CaV2.1 ablation in cortical interneurons selectively impairs fast-spiking basket cells and causes generalized seizures

Elsa Rossignol, Illya Kruglikov, Arn M.J.M. Van Den Maagdenberg, Bernardo Rudy, Gordon Fishell

    Research output: Contribution to journalArticle

    Abstract

    Objective Both the neuronal populations and mechanisms responsible for generalized spike-wave absence seizures are poorly understood. In mutant mice carrying loss-of-function (LOF) mutations in Cacna1a, which encodes the α1 pore-forming subunit of CaV2.1 (P/Q-type) voltage-gated Ca 2+ channels, generalized spike-wave seizures have been suggested to result from excessive bursting of thalamocortical cells. However, other cellular populations including cortical inhibitory interneurons may contribute to this phenotype. We investigated how different cortical interneuron subtypes are affected by the loss of CaV2.1 channel function and how this contributes to the onset of generalized epilepsy. Methods We designed genetic strategies to induce a selective Cacna1a LOF mutation in different cortical γ-aminobutyric acidergic (GABAergic) and/or glutamatergic neuronal populations in mice. We assessed the cellular and network consequences of these mutations by combining immunohistochemical assays, in vitro physiology, optogenetics, and in vivo video electroencephalographic recordings. Results We demonstrate that selective Cacna1a LOF from a subset of cortical interneurons, including parvalbumin (PV)+ and somatostatin (SST)+ interneurons, results in severe generalized epilepsy. Loss of CaV2.1 channel function compromises GABA release from PV+ but not SST + interneurons. Moreover, thalamocortical projection neurons do not show enhanced bursting in these mutants, suggesting that this feature is not essential for the development of generalized spike-wave seizures. Notably, the concurrent removal of CaV2.1 channels in cortical pyramidal cells and interneurons considerably lessens seizure severity by decreasing cortical excitability. Interpretation Our findings demonstrate that conditional ablation of CaV2.1 channel function from cortical PV+ interneurons alters GABA release from these cells, impairs their ability to constrain cortical pyramidal cell excitability, and is sufficient to cause generalized seizures.

    Original languageEnglish (US)
    Pages (from-to)209-222
    Number of pages14
    JournalAnnals of Neurology
    Volume74
    Issue number2
    DOIs
    StatePublished - Aug 1 2013

    Fingerprint

    Interneurons
    Seizures
    Parvalbumins
    Generalized Epilepsy
    Pyramidal Cells
    Somatostatin
    gamma-Aminobutyric Acid
    Mutation
    Optogenetics
    Population
    Absence Epilepsy
    Video Recording
    voltage-dependent calcium channel (P-Q type)
    Phenotype
    Neurons

    ASJC Scopus subject areas

    • Neurology
    • Clinical Neurology

    Cite this

    Rossignol, E., Kruglikov, I., Van Den Maagdenberg, A. M. J. M., Rudy, B., & Fishell, G. (2013). CaV2.1 ablation in cortical interneurons selectively impairs fast-spiking basket cells and causes generalized seizures. Annals of Neurology, 74(2), 209-222. https://doi.org/10.1002/ana.23913

    CaV2.1 ablation in cortical interneurons selectively impairs fast-spiking basket cells and causes generalized seizures. / Rossignol, Elsa; Kruglikov, Illya; Van Den Maagdenberg, Arn M.J.M.; Rudy, Bernardo; Fishell, Gordon.

    In: Annals of Neurology, Vol. 74, No. 2, 01.08.2013, p. 209-222.

    Research output: Contribution to journalArticle

    Rossignol, E, Kruglikov, I, Van Den Maagdenberg, AMJM, Rudy, B & Fishell, G 2013, 'CaV2.1 ablation in cortical interneurons selectively impairs fast-spiking basket cells and causes generalized seizures', Annals of Neurology, vol. 74, no. 2, pp. 209-222. https://doi.org/10.1002/ana.23913
    Rossignol, Elsa ; Kruglikov, Illya ; Van Den Maagdenberg, Arn M.J.M. ; Rudy, Bernardo ; Fishell, Gordon. / CaV2.1 ablation in cortical interneurons selectively impairs fast-spiking basket cells and causes generalized seizures. In: Annals of Neurology. 2013 ; Vol. 74, No. 2. pp. 209-222.
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    AU - Rudy, Bernardo

    AU - Fishell, Gordon

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