Physiologic alterations in ataxia: channeling changes into novel therapies

Abstract

The ataxias constitute a heterogeneous group of diseases in which cerebellar dysfunction typically underlies the major neurologic manifestations. It is increasingly clear that ataxia can result directly from mutations in ion channels or from perturbations in ion channel physiology in the absence of a primary channel defect. Neuronal dysfunction stemming from perturbed channel activity likely explains some motor deficits in episodic and degenerative ataxias. Understanding these pathophysiologic changes may reveal novel therapeutic targets for symptomatic treatment of ataxia.

Figure 1

A schematic diagram of the architecture of the cerebellum, indicating the sites of identified physiologic dysfunction in different ataxic disorders. Excitatory neurons are shown in green and inhibitory neurons in red. Only those cerebellar neuronal cell types currently implicated in ataxia are shown.

Figure 2

A schematic diagram of the stages of physiologic dysfunction and possible sites of therapy in ataxia with prominent cerebellar cortical dysfunction. Panel 1 shows normal intrinsic firing of Purkinje and DCN neurons and their modulation respectively by parallel fibers and Purkinje cell output. Excitatory input shown in green and inhibitory input in red. Many degenerative ataxias traverse a stage with physiologic dysfunction (panel 2) followed by morphologic abnormalities (panel 3) prior to prominent neuronal cell loss (panel 4). Loss or dysfunction of Purkinje neurons would be expected to increase DCN excitability. Therapies aimed at improving cerebellar physiology may be effective at all stages of neurodegeneration; 1. Improvement of both cerebellar cortical function and downstream DCN changes when there is Purkinje neuron dysfunction or minimal Purkinje cell loss; and 2. Improvement of downstream DCN changes when Purkinje cells have died. PC-Purkinje cell, PF — Parallel fiber.