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Mild chronic perturbation of inhibition severely alters hippocampal function.

ABSTRACT: Pentameric GABAA receptors mediate a large share of CNS inhibition. The ?2 subunit is a typical constituent. At least 11 mutations in the ?2 subunit cause human epilepsies, making the role of ?2-containing receptors in brain function of keen basic and translational interest. How small changes to inhibition may cause brain abnormalities, including seizure disorders, is unclear. In mice, we perturbed fast inhibition with a point mutation T272Y (T6'Y in the second membrane-spanning domain) to the ?2 subunit. The mutation imparts resistance to the GABAA receptor antagonist picrotoxin, allowing verification of mutant subunit incorporation. We confirmed picrotoxin resistance and biophysical properties in recombinant receptors. T6'Y ?2-containing receptors also exhibited faster deactivation but unaltered steady-state properties. Adult T6'Y knockin mice exhibited myoclonic seizures and abnormal cortical EEG, including abnormal hippocampal-associated theta oscillations. In hippocampal slices, picrotoxin-insensitive inhibitory synaptic currents exhibited fast decay. Excitatory/inhibitory balance was elevated by an amount expected from the IPSC alteration. Partial pharmacological correction of ?2-mediated IPSCs with diazepam restored total EEG power toward baseline, but had little effect on the abnormal low-frequency peak in the EEG. The results suggest that at least part of the abnormality in brain function arises from the acute effects of truncated inhibition.

SUBMITTER: Sun MY

PROVIDER: S-EPMC6848214 | biostudies-literature | 2019 Nov

REPOSITORIES: biostudies-literature

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Mild chronic perturbation of inhibition severely alters hippocampal function.

Sun Min-Yu MY Ziolkowski Luke L Lambert Peter P Shu Hong-Jin HJ Keiser Micah M Rensing Nicholas N Warikoo Natasha N Martinek Monika M Platnick Carson C Benz Ann A Bracamontes John J Akk Gustav G Steinbach Joe Henry JH Zorumski Charles F CF Wong Michael M Mennerick Steven S

Scientific reports 20191111 1

Pentameric GABA<sub>A</sub> receptors mediate a large share of CNS inhibition. The γ2 subunit is a typical constituent. At least 11 mutations in the γ2 subunit cause human epilepsies, making the role of γ2-containing receptors in brain function of keen basic and translational interest. How small changes to inhibition may cause brain abnormalities, including seizure disorders, is unclear. In mice, we perturbed fast inhibition with a point mutation T272Y (T6'Y in the second membrane-spanning domai ...[more]

PMID: 31712706

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Mild chronic perturbation of inhibition severely alters hippocampal function.

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Mild chronic perturbation of inhibition severely alters hippocampal function.

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