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Triggers of paroxysmal dyskinesia in the calcium channel mouse mutant tottering
Brandy E Fureman1, H A Jinnah, Ellen J Hess
1Department of Neurology, Johns Hopkins University School of Medicine, Meyer Room 6-181, 600 North Wolfe Street, Baltimore, MD 21287, USA.
Abstract:
Mutations in ion channels, or channelopathies, often lead to neurological disorders in which normal behavior is interrupted by attacks of debilitating symptoms such as pain, weakness or abnormal motor control. Attacks are often precipitated by similar stimuli, including stress, caffeine, ethanol, exercise or fatigue. The tottering mouse inherits a mutation in P/Q-type calcium channels and reliably exhibits attacks of abnormal movements, or dyskinesia. To determine if this mouse mutant is an appropriate model to study episodic neurological disorders, tottering mice were exposed to different environmental conditions or drugs known to precipitate attacks in humans. Stress, caffeine and ethanol all reliably induced attacks in tottering mice. Since calcium influx has previously been implicated in stress-induced tottering mouse attacks, the L-type calcium channel antagonist, nimodipine, and the NMDA receptor antagonist, MK 801, were tested for their ability to prevent attacks caused by caffeine or ethanol administration. Nimodipine blocked both caffeine- and ethanol-induced attacks, while MK 801 was effective against stress- and caffeine-induced attacks. These results support a common role for excess neuronal excitability and increased calcium influx in attacks triggered by diverse agents. Together, these results suggest that the tottering mouse is a novel model to investigate triggers of episodic neurological disorders.
Insights
The tottering mouse, with a P/Q-type calcium channel mutation, models episodic neurological disorders. Stress, caffeine, and ethanol trigger attacks, suggesting a role for neuronal excitability and calcium influx in these events.
Area of Science:
- Neuroscience
- Genetics
- Pharmacology
Background:
- Channelopathies, caused by ion channel mutations, lead to episodic neurological disorders.
- Attacks in these disorders are often triggered by common stimuli like stress, caffeine, and ethanol.
- The tottering mouse model exhibits P/Q-type calcium channel mutations and spontaneous dyskinesia attacks.
Purpose of the Study:
- To validate the tottering mouse as a model for studying episodic neurological disorders.
- To investigate the role of specific triggers in precipitating attacks in tottering mice.
- To explore the involvement of calcium influx and neuronal excitability in triggered attacks.
Main Methods:
- Tottering mice were exposed to environmental stressors, caffeine, and ethanol.
- The efficacy of L-type calcium channel antagonist nimodipine and NMDA receptor antagonist MK-801 in preventing attacks was assessed.
- Attacks were monitored following exposure to triggers and drug interventions.
Main Results:
- Stress, caffeine, and ethanol reliably induced dyskinesia attacks in tottering mice.
- Nimodipine prevented caffeine- and ethanol-induced attacks.
- MK-801 prevented stress- and caffeine-induced attacks.
Conclusions:
- These findings support a common mechanism involving neuronal excitability and calcium influx in attacks triggered by diverse agents.
- The tottering mouse is a valuable model for investigating the triggers of episodic neurological disorders.
- Pharmacological interventions targeting calcium channels may offer therapeutic potential for these conditions.
