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- Title
Delayed Postnatal Loss of P/Q-Type Calcium Channels Recapitulates the Absence Epilepsy, Dyskinesia, and Ataxia Phenotypes of Genomic Cacna1A Mutations.
- Authors
Mark, Melanie D.; Maejima, Takashi; Kuckelsberg, Denise; Yoo, Jong W.; Hyde, Robert A.; Shah, Viral; Gutierrez, Davina; Moreno, Rosa L.; Wolfgang Kruse; Noebels, Jeffrey L.; Herlitze, Stefan
- Abstract
Inherited loss of P/Q-type calcium channel function causes human absence epilepsy, episodic dyskinesia, and ataxia, but the molecular "birthdate" of the neurological syndrome and its dependence on prenatal pathophysiology is unknown. Since these channels mediate transmitter release at synapses throughout the brain and are expressed early in embryonic development, delineating the critical circuitry and onset underlying each of the emergent phenotypes requires targeted control of gene expression. To visualize P/Q-type Ca2+channels and dissect their role in neuronal networks at distinct developmental stages, we created a novel conditional Cacna1a knock-in mouse by inserting the floxed green fluorescent protein derivative Citrine into the first exon of Cacna1a and then crossed it with a postnatally expressing PCP2-Cre line for delayed Purkinje cell (PC) gene deletion within the cerebellum and sparsely in forebrain ( purky). PCs in purky mice lacked P/Q-type calcium channel protein and currents within the first month after birth, displayed altered spontaneous firing, and showed impaired neurotransmission. Unexpectedly, adult purky mice exhibited the full spectrum of neurological deficits seen in mice with genomic Cacna1a ablation. Our results show that the ataxia, dyskinesia, and absence epilepsy caused by inherited disorders of the P/Q-type channel arise from signaling defects beginning in late infancy, revealing an early window of opportunity for therapeutic intervention.
- Subjects
EPILEPSY; SEIZURES (Medicine); NEURAL circuitry; GENETIC disorders; ATAXIA
- Publication
Journal of Neuroscience, 2011, Vol 31, Issue 11, p4311
- ISSN
0270-6474
- Publication type
Article
- DOI
10.1523/JNEUROSCI.5342-10.2011