Potentiating a₂ subunit containing perisomatic GABA_A receptors protects against seizures in a mouse model of Dravet syndrome

Key points: Dravet syndrome mice (Scn1a^+/-) demonstrate a marked strain dependence for the severity of seizures which is correlated with GABA_A receptor a₂ subunit expression. The a₂/a₃ subunit selective positive allosteric modulator (PAM) AZD7325 potentiates inhibitory postsynaptic currents (IPSCs) specifically in perisomatic synapses. AZD7325 demonstrates stronger effects on IPSCs in the seizure resistant mouse strain, consistent with higher a₂ subunit expression. AZD7325 demonstrates seizure protective effects in Scn1a^+/- mice without apparent sedative effects in vivo. Abstract: GABA_A receptor potentiators are commonly used for the treatment of epilepsy, but it is not clear whether targeting distinct GABA_A receptor subtypes will have disproportionate benefits over adverse effects. Here we demonstrate that the a₂/a₃ 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, which have been demonstrated to be seizure resistant in the model of Dravet syndrome (Scn1a^+/-), and in which the a₂ GABA_A receptor subunits are expressed at higher levels relative to in the seizure prone C57BL/6J background strain. Consistent with this, treatment of Scn1a^+/- mice with AZD7325 elevated the temperature threshold for hyperthermia-induced seizures without apparent sedative effects. Our results in a model system indicate that selectively targeting a₂ is a potential therapeutic option for Dravet syndrome.