The Role of Metabotropic Glutamate Receptor 5 in Learning and Memory Processes

Abstract

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.

Transcriptional profiling of the rat frontal cortex following administration of the mGlu5 receptor antagonists MPEP and MTEP

“…Many of these proteins are postsynaptic molecular substrates that underlie synaptic plasticity, which may explain the deleterious effects of mGlu5 antagonists on some forms of learning and memory (Simonyi et al, 2005). Despite the wellestablished fact that mGlu5 receptors are coupled to PKC signaling, we did not observe changes in the expression of any PKC isoforms.…”

H-Reflex Operant Conditioning in Mice

“…The greatest potential advantage of performing HR operant conditioning in mice is the availability of animals with mutations in, or genetic modifications to, pathways that are relevant to learning and memory (Elgersma et al 2004;Morgan 2003;Powell 2006;Simonyi et al 2005;Vaillend et al 2002). In addition, the availability of in vitro preparations of the lumbar spinal cord from adult mice offers the opportunity for electrophysiological studies into conditioning-induced changes in spinal neuronal properties (Biscoe and Duchen 1986;Chizh et al 1997;Fulton 1986).…”

“…In recent years, the availability and continuing development of mutant and genetically modified mice have enabled new approaches to the study of learning and memory (Elgersma et al 2004;Morgan 2003;Powell 2006;Simonyi et al 2005;Vaillend et al 2002). To make these experimental tools available to the study of HR operant conditioning, our laboratory has recently developed methods for long-term continuous HR recordings in mice (Carp et al 2005a).…”

Abnormal Mechanisms of Plasticity and Metaplasticity in Autism Spectrum Disorders and Fragile X Syndrome

“…Evidence both from animal FXS models (Simonyi et al 2005) (Huber et al 2002) and from studies in patients with FXS conducted in our laboratory indicate that loss of Fragile X mental retardation protein FMRP (the physiological consequence of the genetic mutation that leads to FXS) leads to abnormalities in synaptic plasticity. Apart from FXS, other animal ASD models also suggest a causal role for abnormal plasticity mechanisms (reviewed in Tordjman et al [2007]).…”