Premium
Dystonia and cerebellar atrophy in Cacna1a null mice lacking P/Q calcium channel activity
Author(s) -
Fletcher Colin F.,
Tottene Angelita,
Len Vanda A.,
Wilson Scott M.,
Dubel Stefan J.,
Paylor Richard,
Hosford David A.,
Tessarollo Lino,
McEnery Maureen W.,
Pietrobon Daniela,
Copeland Neal G.,
Jenkins Nancy A.
Publication year - 2001
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fj.00-0562fje
Subject(s) - calcium channel , atrophy , dystonia , neuroscience , calcium , medicine , cerebellum , endocrinology , biology
ABSTRACT P/Q‐type voltage‐dependent calcium channel CACNA1A mutations cause dominantly inherited migraine, episodic ataxia, and cerebellar atrophy in humans and cause recessively inherited ataxia, episodic dyskinesia, cerebellar atrophy, and absence epilepsy in mice. The basis of these species differences and the disease mechanism(s) are not understood. To address this question and to identify required P/Q function in vivo , we created a germline Cacna1a null mutation (designated Cacna1a Fcrtm1 ) by gene targeting. Null mice develop dystonia and late‐onset cerebellar degeneration in a specific pattern. This indicates a requirement for P/Q function for survival in a subset of cerebellar neurons. Homozygous null mice completely lack P/Q‐type channel activity, and they also lack ω‐CTx‐MVIIC receptors, indicating that a single gene encodes P/Q channel activity. An increase of L‐and N‐type current densities is detected in P/Q‐null granule cells. Heterozygous Cacna1a Fcrtm1 /+ mice are phenotypically normal, despite having a 50% reduction in current density, indicating that reduced current density is not itself sufficient to cause the pathophysiology of spontaneous mouse mutants with ataxia and seizures.