Review
Metabotropic glutamate receptor subtype 5 antagonism in learning and memory

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Abstract

The role of the metabotropic glutamate receptor 5 (mGlu5 receptor) in learning and memory and other behaviors are reviewed by examining the influence of selective antagonists and genetic knockout on performance. This receptor is involved in spatial learning, contextual fear conditioning, inhibitory avoidance, fear potentiated startle, and conditioned taste aversion. However, mGlu5 receptor antagonists have proven to be ineffective in other learning tasks, such as the delayed-match-to-position test and a three-hole spatial learning task. Locomotion is often decreased by mGlu5 receptor antagonists; and other behaviors such as social interaction and consummatory responses can also be affected. In mGlu5 receptor knockout mice, performance in contextual fear conditioning and spatial water maze tasks is impaired. Although the available evidence is suggestive of an important contribution of mGlu5 receptors to cognitive functions, further studies are needed, particularly those with in vivo evaluation of the role of mGlu5 receptors in selective brain regions in different stages of memory formation.

Introduction

Metabotropic glutamate receptor 5 (mGlu5 receptor), a subtype in the group I mGlu receptors, was cloned in 1992 (Abe et al., 1992) and, like the other mGlu receptor subtypes, it is a member of the family 3/C G-protein coupled receptors. The structure and the function of mGlu5 receptors have been reviewed in several articles (see Conn et al., 2005, Hermans & Challis, 2001, Pin & Acher, 2002, Spooren et al., 2003). In this introduction, we will briefly describe some basic features of mGlu5 receptors. Their roles in learning and memory processes will be reviewed in detail.

The mGlu5 receptor has a large N-terminal domain, which contains the glutamate binding side, seven transmembrane-spanning regions that are connected by three extracellular and three intracellular loops, a cysteine-rich domain and an intracellular C-terminal domain (Hermans and Challis, 2001). The receptor is a covalently bound homodimer and interacts with a variety of cytoskeletal, scaffolding and signaling proteins (Fagni et al., 2004, Ferraguti & Shigemoto, 2006, Romano et al., 1996b). Although mGlu5 receptor activation primarily couples to the stimulation of phospholipase C, which leads to the release of calcium from intracellular sources and protein kinase C activation, the signaling cascades of the mGlu5 receptor are much more complex. Multiple mGlu5 receptor-associated signaling pathways, both G-protein-dependent and -independent, have been identified (Gerber et al., 2006, Hermans & Challis, 2001). Some of these have been linked to mGlu5 receptor-dependent forms of synaptic plasticity (Simonyi et al., 2005). However, their contribution to distinct memory stages (acquisition, consolidation, retrieval, extinction, reconsolidation) in different brain regions has yet to be elucidated. In this review, we will summarize psychopharmacological studies using mGlu5 receptor antagonists and knockout animals, and, in doing so, summarize the presently available data on the role of mGlu5 receptors in learning and memory.

Section snippets

Distribution of mGlu5 receptors in the central nervous system

MGlu5 receptors are expressed in two splice variants (mGlu5a and mGlu5b). They differ by a 32-amino acid insert in the intracellular C-terminal domain of mGlu5b receptor (Minakami et al., 1995). The two splice variants are co-expressed in most brain areas, but the mGlu5b receptor predominates in the adult brain (Joly et al., 1995, Romano et al., 1996a). MGlu5 receptors are mainly localized in postsynaptic elements, and highly targeted to perisynaptic regions (Lujan et al., 1997, Shigemoto et

mGlu5 receptor antagonists

The first selective antagonists of mGlu5 receptors were 6-methyl-2-(phenylazo)-pyridinol (SIB-1757) and (E)-2-methyl-6-(phenylethenyl)pyridine (SIB-1893) (Varney et al., 1999). Their discovery led to the development of the systemically active, non-competitive antagonist 2-methyl-6-(phenylethynyle)pyridine (MPEP) (Gasparini et al., 1999). The IC50 value of MPEP is 36 nM. Intraperitoneal injection of a 10 mg/kg dose can reach 100% receptor occupancy in an hour; then returns to the baseline over a

mGlu5 receptors in spatial learning

Spatial learning requires memory processing in the hippocampus, a brain region with high levels of mGlu5 receptors. The first evidence for the role of mGlu5 receptors in spatial learning comes from studies with mGlu5 receptor knockout animals using the Morris water maze (Lu et al., 1997). In this task, knockout mice showed impeded acquisition and poor long-term retention. Similar results were found recently with a newly generated null mutant (Xu et al., 2009). However, mGlu5 receptor antagonism

Concluding remarks

In the past several years, significant progress in behavioral pharmacology of mGlu5 receptor has been made. Data suggest that the involvement of mGlu5 receptor in learning and memory is task specific (Table 1). The mGlu5 receptor has a pivotal role in aversive learning and it is especially important for memory acquisition in avoidance and fear learning tasks. However, there is also some suggestion of a role of the mGlu5 receptor in the consolidation and expression of fear memories. In other

Acknowledgments

Support was provided in part by R01 MH59039-01 and MH64486-01A1 from NIH.

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