Glutamatergic contributions to hippocampal function in senescent rats

Abstract

This dissertation focuses on the effect of aging on the hippocampal glutamatergic system and how modulation of this system affects age-related deficits. Previous studies have shown that the function of glutamatergic system changes with age in a region-specific and receptor-specific manner. The glutamate response ratio in the dentate gyrus increases with age, which might be due to a fixed developmental process or accumulated experience over the lifespan. To address these possibilities, young rats were given one of three different treatments: standard single housing; wheel running and pair-housing; or enriched environment housing. The enrichment-treated rats learned the spatial version of the Morris swim task significantly more rapidly than did the other two groups. Neither the ratio of AMPAR- vs NMDAR-mediated field EPSP amplitudes, nor AMPAR- vs NMDAR-mediated slope conductance measured with whole-cell patch clamp recording differed significantly between groups. These results suggest that the change in the glutamate response ratio in the dentate gyrus over the lifespan is developmentally regulated. Hippocampal complex-spike cells exhibit place-specific firing, and these hippocampal place representations in young rats expand following repeated traversals of a route. The place field expansion is suggested to be important for sequence learning, and is glutamatergic system-dependent. The expansion, however, is less robust in aged rats. One question is whether the place field expansion in old rats can be restored by the application of AMPAR modulator, CX516. Injections of 35mg/kg CX516 did not result in changes in firing characteristics of CA1 pyramidal neuron ensembles, including place field expansion. Aged rats were tested using two versions of the Morris swim task. There was no drug effect on initial learning or memory of the platform location, nor on spatial learning in new visuospatial contexts after extensive training. Spatial memory in aged rats was also assessed using a radial arm maze task. CX516 facilitated memory retrieval but did not affect acquisition or consolidation processes. Thus, administration of 35mg/kg CX516 appeared to have limited effect on spatial memory performance of old rats, and did not affect place field plasticity, suggesting that this short-term plasticity may, in part, share different mechanisms with LTP.