title: Delayed postnatal loss of P/Q-type calcium channels recapitulates the absence epilepsy, dyskinesia, and ataxia phenotypes of genomic Cacna1a mutations.
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 Ca(2+) 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.
authors.affiliation: Department of Zoology and Neurobiology, ND7/31, Ruhr-University Bochum, D-44780 Bochum, Germany.
authors.forename: Melanie D
authors.initials: MD
authors.lastname: Mark
authors.forename: Takashi
authors.initials: T
authors.lastname: Maejima
authors.forename: Denise
authors.initials: D
authors.lastname: Kuckelsberg
authors.forename: Jong W
authors.initials: JW
authors.lastname: Yoo
authors.forename: Robert A
authors.initials: RA
authors.lastname: Hyde
authors.forename: Viral
authors.initials: V
authors.lastname: Shah
authors.forename: Davina
authors.initials: D
authors.lastname: Gutierrez
authors.forename: Rosa L
authors.initials: RL
authors.lastname: Moreno
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Kruse
authors.forename: Jeffrey L
authors.initials: JL
authors.lastname: Noebels
authors.forename: Stefan
authors.initials: S
authors.lastname: Herlitze
mesh_terms: D000704:Analysis of Variance; D000818:Animals; D001259:Ataxia / Q000235:genetics* / Q000378:metabolism; D020865:Calcium Channels, P-Type / Q000235:genetics* / Q000378:metabolism; D020907:Calcium Channels, Q-Type / Q000235:genetics* / Q000378:metabolism; D002531:Cerebellum / Q000378:metabolism; D020820:Dyskinesias / Q000235:genetics* / Q000378:metabolism; D004569:Electroencephalography; D004594:Electrophysiology; D004832:Epilepsy, Absence / Q000235:genetics* / Q000378:metabolism; D007150:Immunohistochemistry; D053444:Inhibitory Postsynaptic Potentials / Q000502:physiology; D051379:Mice; D008822:Mice, Transgenic; D009154:Mutation; D010641:Phenotype; D011689:Purkinje Cells / Q000378:metabolism*
chemical_list: D020865:Calcium Channels, P-Type; D020907:Calcium Channels, Q-Type