CaV2.1 ablation in cortical interneurons selectively impairs fast‐spiking basket cells and causes generalized seizures. Issue 2 (1st July 2013)

• Record Type: Journal Article
• Authors: Rossignol, Elsa; Kruglikov, Illya; van den, Arn M. J. M.; Rudy, Bernardo; Fishell, Gord
• Is Part Of: Annals of neurology. Volume 74:Issue 2(2013:Aug.)
• Page Start: 209
• Page End: 222
• Publication Date: 2013-07-01
• Subjects: Neurology -- Periodicals; Pediatric neurology -- Periodicals; Nervous system -- Surgery -- Periodicals; 616.8
• DOI: 10.1002/ana.23913
• Languages: English
• ISSNs: 0364-5134

Abstract

<abstract abstract-type="main"> <title> <x xml:space="preserve">Abstract</x> </title> <sec id="ana23913-sec-0001" sec-type="section"> <title>Objective</title> <p>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 <italic>Cacna1a, </italic> which encodes the α1 pore‐forming subunit of Ca<sub>V</sub>2.1 (P/Q‐type) voltage‐gated Ca<sup>2+</sup> 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 Ca<sub>V</sub>2.1 channel function and how this contributes to the onset of generalized epilepsy.</p> </sec> <sec id="ana23913-sec-0002" sec-type="section"> <title>Methods</title> <p>We designed genetic strategies to induce a selective <italic>Cacna1a</italic> 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.</p> </sec> <sec id="ana23913-sec-0003" sec-type="section"> <title>Results</title> <p>We demonstrate that selective <italic>Cacna1a</italic> LOF from a subset of cortical interneurons, including parvalbumin (PV)<sup>+</sup> and somatostatin (SST)<sup>+</sup> interneurons, results in severe generalized epilepsy. Loss of Ca<sub>V</sub>2.1 channel function compromises GABA release from PV<sup>+</sup> but not SST<sup>+</sup> 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 Ca<sub>V</sub>2.1 channels in cortical pyramidal cells and interneurons considerably lessens seizure severity by decreasing cortical excitability.</p> </sec> <sec id="ana23913-sec-0004" sec-type="section"> <title>Interpretation</title> <p>Our findings demonstrate that conditional ablation of Ca<sub>V</sub>2.1 channel function from cortical PV<sup>+</sup> interneurons alters GABA release from these cells, impairs their ability to constrain cortical pyramidal cell excitability, and is sufficient to cause generalized seizures. Ann Neurol 2013;74:209–222</p> </sec> </abstract>