Oct 24, 2018

Potentiating α2 subunit containing perisomatic GABAA receptors protects against seizures in a mouse model of Dravet Syndrome

BioRxiv : the Preprint Server for Biology
Toshihiro NomuraAnis Contractor

Abstract

GABAA receptor potentiators are commonly used for the treatment of epilepsy, but it is not clear whether distinct GABAA receptor subtypes contribute to seizure activity, and whether targeting receptor subtypes will have disproportionate benefit over adverse effects. Here we demonstrate that the α2 / α3 selective positive allosteric modulator (PAM) AZD7325 preferentially potentiates hippocampal inhibitory responses at synapses proximal to the soma of CA1 neurons. The effect of AZD7325 on synaptic responses was more prominent in mice on the 129S6/SvEvTac background strain that has been demonstrated to be seizure resistant in the model of Dravet syndrome (Scn1a+/-) and in which the α2 GABAA receptor subunits are higher relative to in the C57BL/6J strain. Consistent with this, treatment of mice with AZD7325 is associated with a higher temperature threshold for hyperthermia-induced seizures in Scn1a+/- mice without apparent sedative effects. Our results in a model system indicate that selective targeting α2 is a potential therapeutic option for Dravet syndrome.

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Mentioned in this Paper

GABA-A Receptor alpha Subunit
poly((2-8)-alpha-N-acetylneuraminic acid)
Infantile Severe Myoclonic Epilepsy
Epilepsy
Neurons
SCN1A gene
Adverse Effects
Protein kinase modulator
Protein Subunits
Synapses

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