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Adult loss of Cacna1a in mice recapitulates childhood absence epilepsy by distinct thalamic bursting mechanisms.

Authors
  • Miao, Qing-Long1
  • Herlitze, Stefan2
  • Mark, Melanie D2
  • Noebels, Jeffrey L1, 3, 4
  • 1 Developmental Neurogenetics Laboratory, Department of Neurology, Baylor College of Medicine, Houston TX, USA.
  • 2 Department of Zoology and Neurobiology, Ruhr University of Bochum, Bochum, Germany. , (Germany)
  • 3 Department of Neuroscience, Baylor College of Medicine, Houston TX, USA.
  • 4 Department of Molecular and Human Genetics, Baylor College of Medicine, Houston TX, USA.
Type
Published Article
Journal
Brain
Publisher
Oxford University Press
Publication Date
Jan 01, 2020
Volume
143
Issue
1
Pages
161–174
Identifiers
DOI: 10.1093/brain/awz365
PMID: 31800012
Source
Medline
Keywords
Language
English
License
Unknown

Abstract

Inborn errors of CACNA1A-encoded P/Q-type calcium channels impair synaptic transmission, producing early and lifelong neurological deficits, including childhood absence epilepsy, ataxia and dystonia. Whether these impairments owe their pathologies to defective channel function during the critical period for thalamic network stabilization in immature brain remains unclear. Here we show that mice with tamoxifen-induced adult-onset ablation of P/Q channel alpha subunit (iKOp/q) display identical patterns of dysfunction, replicating the inborn loss-of-function phenotypes and, therefore demonstrate that these neurological defects do not rely upon developmental abnormality. Unexpectedly, unlike the inborn model, the adult-onset pattern of excitability changes believed to be pathogenic within the thalamic network is non-canonical. Specifically, adult ablation of P/Q channels does not promote Cacna1g-mediated burst firing or T-type calcium current (IT) in the thalamocortical relay neurons; however, burst firing in thalamocortical relay neurons remains essential as iKOp/q mice generated on a Cacna1g deleted background show substantially diminished seizure generation. Moreover, in thalamic reticular nucleus neurons, burst firing is impaired accompanied by attenuated IT. Interestingly, inborn deletion of thalamic reticular nucleus-enriched, human childhood absence epilepsy-linked gene Cacna1h in iKOp/q mice reduces thalamic reticular nucleus burst firing and promotes rather than reduces seizure, indicating an epileptogenic role for loss-of-function Cacna1h gene variants reported in human childhood absence epilepsy cases. Together, our results demonstrate that P/Q channels remain critical for maintaining normal thalamocortical oscillations and motor control in the adult brain, and suggest that the developmental plasticity of membrane currents regulating pathological rhythmicity is both degenerate and age-dependent. © The Author(s) (2019). Published by Oxford University Press on behalf of the Guarantors of Brain. All rights reserved. For permissions, please email: [email protected]

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