Interdependence of functional and structural plasticity in cerebellar climbing fibers in health and disease

ended

Modifications of the structure and intrinsic excitability of neurons (i.e. “structural plasticity” and “intrinsic plasticity”) have been proposed to contribute significantly in encoding memory in synergy with synaptic plasticity and have been shown to contribute to the pathogenesis of several diseases including multiple sclerosis (MS). However, it is still largely unclear how changes in intrinsic excitability affect structural plasticity and how this affects circuit function. A better understanding of this two-way interdependence is crucial to understand how brain circuits encode memory engrams and are affected by diseases. Here I propose to investigate the two sides of this function-structure relationship choosing cerebellar climbing fibers (CF) as a model. Using in vivo viral delivery in the inferior olive nucleus (where climbing fibers originate), electrophysiology, optogenetics and confocal microscopy I will modulate CF function or structure acutely in slice or chronically in vivo and analyze the corresponding effect on CF morphology or physiology, respectively. I will use previously developed viral constructs to silence the expression of the growth-associated protein 43 (GAP-43) or voltage-gated sodium channels to induce structural modifications or a reduction of excitability in CFs, respectively; I will also use optogenetics to specifically stimulate transduced CFs in slice and a recently established conditional knockout mouse for SK2-type calcium-gated potassium channels to increase CF excitability. In order to investigate how CF function and structure may be modified in pathological conditions I will focus on the effects of the upregulation of the RE1-Silencing Transcription Factor (REST) observed in MS and related to alterations of neuronal excitability and axonal structure. This project will show how CF activity can modify its structure and PF plasticity rules, contributing to memory formation and disease.