Neurons are likely the most complex cell in the body with differentiated structures including a soma, dendrites, and axons. This structural diversification allows for a specialized functionality within each of these neuronal elements. Electrical signals develop at synaptic input sites on the dendrite, are compiled at the soma, and are then transmitted to synaptic output sites on the axon as action potentials (APs) following initiation in the axon initial segment (AIS). In myelinated axons of projection (principal) neurons fast salutatory conduction ensures that the resulting APs are rapidly propagated to release sites in a stereotyped manner ensuring a reliable trigger for neurotransmission. Intuitively, the regenerative nature of AP propagation over long distances suggests that the influence of the AIS in determining spike waveform should be spatially differentiated from sites of release. In comparison, AP signaling in the unmyelinated axons of compact interneurons is poorly understood. We hypothesize that axons of interneurons are not exacting relay devices of the AIS, rather, that these processes are also endowed with a capacity to locally determine and sculpt AP waveforms and that this property is an important element in determining dynamics of neurotransmission. In this proposal, we will examine three key parameters that would define and support location-specific control of axonal electrogenesis in cerebellar stellate cell interneurons: (1) directly measure AP waveforms in axons, (2) relate these findings to axon morphology and to the organization of ion channels in axonal compartments, and (3) determine whether the location-specific distribution and properties of ion channels confers activity-dependent control of axonal excitation and release. In this way, this work aims to identify the characteristics that may enable compartmental organization of axonal electrogenesis in interneurons with the goal of relating the specific and dynamic parameters of axon physiology to information processing in neural circuits. This project will help inform the development of therapeutic strategies targeting diseases of axon dysfunction where differentiation of AP initiation, propagation, and release may be required to ameliorate pathological conditions specific to each of these functions.

Public Health Relevance

The fundamental function of an axon is to permit the cell-to-cell transfer of neuronal information by way of action potentials across swaths of brain tissue. Axon dysfunction results in neurological disorders affecting the CNS;therapeutic amelioration of these disorders will be guided by a detailed understanding of action potential signaling in axons in a variety of neuron-types. Thus, extracting rules that govern action potential signaling in axons, particularly in compact inhibitory interneurons, are the focus of this proposal.

National Institute of Health (NIH)
National Institute of Neurological Disorders and Stroke (NINDS)
Research Project (R01)
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Biophysics of Neural Systems Study Section (BPNS)
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Stewart, Randall R
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Max Planck Florida Corporation
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