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

Suhas A Kotecha,Michael F Jackson,Azza Al-Mahrouki,John C Roder,Beverley A Orser,John F Macdonald

doi:10.1074/jbc.m301946200

Abstract

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 alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionate receptor (AMPAR) AMPAR currents. The observed potentiation requires an mGluR5-induced, inositol 1,4,5-trisphosphate receptor-mediated mobilization of intracellular Ca2+, 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.

Highlights

Ber of serine/threonine and tyrosine kinases and phosphatases [5]
The objective of the present study was to elucidate the mechanism by which mGluR5 modulates N-methyl-D-aspartate receptors (NMDARs) and excitatory synaptic transmission
An understanding of the mechanism by which mGluR5 modulates ionotropic glutamate receptors is of particular interest, because Group I metabotropic glutamate receptors (mGluRs) have been reported to both potentiate and, paradoxically, depress excitatory synaptic transmission in the CA1 hippocampus [30]

Summary

Introduction

Ber of serine/threonine and tyrosine kinases and phosphatases [5]. other receptors, including mGluR and IP3R are potentially linked to this complex [6]. 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 proevidence demonstrates that mGluR1 and mGluR5 play separate functional roles, via activation of distinct intracellular signaling pathways in CA1 pyramidal neurons [13]. At many hippocampal synapses low frequency afferent stimulation induces LTD, but brief high frequency stimulation leads to LTP even though both forms of synaptic plasticity require an influx of postsynaptic calcium via NMDARs. In hippocampal slices [17,18,19] and cultures (14, 20 –22) bath applications of either NMDA or of a group I mGluR agonist induce LTD, but not LTP, and enhance AMPA receptor endocytosis [14, 23,24,25]. In the present study we set out to delineate the mechanism by which group I mGluRs modulate NMDA channel activity

Objectives

Methods

Results

Conclusion