Author

Forrest Davis

Date

June 2010

Document Type

Dissertation

Degree Name

Ph.D.

Institution

Oregon Health & Science University

Abstract

Purkinje cells play a central role in motor coordination and movement, two processes that are compromised by cerebellar ataxias. Purkinje cells are called pacemakers because they exhibit an intrinsically generated, tonic firing pattern. The intrinsic firing pattern of Purkinje cells is modified by inhibitory and excitatory input, and constitutes the sole output from the cerebellar cortex. Therefore, aberrations in cerebellar processing are encoded as a modified Purkinje cell output. For example, a decrease in the precision of Purkinje cell pacemaking has been implicated in ataxia. Episodic ataxia/myokymia type 1 (EA1) is caused by mutations of the voltage-gated potassium channel Kv1.1. In patients with EA1, physical or emotional stress can trigger attacks of imbalance and loss of motor control. The carbonic anhydrase inhibitor acetazolamide reduces the frequency and severity of these attacks. In this thesis, I first examined a mouse model of EA1, and sought to determine whether imprecision of Purkinje cell pacemaking causes the stress-induced motor deficits. Increased GABAergic inhibition in Purkinje cells reduced the precision of Purkinje cell pacemaking. The precision deficit was exacerbated by β-adrenergic receptor activation, a model of the effects of stressful events that can precipitate attacks in patients with EA1. The precision deficit was ameliorated by acetazolamide, which also occluded the effects of subsequent β-adrenergic receptor activation. These results suggest that alteration of Purkinje cell pacemaking underlies ataxia in EA1. In the second half of this thesis, I analyzed the relationship between Purkinje cell pacemaking precision and motor coordination in a mouse with reduced expression of the small conductance Ca[superscript 2+]-activated potassium channel SK2 (SK2[superscript fl/fl]). Ca[superscript 2+]-activated potassium currents are central to the timing of action potentials. Purkinje cells in SK2[superscript fl/fl] mice displayed irregular pacemaking in the majority of lobules (I-VII) within the cerebellar vermis, but this deficit did not affect motor skills as measured by balance beam and accelerating rotarod assays. A minority of the cerebellar cortex, comprised of lobules VIII and IX, had normal Purkinje cell pacemaking in SK2[superscript fl/fl] animals. Ablation of this region removed all regular Purkinje cell firing from the SK2[superscript fl/fl] vermis, and unmasked a motor deficit assayed by the balance beam. This result supports the notion that Purkinje cell pacemaking is required for cerebellar dependent motor tasks. Conversely, lobule VIII/IX ablation failed to elicit a performance deficit on the accelerating rotarod in SK2[superscript fl/fl] mice, suggesting that regular Purkinje cell firing in the vermis is not required for all cerebellar-dependent tasks.

Identifier

doi:10.6083/M4Z899DS

Division

Vollum Institute

School

School of Medicine

Share

COinS
 
 

To view the content in your browser, please download Adobe Reader or, alternately,
you may Download the file to your hard drive.

NOTE: The latest versions of Adobe Reader do not support viewing PDF files within Firefox on Mac OS and if you are using a modern (Intel) Mac, there is no official plugin for viewing PDF files within the browser window.