NEUROTROPHIC REGULATION OF NEURONAL SIGNALING

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DESCRIPTION: (Applicant's Abstract) Tremendous progress has been made in identifying new neurotrophic factors in their receptors, and in characterizing their roles in neuronal survival and differentiation. Not surprisingly, abnormalities in neurotrophic interactions have been implicated in several neurological disorders including epilepsy and Parkinson's disease. However, current understanding of the neurotrophic regulation of the basic neuronal functions that underlie these processes and disorders, such as neuronal signaling, remains quite limited. The goal of this research proposal is to understand how neurotrophic factors regulate neuronal excitability and synaptic transmission. The experimental approach will be to study how the expression and function of individual ion channels and neurotransmitter receptors are regulated by defined neurotrophic factors. The specific aims are: 1) To test the hypothesis that trk receptors determine the specificity of action of the neurotrophins. This hypothesis will be tested in the context of the regulation of ion channel and neurotransmitter receptor expression by different neurotrophins and trk receptors; 2) To determine if neurotrophic factors that use completely unrelated signal transduction mechanisms have common regulatory actions. The hypothesis of this specific aim is that unrelated neurotrophic factors will have overlapping effects on excitable properties common to all neurons, but distinct effects on excitable properties unique to particular neuronal types. This hypothesis will be tested for the unrelated factors NGF and ciliary neurotrophic factor; and 3) To determine if neurotrophic factors modulate excitability in the short-term. Activation of neurotrophic factor receptors such as the trk receptors initiates multiple signaling cascades within minutes of neurotrophic factor binding. Do these signaling events, many of which are known to affect excitability in other contexts, cause short term modulation of ion channel function? The proposed studies will use electrophysiological, molecular biological, and optical imaging techniques to study the expression and function of individual ion channel and neurotransmitter receptor species in three experimental settings: neuronal cell lines, cells transfected with specific neurotrophic factor receptors, and primary cultured neurons from hippocampus. The results from these experiments will contribute to the understanding of how neurotrophic factors regulate important neuronal functions such as excitability and synaptic transmission, and how deficiencies in neurotrophic interactions can lead to neuronal dysfunction and neurological disorders.