Many neurological diseases including epilepsy, migraine, and episodic motor disorders are common causes of morbidity. Episodic disease remains poorly understood. One basic question is the mechanism(s) by which a static genetic alteration produces transient neurological dysfunction. Experiments proposed here seek to answer this question which is of fundamental importance to human diseases such as Episodic Ataxia type 2;a human channelopathy caused by mutations of the CACNA1A gene that encodes the human Cav2.1 (P/Q-type) voltage gated Ca2+ channel. Experiments will be conducted in the mutant tottering (tg/tg) mouse, a model for Episodic Ataxia type 2, that exhibits cerebellar dependent paroxysmal motor attacks described as an episodic dystonia. Recently, it was demonstrated that highly abnormal, low frequency oscillations (LFOs) occur in the cerebellar cortex of the tg/tg mouse. These Ca2+-dependent LFOs are transient, greatly accentuated during the motor attacks, and are coherent with the abnormal muscle activity. The overarching hypothesis of this proposal is that transient abnormal Purkinje cell (PC) activity generates the dramatic episodic dystonia characteristic of the tg/tg mouse. Using optogenetic technology, optical imaging, as well as conventional electrophysiological techniques, all in awake animals, this study aims to develop an understanding of the mechanisms of episodic disease.
Specific Aim 1, through PC specific expression of the light gated inhibitory chloride pump halorhodopsin, tests the hypothesis that aberrant PC activity generates the LFOs and the episodic dystonia in tg/tg mice. Photoinhibition of PCs is predicted to suppress the LFOs in the cerebellar cortex and decrease the severity/duration of the attack or abort it entirely.
Specific Aim 2 tests the corollary hypothesis that selective excitation of PCs expressing the light-gated cation channel, channelrhodopsin-2, leads to LFOs in the cerebellar cortex and episodic dystonia in tg/tg mice.
Specific Aim 3 tests the hypothesis that firing of deep cerebellar nuclear neurons is highly abnormal during the motor attacks, possibly consisting of LFOs, as observed in the cerebellar cortex. Furthermore, optogenetic control of PC firing is used to test if the abnormal firing in the DCN is due to the LFOs occurring in the cerebellar cortex. Results of these aims will provide a better understanding for the fundamental events that initiate the transition from the normal to disease state that occurs in episodic disease as well as possibly provide insights into new treatment strategies for paroxysmal neurological disease.

Public Health Relevance

Many of the most common neurological diseases including epilepsy, migraine, and episodic motor disorders cause significant morbidity, though the underlying mechanism(s) that lead to disease expression are poorly understood. Through the use of light-activated ion channels in a mutant mouse that exhibits episodic neurological dysfunction, the experiments outlined in this proposal aim to gain insight into the events in the central nervous system that cause episodes of disease in this mutant mouse. Results of this proposed research could provide a better understanding for the common underlying mechanisms of episodic dysfunction and insights into new treatment strategies for episodic neurological disease.

National Institute of Health (NIH)
National Institute of Neurological Disorders and Stroke (NINDS)
Predoctoral Individual National Research Service Award (F31)
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NST-2 Subcommittee (NST)
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Stewart, Randall R
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University of Minnesota Twin Cities
Schools of Medicine
United States
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Cramer, Samuel W; Gao, Wangcai; Chen, Gang et al. (2013) Reevaluation of the beam and radial hypotheses of parallel fiber action in the cerebellar cortex. J Neurosci 33:11412-24