Mild chronic perturbation of inhibition severely alters hippocampal function

Min Yu Sun, Luke Ziolkowski, Peter Lambert, Hong Jin Shu, Micah Keiser, Nicholas Rensing, Natasha Warikoo, Monika Martinek, Carson Platnick, Ann Benz, John Bracamontes, Gustav Akk, Joe Henry Steinbach, Charles F. Zorumski, Michael Wong, Steven Mennerick

Research output: Contribution to journalArticle

Abstract

Pentameric GABAA 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 domain) to the γ2 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 γ2-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 γ2-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.

Original languageEnglish
Article number16431
JournalScientific reports
Volume9
Issue number1
DOIs
StatePublished - Dec 1 2019

Fingerprint Dive into the research topics of 'Mild chronic perturbation of inhibition severely alters hippocampal function'. Together they form a unique fingerprint.

  • Cite this

    Sun, M. Y., Ziolkowski, L., Lambert, P., Shu, H. J., Keiser, M., Rensing, N., Warikoo, N., Martinek, M., Platnick, C., Benz, A., Bracamontes, J., Akk, G., Steinbach, J. H., Zorumski, C. F., Wong, M., & Mennerick, S. (2019). Mild chronic perturbation of inhibition severely alters hippocampal function. Scientific reports, 9(1), [16431]. https://doi.org/10.1038/s41598-019-52851-w