CaV2.1 ablation in cortical interneurons selectively impairs fast-spiking basket cells and causes generalized seizures
Article first published online: 1 JUL 2013
© 2013 American Neurological Association
Annals of Neurology
Volume 74, Issue 2, pages 209–222, August 2013
How to Cite
Rossignol, E., Kruglikov, I., van den Maagdenberg, A. M. J. M., Rudy, B. and Fishell, G. (2013), CaV2.1 ablation in cortical interneurons selectively impairs fast-spiking basket cells and causes generalized seizures. Ann Neurol., 74: 209–222. doi: 10.1002/ana.23913
- Issue published online: 24 SEP 2013
- Article first published online: 1 JUL 2013
- Accepted manuscript online: 18 APR 2013 04:51AM EST
- Manuscript Accepted: 12 APR 2013
- Manuscript Revised: 3 APR 2013
- Manuscript Received: 4 JUL 2012
- NIH. Grant Numbers: RO1NS039007, RO1NS30989, RO1NS045217, RO1MH071679
- Research and Health Fund of Quebec
- Canadian Institutes of Health Research
- University of Montreal
- Epilepsy Foundation. Grant Number: 260691
- Genomics Initiative/Netherlands Organization for Scientific Research and Community
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 Ca2+ 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.
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.
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.
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. Ann Neurol 2013;74:209–222