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

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 ␣-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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“…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).…”

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