Metabotropic glutamate receptor 5 (mGluR5), a subtype in the group I mGluRs, couples to phospholipase C through Gq protein. Stimulation of mGluR5 leads to the release of calcium from intracellular stores and protein kinase C activation. In addition, links to different ion channels and other signaling mechanisms have also been revealed. MGluR5s are mainly localized postsynaptically on the periphery of synap-ses. MGluR5s have been implicated in synaptic plasticity and learning and memory. The development of the highly potent and selective mGluR5 antagonist 2-methyl-6-(phenylethynyl)-pyridine (MPEP) has facilitated the understanding of the roles of mGluR5s in the central nervous system. Both in vitro and in vivo studies have demonstrated that the activation of mGluR5s is necessary for some forms of long-term potentiation and long-term depression in different brain regions. Investigations of the effects of MPEP in various behavioral paradigms have concluded that mGluR5s play a critical role in aversive learning tasks and in hippocampal-dependent spatial learning. However, MPEP has proved ineffective in certain other learning tasks. MGluR5 knockout mice have shown impairments in water maze and radial arm maze performance as well as in contextual fear conditioning, but not in cue conditioning. This review summarizes recent advances reported on mGluR5 function in synaptic plasticity, learning and memory. The current development of positive and negative allosteric modulators of mGluR5 will provide new pharmacological tools to enhance our knowledge of these receptors in physiological and pathophysiological processes and will further facilitate new investigations on mGluR5 as a therapeutic target for a range of neurological and psychological disorders.

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