Calcium entry and accumulation in neurons are involved in several cellular processes, including direct control of electroresponsiveness; indirect control of membrane potential by activation of other ionic conductances; neurotransmitter release; intracellular control of enzyme systems; and plasticity of synaptic transmission. Modulation of Ca2+ entry and accumulation in neurons, therefore, may have effects on many facets of cellular function. This proposal is aimed at extending findings that beta-adrenergic and muscarinic cholinergic agonists modulate voltage-gated Ca2+ channels in granule cells and CA3 pyramidal cells in the guinea-pig hippocampal formation to the investigation of Ca2+-channel modulation in CA1 pyramidal neurons and mossy-fiber presynaptic terminals. There have been increasing suggestions that activation of the NMDA class of glutamate receptor may affect voltage-gated Ca2+ channels. The experiments proposed here address some fundamental questions about possible interactions of NMDA receptors and voltage-gated Ca2+ channels. If it is found that increased levels of intracellular Ca2+, caused either by Ca2+ entry through NMDA-gated channels or other means, can lead to a subsequent increase in Ca2+-channel activity, this could have significant implications for neuronal function. Several pathological conditions that cause increased Ca2+ accumulation such as anoxia or seizure activity could be exacerbated by such a positive feedback mechanism of Ca2+ influx. Calcium entry through voltage-gated calcium channels at presynaptic terminals is believed to be the requisite first step in the initiation of neurotransmitter release at virtually all synapses in the central nervous system. Although the properties of somatic calcium channels have been described in many preparations, there is little direct evidence supporting the hypothesis that somatic and synaptic terminal calcium channels have similar properties. This hypothesis will be tested directly by comparing the properties of calcium channels in mossy fiber synaptic terminals to those in the cell body that gives rise to the terminal the dentate granule cell, and to the other principle cell types in the hippocampus.
