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CaV 2.1 ablation in cortical interneurons selectively impairs fast-spiking basket cells and causes generalized
Elsa Rossignol1, Illya Kruglikov, Arn M J M van den Maagdenberg
1NYU Neuroscience Institute, New York University School of Medicine, New York, NY; Pediatric Neurology Department of Neuroscience, Saint Justine University Hospital Center, University of Montreal, Montreal, Quebec, Canada.
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 CaV 2.1 (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 CaV 2.1 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 CaV 2.1 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 CaV 2.1 channels in cortical pyramidal cells and interneurons considerably lessens seizure severity by decreasing cortical excitability.
Interpretation:
Our findings demonstrate that conditional ablation of CaV 2.1 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.
Insights
Loss of CaV 2.1 channels in cortical PV+ interneurons impairs GABA release, leading to generalized epilepsy. This finding implicates specific interneurons in absence seizures and offers new therapeutic targets.
Area of Science:
- Neuroscience
- Epilepsy Research
- Channelopathies
Background:
- Generalized spike-wave absence seizures mechanisms are poorly understood.
- CaV 2.1 channels are implicated in epilepsy, but their specific roles in different neuronal populations remain unclear.
- Cortical interneurons are potential contributors to absence seizures.
Purpose of the Study:
- Investigate the role of CaV 2.1 channel function in cortical interneuron subtypes.
- Determine how loss of CaV 2.1 channel function in interneurons contributes to generalized epilepsy.
- Clarify the cellular and network mechanisms underlying absence seizures.
Main Methods:
- Genetic strategies to induce selective Cacna1a loss-of-function mutations in mouse cortical neurons.
- Immunohistochemistry, in vitro physiology, and optogenetics.
- In vivo video electroencephalography (EEG) recordings.
Main Results:
- Selective Cacna1a loss-of-function in parvalbumin (PV)+ and somatostatin (SST)+ interneurons causes severe generalized epilepsy.
- Loss of CaV 2.1 function impairs GABA release from PV+ interneurons but not SST+ interneurons.
- Thalamocortical neuron bursting is not essential for generalized spike-wave seizures; reducing cortical excitability lessens seizure severity.
Conclusions:
- Conditional ablation of CaV 2.1 channels in cortical PV+ interneurons disrupts GABA release.
- Impaired GABA release from PV+ interneurons compromises their ability to regulate cortical pyramidal cell excitability.
- Loss of CaV 2.1 function in PV+ interneurons is sufficient to cause generalized seizures.
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