Kaplan J

References (2)

Title : The serine hydrolase ABHD6 controls survival and thermally induced seizures in a mouse model of Dravet syndrome - Westenbroek_2023_Neurobiol.Dis_180_106099
Author(s) : Westenbroek R , Kaplan J , Viray K , Stella N
Ref : Neurobiol Dis , 180 :106099 , 2023
Abstract : 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.
ESTHER : Westenbroek_2023_Neurobiol.Dis_180_106099
PubMedSearch : Westenbroek_2023_Neurobiol.Dis_180_106099
PubMedID: 36990366
Gene_locus related to this paper: human-ABHD6 , mouse-ABHD6

Title : ABHD6: Its Place in Endocannabinoid Signaling and Beyond - Cao_2019_Trends.Pharmacol.Sci_40_267
Author(s) : Cao JK , Kaplan J , Stella N
Ref : Trends in Pharmacological Sciences , 40 :267 , 2019
Abstract : The endocannabinoid (eCB) signaling system modulates neurotransmission and inflammation, among other physiological functions. Its newest member, alpha/beta-hydrolase domain-containing 6 (ABHD6), has emerged as a promising therapeutic target to treat several devastating diseases, including epilepsy. Here, we review the molecular mechanisms that mediate and control eCB signaling and, within it, the specific role of ABHD6. We also discuss how ABHD6 controls the abundance of additional lipids and the trafficking of ionotropic receptors to plasma membranes. We finish with several unexplored questions regarding this novel enzyme. Our current understanding of the molecular mechanism and biological function of ABHD6 provides a strong foundation for the development of small-molecule therapeutics to treat devastating diseases.
ESTHER : Cao_2019_Trends.Pharmacol.Sci_40_267
PubMedSearch : Cao_2019_Trends.Pharmacol.Sci_40_267
PubMedID: 30853109
Gene_locus related to this paper: human-ABHD6 , mouse-ABHD6