Delayed Postnatal Loss of P/Q-Type Calcium Channels Recapitulates the Absence Epilepsy, Dyskinesia, and Ataxia Phenotypes of GenomicCacna1AMutations

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 GFP derivative Citrine into the first exon of Cacna1a, then crossing 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 due to 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.

Cav2.1 in Cerebellar Purkinje Cells Regulates Competitive Excitatory Synaptic Wiring, Cell Survival, and Cerebellar Biochemical Compartmentalization

“…4 A, D). The reduced cerebellar size and normal dendritic branching are consistent with another line of PC-specific Ca v 2.1 KO mice, Cacna1a purk(Ϫ/Ϫ) (Mark et al, 2011;Todorov et al, 2011) and global Ca v 2.1 KO mice (Miyazaki et al, 2004). The surface of the somata and proximal dendrites was smooth in control mice ( Fig.…”

CACNA1A haploinsufficiency causes cognitive impairment, autism and epileptic encephalopathy with mild cerebellar symptoms

“…In cerebellar networks, Ca V 2.1 channels regulate the whole-cell calcium current density and the intrinsic excitability of Purkinje cells and granule cells, 44,51-53 and exert major control over glutamate release at the parallel fiber onto Purkinje-cell synapses. 50,[54][55][56] Furthermore, targeted deletions of Cacna1a in cerebellar granule cells 57 or in Purkinje cells 58 result in altered cerebellar output by respectively decreasing the excitatory drive on Purkinje cells or their ability to release neurotransmitters, causing ataxia and dyskinesia in mice.…”

Cerebellar Ataxia by Enhanced CaV2.1 Currents Is Alleviated by Ca2+-Dependent K+-Channel Activators inCacna1aS218LMutant Mice

“…Thus, the combination of somatic and dendritic effects of the S218L mutation on Purkinje cell excitability appears to promote irregular activity patterns. Yet, we cannot rule out that our in vitro recording conditions may have, unlike those of other labs (Womack and Khodakhah, 2004;McKay and Turner, 2005), limited the occurrence of irregular Purkinje cell firing in WT (Häusser and Clark, 1997;Walter et al, 2006;Mark et al, 2011) and thus created a bias toward a larger effect of the S218L mutation.…”