Chronic partial TrkB activation reduces seizures and mortality in a mouse model of Dravet syndrome
Feng Gu, Isabel Parada, Tao Yang, Frank M. Longo, David A. Prince
Abstract
Significance Dravet syndrome (DS) is a severe childhood epileptic encephalopathy characterized by intractable seizures and comorbidities, including a high rate of premature mortality. DS is mainly caused by loss-of-function mutations of the Scn1a gene encoding sodium channel Na v 1.1 that is predominantly expressed in inhibitory parvalbumin-containing (PV) interneurons. Decreased Na v 1.1 impairs PV cell function, causing DS phenotypes. Effective pharmacological therapy targeting defective PV interneurons is currently not available. This study demonstrated that early treatment with a partial TrkB receptor agonist, LM22A-4, increased Na v 1.1 expression, improved PV interneuron function, and reduced seizure occurrence and mortality rate in DS mice, suggesting a potential therapy for DS.