 3,5-diyhroxyphenylglycine (DHPG). Recent work has demonstrated that DHPG-induced LTD recruits at least two signal transduction pathways known to couple to translation, the mitogen-activated protein kinase kinase (MEK)-extracellular signal-regulated kinase (ERK) signaling pathway and the phosphoinositide 3-kinase (PI3K)-Akt-mammalian target of rapamycin (mTOR) signaling pathway. However, it remains unclear which translation factors are engaged by these two signaling pathways during mGluR-LTD. In this study, we investigated whether the group I mGluRs couple to the cap-dependent translation proteins: Mnk1, eIF4E, and 4E-BP. We found that both the MEK-ERK and PI3K-mTOR signaling pathways are critical for the DHPG-induced regulation of these translation factors. Furthermore, we demonstrate that increasing eIF4F complex availability via the genetic elimination of 4E-BP2 can enhance the degree of LTD achieved by DHPG application in an ERK-dependent manner. Our results provide direct evidence that cap-dependent translation is engaged during mGluR-LTD and demonstrate that the MEK-ERK and PI3K-mTOR signaling pathways converge to regulate eIF4E activity after induction of DHPG-LTD.

Metabotropic Receptor-Dependent Long-Term Depression Persists in the Absence of Protein Synthesis in the Mouse Model of Fragile X Syndrome

Fragile X syndrome (FXS), a form of human mental retardation, is caused by loss of function mutations in the fragile X mental retardation gene (FMR1). The protein product of FMR1, fragile X mental retardation protein (FMRP) is an RNA-binding protein and may function as a translational suppressor. Metabotropic glutamate receptor-dependent long-term depression (mGluR-LTD) in hippocampal area CA1 is a form of synaptic plasticity that relies on dendritic protein synthesis. mGluR-LTD is enhanced in the mouse model of FXS, Fmr1 knockout (KO) mice, suggesting that FMRP negatively regulates translation of proteins required for LTD. Here we examine the synaptic and cellular mechanisms of mGluR-LTD in KO mice and find that mGluR-LTD no longer requires new protein synthesis, in contrast to wild-type (WT) mice. We further show that mGluR-LTD in KO and WT mice is associated with decreases in AMPA receptor (AMPAR) surface expression, indicating a similar postsynaptic expression mechanism. However, like LTD, mGluR-induced decreases in AMPAR surface expression in KO mice persist in protein synthesis inhibitors. These results are consistent with recent findings of elevated protein synthesis rates and synaptic protein levels in Fmr1 KO mice and suggest that these elevated levels of synaptic proteins are available to increase the persistence of LTD without de novo protein synthesis.

Extracellular Signal-Regulated Protein Kinase Activation Is Required for Metabotropic Glutamate Receptor-Dependent Long-Term Depression in Hippocampal Area CA1

Activation of group 1 metabotropic glutamate receptors (mGluRs) induces long-term depression (LTD) of synaptic transmission that relies on dendritic protein synthesis. We investigated the signal transduction pathways required for mGluR-LTD to identify candidate mechanisms for mGluR regulation of synaptic protein synthesis. Our results demonstrate a role for extracellular signal-regulated protein kinase (ERK), a subclass of the mitogen-activated protein kinases (MAPKs), in mGluR-LTD in area CA1 of the rat hippocampus. Inhibitors of the upstream kinase of ERK, MAP/ERK kinase significantly reduce mGluR-LTD induced by the group 1 agonist dihydroxyphenylglycine (DHPG) and synaptic stimulation but do not affect NMDA receptor-dependent LTD. In contrast, inhibitors of p38 MAPK were ineffective against DHPG-induced LTD. Consistent with the role of ERK in mGluR-LTD, we observed that DHPG treatment of hippocampal slices (isolated CA1), at concentrations that induce LTD, results in a robust phosphorylation of ERK but not of p38 MAPK. These results point to ERK as an important regulator of mGluR-LTD and a potential mechanism for mGluR regulation of synaptic protein synthesis.

12-Lipoxygenase Metabolites of Arachidonic Acid Mediate Metabotropic Glutamate Receptor-Dependent Long-Term Depression at Hippocampal CA3-CA1 Synapses

Arachidonic acid metabolites have been proposed as signaling molecules in hippocampal long-term potentiation (LTP) and long-term depression (LTD) for >15 years. However, the functional role of these molecules remains controversial. Here we used a multidisciplinary biochemical, electrophysiological, and genetic approach to examine the function of the 12-lipoxygenase metabolites of arachidonic acid in long-term synaptic plasticity at CA3-CA1 synapses. We found that the 12-lipoxygenase pathway is required for the induction of metabotropic glutamate receptor-dependent LTD (mGluR-LTD), but is not required for LTP: (1) Hippocampal homogenates were capable of synthesizing the 12-lipoxygenase metabolite of arachidonic acid, 12(S)-hydroxyeicosa-5Z,8Z,10E,14Z-tetraenoic acid (HETE). (2) Stimulation protocols that induce mGluR-LTD lead to a release of 12-(S)-HETE from acute hippocampal slices. (3) A mouse in which the leukocyte-type 12-lipoxygenase (the neuronal isoform) was deleted through homologous recombination was deficient in mGluR-LTD, but showed normal LTP. (4) Pharmacological inhibition of 12-lipoxygenase also blocked induction of mGluR-LTD. (5) Finally, direct application of 12(S)-HPETE, but not 15(S)-HPETE, to hippocampal slices induced a long-term depression of synaptic transmission that mimicked and occluded mGluR-LTD induced by synaptic stimulation. Thus, 12(S)-hydroperoxyeicosa-5Z, 8Z, 10E, 14Z-tetraenoic acid (12(S)-HPETE), a 12-lipoxygenase metabolite of arachidonic acid, satisfies all of the criteria of a messenger molecule that is actively recruited for the induction of mGluR-LTD.

Synaptically stimulated induction of group i metabotropic glutamate receptor-dependent long-term depression and depotentiation is inhibited by prior activation of metabotropic glutamate receptors and PROTEIN KINASE C

We have investigated metaplasticity of the group I metabotropic glutamate receptor (mGluR)-dependent long-term depression (LTD) and depotentiation (DP) induced by physiological synaptic stimulation in the medial perforant path of the dentate gyrus in vitro. Group I mGluR-LTD/DP was inhibited by prior preconditioning brief high frequency stimulation (HFS) if the preconditioning HFS induced long-term potentiation (LTP) or if the induction of LTP was inhibited by an NMDA receptor antagonist. The inhibitory effect of the preconditioning HFS on LTD/DP was dependent upon activation of mGluRs, as it was blocked by the presence of the mGluR antagonist ( S)-α-methyl-4-carboxyphenylglycine during the preconditioning stimulation. The inhibitory effect of the preconditioning HFS involved stimulation of PKC, as the presence of the PKC inhibitor bisindolylmaleimide (BIS) during the preconditioning stimulation prevented the inhibitory effect of such preconditioning stimulation. Activation of PKC was also necessary for the induction of mGluR-LTD itself, as the PKC inhibitor BIS prevented the induction of the mGluR-LTD. We suggest that the physiological stimulation of mGluRs by the preconditioning stimulation produces a PKC-dependent inactivation of subsequent group I mGluR functioning and thereby an inhibition of induction of group I mGluR-dependent LTD/DP induction.

Altered Presynaptic Vesicle Release and Cycling during mGluR-Dependent LTD

The site of modification of synaptic transmission during long-term plasticity in the mammalian hippocampus remains controversial. Here we used a fluorescent marker of presynaptic activity, FM 1-43, to directly image presynaptic function during metabotropic glutamate receptor-dependent long-term depression (mGluR-LTD) at CA3-CA1 excitatory synapses in acute hippocampal slices. We found a significant decrease in the rate of FM 1-43 release in response to synaptic stimulation following induction of mGluR-LTD, providing direct evidence for altered presynaptic function. Moreover, we found that mGluR-LTD causes several changes in FM dye release properties that are consistent with a change in the mode of vesicle cycling, possibly involving a switch from a full fusion mode of release to a “kiss-and-run” mode of release through the transient opening of a fusion pore.

Dual MAP kinase pathways mediate opposing forms of long-term plasticity at CA3-CA1 synapses.

Although the function of the p42/p44 mitogen-activated protein (MAP) kinase pathway in long-term potentiation at hippocampal CA3-CA1 synapses has been well described, relatively little is known about the importance of the p38 MAP kinase pathway in synaptic plasticity. Here we show that the p38 MAP kinase pathway, a parallel signaling cascade activated by distinct upstream kinases, mediates the induction of metabotropic glutamate receptor-dependent long-term depression at CA3-CA1 synapses. Thus, two parallel MAP kinase pathways contribute to opposing forms of long-term plasticity at a central synapse.