Modulation of learning processes by ionotropic glutamate receptor ligands

A great body of evidence has been provided for the role of N-methyl-d-aspartate (NMDA) receptors in learning processes, since the pioneering work of Morris et al. (1986) showing impairment of water maze learning and long-term potentiation (LTP) during i.c.v. infusion of the NMDA receptor antagonst 2-amino-5-phosphonovaleric acid (AP5). The existing literature, based on pharmacological studies, suggests the importance of NMDA receptors for the acquisition and/or the initial phase of long-term memory consolidation in many, but not all, learning paradigms. Data on short-term memory are inconsistent, probably due to difficulties in separation of learning deficits from performance. Although it is generally accepted that NMDA receptor antagonists impair learning, more recent data suggest that, under certain conditions, the opposite effect, enhancement of learning, can be obtained. The role of alpha-amino-3-hydroxy-5-methyl-4-isoxazole-propionic acid (AMPA) receptors in learning, although accepted in LTP, is less well documented. It has been suggested that positive modulation of these receptors could result in cognitive enhancement that might find therapeutic application. The present paper reviews the literature dealing with these issues and discusses possible consequences for the therapy of dementia.