Pathophysiology of cerebellar-induced motor disorders

Abstract

Inherited ataxias comprise a genetically highly heterogeneous group of disorders, with their underlying dysfunction typically cerebellar in origin. Even so, in all of them a similar set of motor symptoms ultimately characterizes the phenotype in affected individuals. The physiological basis of most hereditary forms of ataxia is poorly understood and the therapeutic options either limited or nonexistent. The wide range of genes and mutations implicated in motor deficits implicating the cerebellum indicate that multiple pathways can induce cerebellar dysfunction. The overarching goal of this thesis is to characterize cerebellar pathophysiology by examining cerebellar output patterns associated with the expression of symptoms as part of inherited syndromes. Chapter 2 investigates a physiological basis for the cerebellum's debated involvement in the expression of abnormal involuntary movements in a mouse model of episodic ataxia type 2. In chapter 3, a potential mechanism underlying the paroxysmal nature of these motor symptoms in episodic ataxia is proposed. Chapter 4 evaluates whether spinocerebellar ataxias always result from neuronal degeneration by examining the physiological underpinnings of spinocerebellar ataxia 8. Chapter 5 investigated whether cerebellar activity is altered in a mutant mouse whose genetic mutations in humans results in cerebellar malformation. Although the mutated genes in episodic ataxia, spinocerebellar ataxia and cerebellar hypoplasia are different and the symptoms involve dyskinesia and dystonia in the former and mild ataxia in the latter, similar aberrant cerebellar output patterns were found to associate with all three syndromes. The final chapter investigated the hypothesis that similar changes in the firing pattern of cerebellar output neurons can give rise to a spectrum of motor dysfunction delimited on one end by ataxia and on the other by dystonia.