Neurodevelopmental defects in Dravet syndromeScn1a^+/-mice: selective rescue of behavioral alterations but not seizures by targeting GABA-switch

Abstract

Dravet syndrome (DS) is a developmental and epileptic encephalopathy (DEE) caused by mutations of the SCN1A gene and characterized by seizures, motor disabilities and cognitive/behavioral deficits, including autistic traits. The relative role of seizures and neurodevelopmental defects in disease progression is not clear yet. A delayed switch of GABAergic transmission from excitatory to inhibitory (GABA-switch) has been reported in models of DS, but its effects on the phenotype have not been investigated. In the Scn1a+/- mouse model of DS, we studied GABA-switch and neurodevelopmental defects before the onset of spontaneous seizures, and assessed their impact on epileptic and behavioral phenotypes performing specific treatments. We evaluated in vivo features performing behavioral tests and cellular/network properties performing ex-vivo electrophysiological recordings. Rescue of GABA-switch with the drugs KU55933 (KU) or bumetanide improved cognitive/behavioral defects. However, the treatments had no effect on seizures or mortality rate. Moreover, we observed early behavioral defects and delayed neurodevelopmental milestones well before seizure onset. Thus, we disclosed neurodevelopmental components in DS that selectively underlie some cognitive/behavioral defects, but not seizures, and provide evidence to the hypothesis that seizures and neuropsychiatric dysfunctions can be uncoupled in DEEs. They could be treated separately with targeted pharmacological strategies.