Westenbroek_2023_Neurobiol.Dis_180_106099

Evidence suggests that inhibition of alpha/beta hydrolase-domain containing 6 (ABHD6) reduces seizures; however, the molecular mechanism of this therapeutic response remains unknown. We discovered that heterozygous expression of Abhd6 (Abhd6(+/-)) significantly reduced the premature lethality of Scn1a(+/-) mouse pups, a genetic mouse model of Dravet Syndrome (DS). Both Abhd6(+/-) mutation and pharmacological inhibition of ABHD6 reduced the duration and incidence of thermally induced seizures in Scn1a(+/-) pups. Mechanistically, the in vivo anti-seizure response resulting from ABHD6 inhibition is mediated by potentiation of gamma-aminobutyric acid receptors Type-A (GABA(A)R). Brain slice electrophysiology showed that blocking ABHD6 potentiates extrasynaptic (tonic) GABA(A)R currents that reduce dentate granule cell excitatory output without affecting synaptic (phasic) GABA(A)R currents. Our results unravel an unexpected mechanistic link between ABHD6 activity and extrasynaptic GABA(A)R currents that controls hippocampal hyperexcitability in a genetic mouse model of DS. BRIEF SUMMARY: This study provides the first evidence for a mechanistic link between ABHD6 activity and the control of extrasynaptic GABA(A)R currents that controls hippocampal hyperexcitability in a genetic mouse model of Dravet Syndrome and can be targeted to dampened seizures.