Abstracts

Rationale: Inborn errors of CACNA1A-encoded P/Q-type calcium channels impair neuronal functions, producing pediatric and lifelong lasting neurological deficits, including child-hood absence epilepsy, ataxia, dystonia, tonic clonic epilepsy, and migraine in human beings. Critical period is an early developmental time window during which the brain is extremely sensitive to sensory experience that is required for proper circuit formation and brain functions. Disrupted development in the critical period is thought to be responsible for the severity of many pediatric neurological diseases. However, whether the development of those neurological syndromes indeed depends on the inborn malfunction of P/Q-type calcium channels remains unknown.  Methods: Here, by using genetic animal models, we aimed to investigate how deleting P/Q-type calcium channel beyond critical period, namely, in adulthood, would affect neurological functions. In our models, the pore-forming alpha subunit of P/Q channel was ablated by activating a tamoxifen inducible Cre in adult Cacna1a floxed mice.  Results: Using video-EEG (electroencephalogram) recordings, behavioral monitoring, we showed that mice with adult-onset deletion of P/Q channel alpha subunit display identical patterns of absence epilepsy, ataxia, and episodic dystonia, replicating the phenotypes caused by inborn errors. Furthermore, this will enable us to shed light on essential mechanisms underlying the generation of childhood absence epilepsy without confounding neurodevelopmental factors. By using whole-cell patch-clamp recordings, immunohistochemistry and genetic approaches, we found that, the seizures provoked by ablating P/Q channels in mature mouse brain arise from different alterations of neuronal excitability at key thalamic network hubs than those reported in inborn genomic models. Cell-type specific changes in transient (T)-type calcium currents in excitatory thalamic relay and inhibitory reticular neurons varied between inborn and adult-induced mutants, indicating that it is urgent to establish a causal link between key molecular and network alterations and the genesis of absence epilepsy.  Conclusions: Together, our study demonstrates that P/Q channels remain critical for the normal function of adult brain, and that spike-wave absence seizures, the most common form of childhood epilepsy, can be generated in the adult animals due to P/Q channel dysfunction beyond neurodevelopmental critical period. Uncoupling the neuronal synchronization disease phenotype from downstream neonatal remodeling during vulnerable developmental periods holds significant promise for gene-guided precision rescue strategies at later stages of the disorder.  Funding: NINDS NS29709 (to J.L.N.).