Review articleGlutamate receptor function in learning and memory
Introduction
Glutamate is the major excitatory neurotransmitter in the central nervous system. Since its discovery [175], it has attracted an armada of researchers to investigate its function in various processes including neuronal development, neurotoxicity, or various models of neuronal plasticity as possible cellular substrates for learning, to name but a few.
Summarising our current knowledge of the different families of glutamate receptors and the increasing number of emerging subtypes would mean writing a book. Therefore, the aim of this review is to provide an overview of data available to date that are related to the understanding of the role of glutamate and its different receptor subtypes in learning and memory, mainly based on psychopharmacological in vivo studies. In order to help new researchers and students to understand the basics, we have included brief descriptions of the basic physiological and pharmacological properties of glutamate receptors and relevant drugs. However, the drugs discussed here are limited to those which have been tested in learning experiments, and psychological descriptions concentrate on how to define the various processes underlying learning and memory formation. Space limitations also restrict the details outlined for experimental procedures. Since we concentrate on the behavioural role of glutamate receptors, we have decided to exclude many ‘cellular’ research results, and include literature on long-term potentiation (LTP) and long-term depression (LTD), the most commonly used models for the cellular mechanisms underlying memory formation, only when directly relevant. Evidence for the potential role of the different glutamate receptor subtypes in LTP and LTD has been reviewed elsewhere (e.g. [35], [47], [411]). It should be noted, however, that data obtained from electrophysiological experiments both in vitro and in vivo have been very influential for psychopharmacological investigations on glutamate receptor function in learning. Such experiments have provided considerable insight into the pharmacological properties of glutamate receptors and hence given useful information about actions of specific agonists and antagonists.
In recent years, advances in molecular and biochemical techniques have also contributed considerably to the detailed picture about glutamate receptor composition, function and physiology. Although a description of such experiments would be interesting, it does not directly enhance our understanding of glutamate receptor functions in learning. Thus, only some of the molecular results with direct implications for the understanding of behavioural functions of glutamate receptors will be mentioned. Considerable advances have also been reported for the role of glutamate receptors in several forms of diseases, including dissociative thought disorder, schizophrenia or various other forms of dementia such as Alzheimer's disease. These advances have been reviewed (e.g. [127], [373]) and will not form a major part of this paper.
Section snippets
Glutamate receptors
Synaptic transmission via glutamate receptors supplies the excitatory drive for the highways formed by projection neurones that connect the principal regions of the brain [419]. Both ionotropic (iGluR, ion channel coupled) and metabotropic (mGluR, second messenger coupled) receptors are differentially distributed on pre- and postsynaptic sites to contribute to neuronal communication and signal processing, functions that determine learning and memory formation [498], [499].
Fast transmission is
Structure, localisation and pharmacology of mGluRs
In the mid-1980s, it became apparent that glutamate, apart from its fast action on iGluR, also activates G-protein coupled receptors linked to various intracellular second messenger cascades. The first to be described was an mGluR response leading to glutamate-stimulated phosphoinositide hydrolysis in cultured striatal neurones [473]. mGluRs were also detected in brain slices [343] and cloned [195], [286]. Quickly, a complete family of mGluRs emerged [506] and it currently consists of eight
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