The inferior olivary nucleus plays a vital role in cerebellar function and motor control, and olivary degeneration is central to the pathophysiology of tremor and ataxia. A striking feature of olivary neurons is that they are susceptible to degeneration both from intrinsic molecular pathology (e.g., in spinocerebellar ataxias) as well as from extrinsic denervation of inhibitory cerebellar input which causes hypertrophic olivary degeneration (HOD). These triggers for olivary degeneration are assumed to reflect distinct cell death mechanisms, but our recent data strongly suggests that these different etiologies utilize shared molecular events key to olivary neuron viability. This proposal will test this novel hypothesis, which has profound implications for inferior olivary neuron survival and function. In a genetically precise mouse model of spinocerebellar ataxia type 1 (SCA1; SCA1- knockin or SCA1-KI mice), we find olivary neuron hypertrophy accompanied by the characteristic increase in dendrite length. Remarkably, these features occur in the absence of loss of inhibitory input. Moreover, we find no olivary pathology in a separate line of SCA1 transgenic mice that exhibit more severe but restricted cerebellar Purkinje neuron degeneration. A significant loss of calbindin positive neurons, characteristic of olivary degeneration, accompanies HOD in SCA1-KI mice. Considered together, these findings challenge current dogma by dissociating HOD and denervation. Preliminary studies using in vivo electrophysiological recordings demonstrate that synaptic (extrinsic) excitation on the olive, the cause of HOD due to inhibitory neuron denervation, is not increased. Additional studies demonstrate that hypertrophic olivary neurons exhibit increased intrinsic excitability of neurons due to potassium (K+) channel loss-of-function. Based on these findings, we hypothesize that this increased intrinsic excitability is the trigger for olivary degeneration in SCA1, and that increased excitability from whatever source (intrinsic or extrinsic) is a shared mechanism for inferior olive degeneration. We further hypothesize that olivary degeneration can therefore be prevented by normalizing membrane excitability. We will test these hypotheses through the following Specific Aims: Aim 1. Define the relationship between membrane excitability and olivary degeneration in SCA1. Aim 2: Define intrinsic and extrinsic contributions to olivary dysfunction in models of SCA1. Aim 3: Determine the basis for increased intrinsic excitability in hypertrophic olivary degeneration in SCA1. Results from these studies are expected to establish that increased membrane excitability is a convergent mechanism for olivary degeneration. These studies would be expected to provide insight into whether neuronal degeneration due to synaptic excitotoxicity may be addressed by reducing intrinsic excitability as a therapeutic strategy.