Neuron
Volume 83, Issue 2, 16 July 2014, Pages 361-371
Journal home page for Neuron

Article
ABHD6 Blockade Exerts Antiepileptic Activity in PTZ-Induced Seizures and in Spontaneous Seizures in R6/2 Mice

https://doi.org/10.1016/j.neuron.2014.06.030Get rights and content
Under an Elsevier user license
open archive

Highlights

  • ABHD6 blockade by WWL123 controls PTZ-induced seizures without psychomotor effects

  • The effect of WWL123is retained in Cnr1−/− and Cnr2−/− mice but blocked by picrotoxin

  • WWL123 also blocks spontaneous seizures in the R6/2 mouse model of juvenile HD

  • R6/2 hippocampi feature electrographic abnormalities and profound loss of NPY

Summary

The serine hydrolase α/β-hydrolase domain 6 (ABHD6) hydrolyzes the most abundant endocannabinoid (eCB) in the brain, 2-arachidonoylglycerol (2-AG), and controls its availability at cannabinoid receptors. We show that ABHD6 inhibition decreases pentylenetetrazole (PTZ)-induced generalized tonic-clonic and myoclonic seizure incidence and severity. This effect is retained in Cnr1−/− or Cnr2−/− mice, but blocked by addition of a subconvulsive dose of picrotoxin, suggesting the involvement of GABAA receptors. ABHD6 inhibition also blocked spontaneous seizures in R6/2 mice, a genetic model of juvenile Huntington’s disease known to exhibit dysregulated eCB signaling. ABHD6 blockade retained its antiepileptic activity over chronic dosing and was not associated with psychomotor or cognitive effects. While the etiology of seizures in R6/2 mice remains unsolved, involvement of the hippocampus is suggested by interictal epileptic discharges, increased expression of vGLUT1 but not vGAT, and reduced Neuropeptide Y (NPY) expression. We conclude that ABHD6 inhibition may represent a novel antiepileptic strategy.

Cited by (0)

10

Co-first author