Several cellular factors--with profoundly different spatial and temporal properties--contribute to the ability of dendrites to integrate and shape synaptic responses in neurons. The primary goal of this project will be to investigate how Ca2+ release from intracellular stores in hippocampal CA1 and CA3 pyramidal neurons contributes to dendritic function. To accomplish this goal we will use whole-cell patch-clamp recording and high-speed fluorescence imaging in slices from adult (>6 weeks old) mice and rats. The underlying theme is that internal Ca2+ release, and consequent propagation of intracellular Ca2+ waves, is not only capable of contributing to synaptic plasticity such that occurs with long-term potentiation (LTP) and long-term depression (LTD), but also provides a temporally unique and biochemically robust means for communication within individual neurons. In addition to investigating internal Ca2+ release, we propose to examine whether Ca2+ release modulates ion-gated and ligand-gated channels, and how this modulation affects dendritic function and synaptic integration. More specifically, our first aim will be to continue studies characterizing the basic properties of synaptically evoked internal Ca2+ release in hippocampal neurons under physiologically realistic conditions. We will also test the hypothesis that kainate receptor-activation can lead to internal Ca2+ release via metabotropic receptor activation. In the second aim we will investigate the hypothesis that an increase in InsP3 at hippocampal mossy fiber synapses, and consequent internal Ca2+ release, is capable of inducing long-term changes in synaptic strength such that occurs with LTP and LTD. In the third aim we will examine whether internal Ca2+ release and Ca2+ waves can modulate backpropagating action potentials and ligand-gated channels, and if so, determine how this modulation contributes to dendritic function and synaptic integration, particularly as it relates to modifying input from convergent subsets of synapses on pyramidal neurons. More generally, the results of these experiments will provide essential information concerning the functional properties of hippocampal pyramidal neurons, and will also clarify at a more global level the cellular mechanisms underlying information processing by single neurons in the hippocampus.
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