Emerging Insights into the Pathogenic Mechanisms of Dravet Syndrome

Abstract

Dravet syndrome (DS) is a rare monogenic developmental and epileptic encephalopathy (DEE) most frequently caused by SCN1A gene mutations that lead to Na_v1.1 sodium channel haploinsufficiency. DS is now recognized as a multisystem disorder with widespread developmental consequences that go beyond epilepsy. Indeed, children with DS often exhibit cognitive impairment, motor and speech delays, and neuropsychiatric comorbidities such as anxiety, attention deficits, and autistic traits. Sudden unexpected death in epilepsy (SUDEP) is also frequent. This complex phenotype underscores the need for multidisciplinary care approaches and novel pharmacological therapies. Mechanistically, recent studies in DS mouse models revealed a more complex scenario than previously thought. According to recent works, some well described neuronal defects in DS are restored during development while other impairments persist throughout life. Furthermore, evidence reveal which mechanisms are involved in cognitive impairments but not in seizures. Recently approved drugs such as cannabidiol (CBD) and fenfluramine (FFA) also help to better understand the mechanisms underlying the different disease symptoms. Here, we review most recent advances on the cellular and molecular mechanisms involved in DS complex phenotype. We also propose that in DS, one of the main consequences of the defective GABAergic signalling during development is to impair glial cells maturation and functions, including their role in synaptogenesis, synaptic refinement and inflammatory responses. Developing new tools to restore GABAergic signalling and/or glial functions may pave the way for new more effective treatments in Dravet Syndrome.

Keywords: Epillepsy; GABA; Neurodevelopmental disorders; SCN1A; Seizures.