L-type calcium channel regulation in the P/Q-type calcium channel mutant mouse, tottering, a model for episodic neurological disorders
Open Access
- Author:
- Fureman, Brandy Ellen
- Graduate Program:
- Neuroscience
- Degree:
- Doctor of Philosophy
- Document Type:
- Dissertation
- Date of Defense:
- June 15, 2001
- Committee Members:
- Ellen J Hess, Committee Chair/Co-Chair
Theresa L Wood, Committee Member
Robert G Levenson, Committee Member
Robert J Milner, Committee Chair/Co-Chair
Melvin Lee Billingsley, Committee Member - Keywords:
- mutant mouse
tyrosine hydroxylase
nimodipine
dyskinesia
trigger
voltage-dependent calcium channel
development
BAY K8644
animal model
behavior
paroxysmal
movement disorder - Abstract:
- Mutations in calcium channels cause episodic neurological disorders in humans and paroxysmal phenotypes in mice. Tottering mice display stress-induced attacks of a movement disorder due to a P/Q-type calcium channel mutation and cerebellar L-type calcium channel upregulation.L-type calcium channels were assessed in studies of calcium uptake, radioligand binding and in situ hybridization in tottering mice. These studies confirmed the increase in tottering cerebellar L-type calcium channels. Mutant mice also exhibited unique responses to repeated exposure to an L-type calcium channel antagonist (nimodipine) and agonist (BAY K8644). These studies provide further evidence of L-type calcium channel misregulation in the tottering mouse cerebellum. In developing tottering mice, restraint stress did not produce motor attacks until twenty-two days of age; attack frequencies at p22 were similar to adults. A second phenotype, aberrant cerebellar tyrosine hydroxylase mRNA expression, was not detected until after the onset of stress-induced motor attacks. These studies more precisely define the temporal relationship between these phenotypes, suggesting that aberrant calcium-responsive gene expression is a consequence of the intense cerebellar activation associated with motor attacks. In adult tottering mice, attacks were reliably precipitated by stressful environmental disturbances, caffeine and alcohol administration; these agents are widely known triggers in human episodic disorders. Thus, tottering mice provide an excellent model to study common pathophysiological mechanisms underlying trigger phenomena in ion channelopathies. As activation of hormonal systems is a common feature of tottering mouse triggers, the influence of stress hormones on tottering mouse attacks was assessed. Glucocorticoids were neither necessary nor sufficient for the expression of this behavior; pharmacological blockade of the corticotropin-releasing hormone receptor type 1 (CRF-1) did not prevent stress-induced motor attacks. Potential therapeutics including ethosuximide, phenytoin and carbamazepine failed to prevent motor attacks. However, L-type calcium channel antagonist nimodipine prevented caffeine- and alcohol-induced attacks, and the glutamatergic antagonist MK-801 was effective in preventing attacks induced by restraint stress. The results of these studies suggest that abnormal ionic signaling triggered through calcium-dependent mechanisms in cerebellar networks produces periods of hyperexcitability in the tottering mouse brain. The unique neurocircuitry of the cerebellum may amplify these abnormal signals once they are produced.