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