Cacna1g is a genetic modifier of epilepsy in a mouse model of Dravet syndrome
Open Access
- 28 May 2017
- Vol. 58 (8), e111-e115
- https://doi.org/10.1111/epi.13811
Abstract
Dravet syndrome, an early onset epileptic encephalopathy, is most often caused by de novo mutation of the neuronal voltage‐gated sodium channel gene SCN1A. Mouse models with deletion of Scn1a recapitulate Dravet syndrome phenotypes, including spontaneous generalized tonic–clonic seizures, susceptibility to seizures induced by elevated body temperature, and elevated risk of sudden unexpected death in epilepsy. Importantly, the epilepsy phenotype of Dravet mouse models is highly strain‐dependent, suggesting a strong influence of genetic modifiers. We previously identified Cacna1g, encoding the Cav3.1 subunit of the T‐type calcium channel family, as an epilepsy modifier in the Scn2aQ54 transgenic epilepsy mouse model. In this study, we asked whether transgenic alteration of Cacna1g expression modifies severity of the Scn1a+/− Dravet phenotype. Scn1a+/− mice with decreased Cacna1g expression showed partial amelioration of disease phenotypes with improved survival and reduced spontaneous seizure frequency. However, reduced Cacna1g expression did not alter susceptibility to hyperthermia‐induced seizures. Transgenic elevation of Cacna1g expression had no effect on the Scn1a+/− epilepsy phenotype. These results provide support for Cacna1g as a genetic modifier in a mouse model of Dravet syndrome and suggest that Cav3.1 may be a potential molecular target for therapeutic intervention in patients.Keywords
Funding Information
- National Institutes of Health (R01-NS0537972, R01-NS084959)
This publication has 15 references indexed in Scilit:
- Cacna1g is a genetic modifier of epilepsy caused by mutation of voltage‐gated sodium channel Scn2aEpilepsia, 2016
- Strain- and age-dependent hippocampal neuron sodium currents correlate with epilepsy severity in Dravet syndrome miceNeurobiology of Disease, 2014
- Mapping genetic modifiers of survival in a mouse model of Dravet syndromeGenes, Brain and Behavior, 2013
- Dravet syndrome (severe myoclonic epilepsy in infancy)Handbook of Clinical Neurology, 2013
- Confirmation of an epilepsy modifier locus on mouse chromosome 11 and candidate gene analysis by RNA‐SeqGenes, Brain and Behavior, 2012
- Neuronal voltage-gated ion channels are genetic modifiers of generalized epilepsy with febrile seizures plusNeurobiology of Disease, 2011
- Genetic Enhancement of Thalamocortical Network Activity by Elevating α1G-Mediated Low-Voltage-Activated Calcium Current Induces Pure Absence EpilepsyJournal of Neuroscience, 2009
- Nav1.1 Localizes to Axons of Parvalbumin-Positive Inhibitory Interneurons: A Circuit Basis for Epileptic Seizures in Mice Carrying anScn1aGene MutationJournal of Neuroscience, 2007
- Reduced sodium current in GABAergic interneurons in a mouse model of severe myoclonic epilepsy in infancyNature Neuroscience, 2006
- Genetic modifiers affecting severity of epilepsy caused by mutation of sodium channelScn2aMammalian Genome, 2005