The serine hydrolase ABHD6 controls survival and thermally induced seizures in a mouse model of Dravet syndrome

Evidence suggests that inhibition of α/β 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_AR). Brain slice electrophysiology showed that blocking ABHD6 potentiates extrasynaptic (tonic) GABA_AR currents that reduce dentate granule cell excitatory output without affecting synaptic (phasic) GABA_AR currents. Our results unravel an unexpected mechanistic link between ABHD6 activity and extrasynaptic GABA_AR 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_AR currents that controls hippocampal hyperexcitability in a genetic mouse model of Dravet Syndrome and can be targeted to dampened seizures.