Synaptic Transmission During Neuronal Differentiation

George Washington University, Washington DC

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Abstract

DESCRIPTION (provided by applicant): Unilateral peripheral vestibular lesions result in deficits in eye movements, posture, and balance, but the static symptoms usually diminish rapidly due to the process of vestibular compensation. Vestibular nuclei neurons must be intact for recovery, suggesting that adaptation involves these neurons. In fact, recovery of spontaneous spike firing in vestibular nuclei neurons bilaterally is a critical step for vestibular compensation to proceed. Our broad, long-term goal is to identify key cellular and molecular events orchestrating changes in vestibular nuclei neuron activity at early stages after lesions. Since a significant proportion of patients remain uncompensated, controls, compensated, and uncompensated subjects are studied. Experiments are focused on a distinct class of vestibular nuclei neurons, the principal cells of the tangential nucleus, from an established animal model, the chicken. Like humans, most chickens respond to unilateral vestibular ganglionectomy by compensating rapidly, but others remain uncompensated. We will study two critical stages: one day after the lesion when all the animals are uncompensated, and three days, when the majority of animals have compensated. We hypothesize that changes in the intact primary vestibular inputs and/or non-vestibular inputs dominate each stage of recovery. The specific aims include whole-cell patch-clamp recordings of frequency and kinetics of excitatory and inhibitory spontaneous synaptic events, and postsynaptic responses on vestibular-nerve and non-vestibular-nerve stimulation. We will determine the location and density of voltage-dependent sodium channels and AMPA receptor subunit expression in recorded PCs. The exact nature of non-vestibular terminals in the tangential nucleus will be determined using biocytin extracellular injections, combined with glutamate and GABA immunolabeling, and potassium channel immunolabeling of the terminals after lesions. Lesions in the labyrinths impair the quality of life and survival of the patient. Using drug interventions immediately after the onset of the vestibular syndrome could vastly improve patient rehabilitation. As we learn more about the pathology induced by vestibular deafferentation at the level of vestibular nuclei neurons, effective therapies can be targeted selectively to improve the clinical management of patients with balance disorders.