Developing Purkinje Cell Synaptic Therapies to Restore Circuit Function in Cerebellar Degeneration

PROJECT SUMMARY/ ABSTRACT Individuals with cerebellar degeneration suffer from incapacitating ataxia symptoms, such as imbalance, frequent falls, and loss of movement control. Regrettably, no existing therapies are available to treat ataxia symptoms, partly due to an incomplete understanding of the brain circuit alterations responsible for these symptoms, resulting in many patients being left disabled. Prior research in animal models and postmortem human brains have elucidated a defined sequence of cerebellar degeneration: Purkinje cells (PCs), the principal neurons of the cerebellar circuit, initially prune their excitatory synapses, including climbing fiber (CF)- PC synapses, in the early stage of degeneration, followed by subsequent PC loss in the late stage of degeneration. Therefore, targeting these circuit changes in a stage-specific manner holds promise for restoring circuit function in cerebellar degeneration. Our preliminary data showed that inhibition of CF-PC synaptic activity directly induces ataxia-like behaviors and disrupts cerebellar physiology, specifically reducing the cerebellar alpha rhythm (8-13Hz) in mice. CF-PC synaptic interventions thus have the potential to restore circuit function, and cerebellar alpha rhythm may serve as a means to monitor circuit function. However, before progressing to clinical trials for synaptic therapies, knowledge gaps still exist: 1) Does CF-PC synaptic intervention improve ataxia symptoms? 2) Are the effects of the intervention different in the early vs. late stages of degeneration? 3) Does cerebellar alpha rhythm track stages of degeneration in vivo and reflect therapeutic responses? To address these questions, we propose testing the hypothesis that loss of CF-PC synapses differentially contributes to disturbed cerebellar physiology and ataxia symptoms in early vs. late stages of cerebellar degeneration. In this proposal, we will study a mouse model of cerebellar degeneration and determine the anatomical basis of reduced cerebellar alpha rhythm in early vs. late stages of degeneration to validate the future use of cerebellar alpha rhythm to monitor circuit function (Aim 1). We will assess if enhancing the activity of remaining CF-PC synapses can be a therapeutic strategy to improve the cerebellar alpha rhythm and ataxia symptoms in early vs. late stages of degeneration (Aim 2). Finally, we will examine another therapeutic approach and determine if promoting new CF-PC synapses improves the cerebellar alpha rhythm and ataxia symptoms in early vs. late stages of degeneration (Aim 3). The knowledge gained from this research will provide insights for developing disease-stage-specific therapies to restore circuit function in cerebellar degeneration.