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

Toshihiro Nomura, Nicole Alise Hawkins, Jennifer A Kearney, Alfred L George Jr, Anis Contractor*

*Corresponding author for this work

Research output: Contribution to journalArticle

1 Citation (Scopus)

Abstract

Key points: Dravet syndrome mice (Scn1a+/-) demonstrate a marked strain dependence for the severity of seizures which is correlated with GABAA 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: GABAA receptor potentiators are commonly used for the treatment of epilepsy, but it is not clear whether targeting distinct GABAA 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 GABAA 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.

Original languageEnglish (US)
Pages (from-to)4293-4307
Number of pages15
JournalJournal of Physiology
Volume597
Issue number16
DOIs
StatePublished - Jan 1 2019

Fingerprint

Myoclonic Epilepsy
GABA-A Receptors
Seizures
Inhibitory Postsynaptic Potentials
Hypnotics and Sedatives
Synapses
Induced Hyperthermia
Carisoprodol
4-amino-8-(2-fluoro-6-methoxy-phenyl)-N-propylcinnoline-3-carboxamide
Epilepsy
Therapeutics
Neurons
Temperature

Keywords

  • Dravet syndrome
  • GABA receptor
  • a subunit

ASJC Scopus subject areas

  • Physiology

Cite this

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title = "Potentiating a2 subunit containing perisomatic GABAA receptors protects against seizures in a mouse model of Dravet syndrome",
abstract = "Key points: Dravet syndrome mice (Scn1a+/-) demonstrate a marked strain dependence for the severity of seizures which is correlated with GABAA 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: GABAA receptor potentiators are commonly used for the treatment of epilepsy, but it is not clear whether targeting distinct GABAA 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 GABAA 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.",
keywords = "Dravet syndrome, GABA receptor, a subunit",
author = "Toshihiro Nomura and Hawkins, {Nicole Alise} and Kearney, {Jennifer A} and {George Jr}, {Alfred L} and Anis Contractor",
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T1 - Potentiating a2 subunit containing perisomatic GABAA receptors protects against seizures in a mouse model of Dravet syndrome

AU - Nomura, Toshihiro

AU - Hawkins, Nicole Alise

AU - Kearney, Jennifer A

AU - George Jr, Alfred L

AU - Contractor, Anis

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N2 - Key points: Dravet syndrome mice (Scn1a+/-) demonstrate a marked strain dependence for the severity of seizures which is correlated with GABAA 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: GABAA receptor potentiators are commonly used for the treatment of epilepsy, but it is not clear whether targeting distinct GABAA 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 GABAA 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.

AB - Key points: Dravet syndrome mice (Scn1a+/-) demonstrate a marked strain dependence for the severity of seizures which is correlated with GABAA 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: GABAA receptor potentiators are commonly used for the treatment of epilepsy, but it is not clear whether targeting distinct GABAA 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 GABAA 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.

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