Pharmacological manipulation of mGlu2 receptors influences cognitive performance in the rodent

Abstract

Atrophy of the medial temporal lobes, including the glutamatergic cortical-hippocampal circuitry, is an early event in Alzheimer’s disease (AD) and probably contributes to the characteristic short-term mnemonic decline. Pharmacological strategies directly targeted to ameliorating this functional decline may represent a novel approach for the symptomatic treatment of AD. Presynaptic group II metabotropic glutamate receptors (i.e. mGlu2 and mGlu3) exert a powerful modulatory influence on the function of these pathways, in particular the perforant pathway. Using a combination of mGlu2 receptor knockout mice and the group II agonist LY354740, we show that activation of mGlu2 receptors produces a cognitive impairment, i.e. a delay-dependent deficit in delayed matching and non-matching to position, and impaired spatial learning in a Morris water maze. Conversely, a group II antagonist, LY341495, improved acquisition of spatial learning. LY354740 potently reduced field excitatory postsynaptic potentials in hippocampal slices from wild type but not mGlu2 receptor knockout mice. Taken together, these results suggest that activation of mGlu2 receptors evokes a powerful inhibitory effect on hippocampal synaptic transmission and mGlu2 agonists produce a cognitive deficit consistent with this change. Conversely, mGlu2 receptor antagonists may improve certain aspects of cognition and thus represent a novel approach for the symptomatic treatment of AD.

Introduction

The major excitatory neurotransmitter, glutamate, activates both ionotropic—AMPA, kainate and NMDA—receptors and a family of G-protein-coupled metabotropic glutamate receptors (mGlu receptors). Whilst fast excitatory transmission is mediated via the ionotropic receptors, mGlu receptor activation can modulate neuronal excitability and synaptic transmission. Eight mGlu receptors have now been cloned, which can be divided into three groups according to their amino acid sequence identity: group I receptors, mGlu 1 and 5; group II receptors, mGlu 2 and 3; and group III receptors, mGlu 4, 6, 7 and 8 (Conn and Pin, 1997).

Whereas group I mGlu receptors are primarily localised postsynaptically, groups II and III receptors are typically presynaptic and can regulate neurotransmitter release (Cartmell and Schoepp, 2000). Of the group II mGlu receptors, mGlu3 is highly expressed in glia whilst mGlu2 is largely neuronal (Ohishi et al., 1993b, Ohishi et al., 1993a, Ohishi et al., 1994, Yokoi et al., 1996). In accordance with the distribution of mGlu2 mRNA (Ohishi et al., 1993b), immunohistochemical studies indicate that the mGlu2 receptor exhibits a regionally distinct expression pattern in adult brain with high levels in areas including the olfactory bulb, cerebellar cortex, caudate-putamen, cerebral cortex and the terminal fields of the perforant path input from the entorhinal cortex in the hippocampus (Neki et al., 1996, Shigemoto et al., 1997, Ohishi et al., 1998, Shigemoto and Mizuno, 2000). Furthermore, high binding densities of the group II selective agonists [³H]-DCG IV (Mutel et al., 1998, Wichmann et al., 2000) and [³H]-LY354740 (Schaffhauser et al., 1998) have been demonstrated by radioautography in these regions. Considerable pharmacological evidence suggests that group II mGlu receptors can markedly inhibit synaptic transmission (Anwyl, 1999, Cartmell and Schoepp, 2000) and the reported activity-dependent activation of presynaptic group II metabotropic autoreceptors by synaptically released glutamate at hippocampal mossy fibre (Scanziani et al., 1997) and perforant path synapses (Kew et al., 2001, Kew et al., 2002) indicates that these receptors may limit excitatory neurotransmission under conditions of high frequency repetitive activation.

The perforant path provides the major neuronal input to the hippocampus from the entorhinal cortex and, thus, relays multimodal sensory information derived from cortical zones (Jones, 1993). Studies in humans as well as rodent and primate models have identified a critical role of the perforant path and associated temporal lobe structures in declarative memory formation (Squire and Zola-Morgan, 1991, Milner et al., 1998, Eichenbaum, 2000). For instance, bilateral lesions to the perforant path in rats produces robust deficits in spatial learning and delayed recall measured using an operant delayed matching paradigm (Skelton and McNamara, 1992, Kirkby and Higgins, 1998). Since the mGlu2 receptor is expressed at high levels in these and other regions likely to play critical roles in learning and memory, we have examined the effects of the selective group II agonist LY354740, its inactive enantiomer, LY366563 (Monn et al., 1997), and the group II selective mGlu antagonist, LY341495 (Kingston et al., 1998, Ornstein et al., 1998), in a rat operant delayed match and non-match to position task (Dunnett, 1985) and the Morris water maze task using both wild type and mGlu2−/− mice (Yokoi et al., 1996). Some of this work has previously been published in the form of an abstract (Ballard et al., 2001, Ballard et al., 2002).