The most fundamental roles of nerve cells are the detection of chemical neurotransmitters to generate synaptic potentials; the summation of these potentials to create their output signals; and the consequent release of their own neurotransmitter molecules. All of these functions require the orchestrated work of hundreds of molecules targeted to specialized regions of the cells. In nerve cells, more than in any other cell type, a single molecule could fulfill very different functional roles depending on its subcellular location. For example, dendritic voltage-gated Ca2+ channels play a role in the integration and plasticity of synaptic inputs, whereas the same channels when concentrated in presynaptic active zones are essential for neurotransmitter release. Thus, the function of a protein in nerve cells cannot be understood from its expression or lack of it, but its precise subcellular location, density and molecular environment needs to be determined. The major aim of the present proposal is to create a quantitative molecular map of the surface of hippocampal pyramidal cells (PCs). We will start by examining voltage-gated ion channels due to their pivotal roles in input summation, output generation and neurotransmitter release. We will apply high resolution quantitative molecular neuroanatomical techniques to reveal their densities in 19 different axo-somato-dendritic plasma membrane compartments of CA1 PCs. Functional predictions will be generated using detailed, morphologically realistic multicompartmental PC models with experimentally determined ion channel distributions and densities. Such predictions will be tested by combining in vitro patch-clamp electrophysiology and imaging techniques with correlated light- and electron microscopy. Our results will provide the first quantitative molecular map of the neuronal surface and will reveal new mechanisms that increase the computational power and the functional diversity of nerve cells.
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