Dendrites constitute the input structure of most neurons in the central nervous system. These elaborately branching structures receive tens of thousands of synaptic inputs, which produce synaptic potentials-transient changes in the membrane potential of the neuron that are processed by the dendrites passed on to the axon. In response to this synaptic integration, the axon produces an output in the form of an action potential, when appropriate. The complexity of this dendrite processing is determined by many factors, including the structure of the dendrites, the properties and distribution of synapses and neurotransmitter-gated ion channels, as well as the properties and distribution of voltage-gated ion channels. Defects in dendritic structure and function have been linked to neural diseases such as epilepsy, Parkinson's disease, and schizophrenia. Furthermore, much of the synaptic restructuring (synaptic plasticity) believed to underlie learning takes place in dendrites, and therefore may be affected by the dendritic abnormalities present in disorders characterized by deficiencies in learning and memory, such as Alzheimer's disease and Down's syndrome. Several recent studies have demonstrated that dendrites contain voltage- gated ion channels, which actively shape the response of a neuron to synaptic input, providing neurons with the potential to perform complex computations in the process of converting inputs and outputs. We and others have found that these channels mediate several different forms of dendritic excitability. This proposal explores three hypotheses related to the role of dendritic excitability in synaptic integration and plasticity: 1) That dendritic excitability is involved in the induction of synaptic plasticity, 2) That dendritic excitability itself can be modified by activity, and 3) That dendritic excitability can be modulated by neurotransmitter systems. We will test these hypotheses by applying dendritic patch-clamp recording and Ca 2+ -imaging methods to CA1 pyramid neurons in the hippocampal slice preparation. In addition to exploring the role of dendritic excitability in the synaptic plasticity underlying, these studies explore the idea that changes in dendritic excitability can modify the input -output function of a neuron, which may constitute another form of learning at the cellular level. Thus, these studies test the hypothesis that dendritic excitability is functionally important, both locally in the dendrites (triggering changes in synaptic strength) and at the output of the neuron, in the soma and axon, increasing the probability that an axonal potential will be produced.
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