The general objectives of this research proposal are to establish the mechanisms that control the dendritic processing of incoming synaptic information. In most CNS neurons, incoming synaptic inputs are widely distributed across dendritic arborizations that are both morphologically and electrically complicated and it is in these dendrites that tens of thousands of excitatory and inhibitory synaptic inputs are blended together to generate a coherent output response. In hippocampal CA1 pyramidal neurons, 85% of excitatory synaptic input is received by radial oblique dendrites. These are relatively short, small diameter secondary branches off the main dendrite trunk whose morphology suggests they might provide a favorable site for highly non-linear forms of synaptic processing. At present very little is known about the active properties of these dendrites or of the properties of the synapses that are formed on them. We propose to test the central hypotheses that: specific properties of oblique dendrites and the synapses formed on them provide CA1 neurons with multiple modes of processing synaptic input. The key players in determining the form of synaptic integration in these cells should be both the spatio-temporal aspects of the input itself and the availability of the voltage-gated ion channels within the obliques. We have designed experiments using a variety of dendritic whole-cell patch-clamp and advanced optical recording techniques to determine 1) the types and properties of voltage-gated ion channels located in these branches, 2) the properties of the synaptic inputs to the branches 3) precisely how synaptic input and active channels interact to shape integration within the branches and 4) how physiologically-relevant channel modulation can produce different forms of synaptic processing, all the while trying to relate the findings to the naturally occurring functional states of the hippocampus. The information produced by these experiments should provide us with a greater understanding of how information processing proceeds in central neurons and therefore a more fundamental understanding of both normal and pathological brain functioning. ? ?
