When Are Class I Metabotropic Glutamate Receptors Necessary for Long-Term Potentiation?

Wilsch, Volker W.; Behnisch, Thomas; Jäger, Tino; Reymann, Klaus G.; Balschun, Detlef

doi:10.1523/jneurosci.18-16-06071.1998

Cited by 112 publications

(74 citation statements)

References 59 publications

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“…For instance, strong depolarization of the postsynaptic neuron may allow sufficient calcium entry via NMDARs to trigger the release of calcium via internal stores and initiation of the PKC/CAK␤/Src cascade to enhance NMDAR activity. Under this scheme, the calcium influx via NMDARs may override the necessity of calcium mobilization in response to mGluR5 stimulation (66). One must also consider the possibility that strong stimulation of mGluR5 may initiate the IP 3 R/PKC/CAK␤/Src cascade independently of NMDAR activity.…”

Section: Discussionmentioning

confidence: 99%

Co-stimulation of mGluR5 and N-Methyl-D-aspartate Receptors Is Required for Potentiation of Excitatory Synaptic Transmission in Hippocampal Neurons

Kotecha

Jackson

Al‐Mahrouki

et al. 2003

Journal of Biological Chemistry

100

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In the central nervous system, excitatory synaptic transmission is mediated by the neurotransmitter glutamate and its receptors. Interestingly, stimulation of group I metabotropic glutamate receptors (mGluRs) can either enhance or depress synaptic transmission at CA1 hippocampal synapses. Here we report that co-activation of mGluR5, a member of the group I mGluR family, and N-methyl-D-aspartate receptors (NMDARs) potentiates NMDAR currents and induces a long lasting enhancement of excitatory synaptic transmission in primary cultured hippocampal neurons. Unexpectedly, activation of mGluR5 alone fails to enhance evoked NMDAR currents and synaptic ␣-amino-3-hydroxy-5-methyl-4-isoxazolepropionate receptor (AMPAR) AM-PAR currents. The observed potentiation requires an mGluR5-induced, inositol 1,4,5-trisphosphate receptormediated mobilization of intracellular Ca 2؉ , which acts in concert with a protein kinase C, calcium-activated tyrosine kinase cascade to induce a long lasting enhancement of NMDAR and AMPAR currents.The transmitter glutamate, together with its postsynaptic receptors, mediates much of the excitatory neurotransmission in the central nervous system. Of these postsynaptic receptors, the NMDAR 1 is an ionotropic receptor implicated in neuronal development (1), synaptic plasticity (2), and excitotoxicity (3). In the pyramidal cell synapses of the CA1 region of the hippocampus, the NMDAR is composed of at least one NR1 subunit as well as multiple NR2B or NR2A subunits (4). These postsynaptic NMDARs are associated with a complex of proteins (the "NMDAR complex"), which includes the scaffolding proteins PSD-95, Homer, Shank, and GKAP as well as a number of serine/threonine and tyrosine kinases and phosphatases (5). Furthermore, other receptors, including mGluR and IP 3 R are potentially linked to this complex (6). The presence and activity of many of these proteins is integral for LTP and LTD, which are the leading cellular and molecular models for learning and memory (7).Glutamate also activates postsynaptic mGluRs, which are coupled via G-protein activation to intracellular signaling cascades. Eight mGluRs have been cloned, and they are classified into three groups (I, II, and III) based upon sequence homology, similarities in signal transduction cascades, and pharmacological profiles (8). The group I metabotropic glutamate receptor, mGluR5, is positively coupled to phospholipase C␤ activity (9), PKC, and mobilization of intracellular calcium via IP 3 Rs. Of the group I mGluRs, mGluR5 expression in the CA1 hippocampus has been found to be localized to extrasynaptic and perisynaptic sites (10, 11) of CA1 pyramidal neurons, whereas mGluR1 is not highly expressed in CA1 pyramidal neurons and is more predominantly expressed in interneurons (12). Recent evidence demonstrates that mGluR1 and mGluR5 play separate functional roles, via activation of distinct intracellular signaling pathways in CA1 pyramidal neurons (13).Group I mGluRs can either enhance or depress excitatory synapses (14). The mechanisms by which ...

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Section: Discussionmentioning

confidence: 99%

Co-stimulation of mGluR5 and N-Methyl-D-aspartate Receptors Is Required for Potentiation of Excitatory Synaptic Transmission in Hippocampal Neurons

Kotecha

Jackson

Al‐Mahrouki

et al. 2003

Journal of Biological Chemistry

100

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“…This indicates that maximal glutamate stimulation or depolarization elicits Ca 2ϩ signals sufficient to activate PLC␦ and thus to produce the necessary DAG for PKC␥ activation. This Ca 2ϩ -triggered production of DAG may explain how PKC␥ can be activated during LTP protocols that do not involve coactivation of mGluRs (Wilsch et al, 1998).…”

Section: Maximal Activation Of Iglurs Is Sufficient To Promote Dag Prmentioning

confidence: 99%

“…The role of mGluRs in synaptic plasticity has been mostly discussed as a means to release Ca 2ϩ from IP 3 -sensitive stores, leading to increases in [Ca 2ϩ ] i within the spine (Wilsch et al, 1998;Kotecha et al, 2003). This view reflects the widely accepted notion that the extent of [Ca 2ϩ ] i elevation represents a major determinant in the induction of synaptic plasticity (Lynch et al, 1983;Malenka and Nicoll, 1999;Lamprecht and LeDoux, 2004;Malenka and Bear, 2004).…”

Section: Synergistic Activation Of Pkc␥ After Iglur and Mglur Stimulamentioning

confidence: 99%

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Synergistic Control of Protein Kinase Cγ Activity by Ionotropic and Metabotropic Glutamate Receptor Inputs in Hippocampal Neurons

Codazzi¹,

Cesare²,

Chiulli³

et al. 2006

J. Neurosci.

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Conventional protein kinase C (PKC) isoforms are abundant neuronal signaling proteins with important roles in regulating synaptic plasticity and other neuronal processes. Here, we investigate the role of ionotropic and metabotropic glutamate receptor (iGluR and mGluR, respectively) activation on the generation of Ca 2ϩ and diacylglycerol (DAG) signals and the subsequent activation of the neuronspecific PKC␥ isoform in hippocampal neurons. By combining Ca 2ϩ imaging with total internal reflection microscopy analysis of specific biosensors, we show that elevation of both Ca 2ϩ and DAG is necessary for sustained translocation and activation of EGFP (enhanced green fluorescent protein)-PKC␥. Both DAG production and PKC␥ translocation were localized processes, typically observed within discrete microdomains along the dendritic branches. Markedly, intermediate-strength NMDA receptor (NMDAR) activation or moderate electrical stimulation generated Ca 2ϩ but no DAG signals, whereas mGluR activation generated DAG but no Ca 2ϩ signals. Both receptors were needed for PKC␥ activation. This suggests that a coincidence detection process exists between iGluRs and mGluRs that relies on a molecular coincidence detection process based on the corequirement of Ca 2ϩ and DAG for PKC␥ activation. Nevertheless, the requirement for costimulation with mGluRs could be overcome for maximal NMDAR stimulation through a direct production of DAG via activation of the Ca 2ϩ -sensitive PLC␦ (phospholipase C␦) isoform. In a second important exception, mGluRs were sufficient for PKC␥ activation in neurons in which Ca 2ϩ stores were loaded by previous electrical activity. Together, the dual activation requirement for PKC␥ provides a plausible molecular interpretation for different synergistic contributions of mGluRs to long-term potentiation and other synaptic plasticity processes.

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“…This, in turn, is used for the synthesis of phosphatidylinositol and the replenishment of the precursor by phosphorylations to phosphatidylinositol 4-phosphate (PIP) and PIP 2 . Activation of inositide lipid signaling through mGluR1 and PKC is involved in synaptic plasticity such as in learning, memory, LTP (15)(16)(17)(18)(19)(20), and long-term depression (21). Moreover, alterations of this signaling have been implicated in neurological and psychiatric diseases such as epilepsia, Alzheimer's disease, and depression (2,22,23).…”

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confidence: 99%

Diacylglycerol kinase ɛ regulates seizure susceptibility and long-term potentiation through arachidonoyl– inositol lipid signaling

Turco

Tang

Topham

et al. 2001

Proc. Natl. Acad. Sci. U.S.A.

152

167

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Arachidonoyldiacylglycerol (20:4-DAG) is a second messenger derived from phosphatidylinositol 4,5-bisphosphate and generated by stimulation of glutamate metabotropic receptors linked to G proteins and activation of phospholipase C. 20:4-DAG signaling is terminated by its phosphorylation to phosphatidic acid, catalyzed by diacylglycerol kinase (DGK). We have cloned the murine DGK gene that showed, when expressed in COS-7 cells, selectivity for 20:4-DAG. The significance of DGK in synaptic function was investigated in mice with targeted disruption of the DGK . DGK ؊/؊ mice showed a higher resistance to eletroconvulsive shock with shorter tonic seizures and faster recovery than DGK ؉/؉ mice. The phosphatidylinositol 4,5-bisphosphate-signaling pathway in cerebral cortex was greatly affected, leading to lower accumulation of 20:4-DAG and free 20:4. Also, long-term potentiation was attenuated in perforant path-dentate granular cell synapses. We propose that DGK contributes to modulate neuronal signaling pathways linked to synaptic activity, neuronal plasticity, and epileptogenesis.

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When Are Class I Metabotropic Glutamate Receptors Necessary for Long-Term Potentiation?

Cited by 112 publications

References 59 publications

Co-stimulation of mGluR5 and N-Methyl-D-aspartate Receptors Is Required for Potentiation of Excitatory Synaptic Transmission in Hippocampal Neurons

Co-stimulation of mGluR5 and N-Methyl-D-aspartate Receptors Is Required for Potentiation of Excitatory Synaptic Transmission in Hippocampal Neurons

Synergistic Control of Protein Kinase Cγ Activity by Ionotropic and Metabotropic Glutamate Receptor Inputs in Hippocampal Neurons

Diacylglycerol kinase ɛ regulates seizure susceptibility and long-term potentiation through arachidonoyl– inositol lipid signaling

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