GLUTAMATE RECEPTORS, LONG TERM POTENTIATION AND AGING

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The mechanisms underlying human memory are poorly understood but of importance to understanding the pathophysiology of Alzheimer's disease (AD) and other neurodegenerative disorders. Currently it is believed that memory involves changes in the efficacy of synaptic transmission and that long-term potentiation (LTP), a long-lived use-dependent enhancement of synaptic responses which follows brief high frequency activation of certain neural pathways, is a potential physiological process involved in memory. In certain regions of the central nervous system, LTP is critically dependent on activation of N-methyl-D-aspartate (NMDA) receptors and the influx of calcium into postsynaptic neurons. Calcium, in turn, is thought to activate a cascade of biochemical events leading to the pre- and postsynaptic changes which enhance synaptic transmission. Relevant to the memory deficits of dementing illnesses, a number of fundamental questions about LTP remain. These include uncertainties regarding how LTP changes as a function of aging, how changes in the extracellular concentration of excitatory amino acids (EAA) which can vary with disease state affect LTP, and whether modulatory transmitter systems which are altered in neurodegenerative diseases are involved in LTP at various ages. in the proposed studies we will investigate these issues using intra- and extracellular electrophysiological recordings from the CA1 region of in vitro rat hippocampal slices. In the first set of experiments we will examine the role of NMDA and metabotropic glutamate receptors in LTP in hippocampal slices prepared from rats of various postnatal ages, ranging from neonates to aged adults. A second set of experiments will examine the effects of low-level activation of EAA receptors on LTP generation. These studies will extend our preliminary observation that low micromolar concentrations of NMDA block LTP if given in the period immediately preceding or following high frequency synaptic stimulation. Finally, we will examine whether certain neuromodulators participate in LTP as a function of aging and whether these neuromodulators alter the NMDA-mediated inhibition of LTP. In these studies we will concentrate on norepinephrine, acetylcholine and dopamine, transmitter systems known to innervate the CA1 region and known to be affected in AD. These studies have the potential to provide information concerning the effects of aging on LTP generation and possibly on the memory deficits in dementing illnesses.