Age-related memory impairment and L-type calcium channel expression in the hippocampus

It is well established that the hippocampus is critical for spatial memory formation in rodents. Furthermore, it is thought that long-term potentiation (LTP) in the hippocampus represents a cellular mechanism of memory formation. During aging, spatial memory ability and hippocampal LTP decline and many features of hippocampal cell excitability are altered.; The calcium (Ca2+) hypothesis of aging states that age-related alterations in neuronal Ca2+ homeostasis may be responsible for the alterations in hippocampal synaptic plasticity and the cognitive decline so frequently observed in aging. Interestingly, Ca2+ currents through L-type voltage-sensitive calcium channels (L-VSCCs) are increased in CA1 neurons of the hippocampus of aged rats. We and others have speculated that excessive Ca2+ influx though L-VSCC may be detrimental to hippocampal synaptic plasticity and memory formation. The goal of this thesis was to investigate expression of the Ca2+ conducting L-VSCC subunit proteins α_1C (Ca_V1.2) and α _1D (Ca_V1.3) in the hippocampus of aged rats and their relationship to spatial memory. In addition, we have studied the effects of chronic treatment with the L-VSCC antagonist nimodipine (NIM) on working memory and α _1D expression in the aged hippocampus. Lastly, we have determined the functional, membrane-associated fraction of α_1C subunit proteins in area CA1 of the hippocampus.; We find that expression of the L-VSCC subunit α_1D is selectively increased in area CA1 of aged rats, where its expression correlates with working memory impairment. Chronic NIM treatment ameliorates both age-related working memory deficits and increased expression of α_1D protein in the hippocampus. In area CA1, a large fraction of α_1C protein is membrane-associated and in aging the functional pool of α _1C is increased.; The present results suggest that L-VSCCs participate in processes underlying memory formation and that increases in L-VSCC protein expression in the aged hippocampus may play a role in age-related memory decline. Furthermore, the amelioration in age-related memory decline produced by NIM treatment may be mediated, at least in part, by reductions in the abnormally high levels of α _1D protein in the aged hippocampus. These findings may have implications for patients with Alzheimer's disease, who show increased L-VSCC protein expression in the hippocampus.