SYNAPTIC TRANSMISSION DURING NEURONAL DIFFERENTIATION

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DESCRIPTION (provided by applicant): The central vestibular system exhibits a remarkable natural recovery of many functions after peripheral vestibular lesions. The first brain centers involved in this plasticity are the vestibular nuclei, and their integrity is crucial for recovery. The major goal of this work is to understand how excitability and synaptic transmission change in an identified class of vestibular nucleus neurons during compensation from unilateral vestibular ganglionectomy's. The chick tangential nucleus (lateral vestibular nucleus) will be studied in brain slices of hatchling chicks and in whole animals. Its principal cells participate in two vestibular reflexes affected by the lesion, but show recovery. We propose that changes in synaptic and intrinsic membrane properties and/or dendritic terminals may occur in vestibular nuclei during compensation. The techniques include patch-clamp recording in brain slices, pharmacological testing, and immunolabeling combined with confocal imaging. Lesion will be made in hatchling chicks (4-5 days postnatal) that are sacrificed at selected stages during compensation (6, 12, 24 hours; 3 and 7 days after surgery). By H4-5, the mature firing pattern, including spontaneous spike firing and evoked repetitive firing, is established in these neurons. The specific aims include whole-cell patch-clamp recordings of spontaneous spike firing, spontaneous synaptic activity, and voltage-gated outward potassium currents in the ipsi- and contra lateral tangential principal cells, studies on vestibular-evoked spike firing and synaptic currents in the contra lateral tangential principal cells, and immunocytochemical studies of AMPA receptor subunits (GluR1, GluR2, GluR2/3, GluR4), potassium (Kv1.1, Kv1.2) and gap junction channels (connexins) in the ipsi- and contra lateral tangential nucleus. The scope of the study will be broadened by sampling other vestibular neurons likely to contribute to compensation, including elongate cells of the tangential nucleus and cell type B of the medial vestibular nucleus. For the first time, signal processing will be studied using state-of-art methods in a homogeneous, morphologically identified group of vestibular nucleus neurons at selected times during behavioral recovery from unilateral vestibular ganglionectomy's. As the basic mechanisms controlling excitability and synaptic transmission in vestibular nucleus neurons are better understood and molecular targets are identified, more effective therapies will be devised to treat central vestibular disorders resulting from disease, injury and aging.