دورية أكاديمية
أعرض في EDS

Mild chronic perturbation of inhibition severely alters hippocampal function.

التفاصيل البيبلوغرافية
العنوان: Mild chronic perturbation of inhibition severely alters hippocampal function.
المؤلفون: Sun MY; Department of Psychiatry, Washington University School of Medicine, St. Louis, USA., Ziolkowski L; Department of Psychiatry, Washington University School of Medicine, St. Louis, USA., Lambert P; Department of Psychiatry, Washington University School of Medicine, St. Louis, USA.; MSTP Training Program, Washington University School of Medicine, St. Louis, USA., Shu HJ; Department of Psychiatry, Washington University School of Medicine, St. Louis, USA., Keiser M; Department of Psychiatry, Washington University School of Medicine, St. Louis, USA., Rensing N; Department of Neurology, Washington University School of Medicine, St. Louis, USA., Warikoo N; Department of Psychiatry, Washington University School of Medicine, St. Louis, USA., Martinek M; Department of Psychiatry, Washington University School of Medicine, St. Louis, USA., Platnick C; Department of Psychiatry, Washington University School of Medicine, St. Louis, USA., Benz A; Department of Psychiatry, Washington University School of Medicine, St. Louis, USA., Bracamontes J; Department of Anesthesiology, Washington University School of Medicine, St. Louis, USA., Akk G; Department of Anesthesiology, Washington University School of Medicine, St. Louis, USA.; Taylor Family Institute for Innovative Psychiatric Research, St. Louis, USA., Steinbach JH; Department of Anesthesiology, Washington University School of Medicine, St. Louis, USA.; Taylor Family Institute for Innovative Psychiatric Research, St. Louis, USA., Zorumski CF; Department of Psychiatry, Washington University School of Medicine, St. Louis, USA.; Department of Neuroscience, Washington University School of Medicine, St. Louis, USA.; Taylor Family Institute for Innovative Psychiatric Research, St. Louis, USA., Wong M; Department of Neurology, Washington University School of Medicine, St. Louis, USA., Mennerick S; Department of Psychiatry, Washington University School of Medicine, St. Louis, USA. menneris@wustl.edu.; Department of Neuroscience, Washington University School of Medicine, St. Louis, USA. menneris@wustl.edu.; Taylor Family Institute for Innovative Psychiatric Research, St. Louis, USA. menneris@wustl.edu.
المصدر: Scientific reports [Sci Rep] 2019 Nov 11; Vol. 9 (1), pp. 16431. Date of Electronic Publication: 2019 Nov 11.
نوع المنشور: Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't
اللغة: English
بيانات الدورية: Publisher: Nature Publishing Group Country of Publication: England NLM ID: 101563288 Publication Model: Electronic Cited Medium: Internet ISSN: 2045-2322 (Electronic) Linking ISSN: 20452322 NLM ISO Abbreviation: Sci Rep Subsets: MEDLINE
أسماء مطبوعة: Original Publication: London : Nature Publishing Group, copyright 2011-
مواضيع طبية MeSH: Neural Inhibition*, Hippocampus/*metabolism , Hippocampus/*physiopathology, Animals ; Biomarkers ; Cell Line ; Diazepam/pharmacology ; Disease Susceptibility ; Electroencephalography ; Excitatory Postsynaptic Potentials/drug effects ; Humans ; Immunohistochemistry ; Inhibitory Postsynaptic Potentials/drug effects ; Mice ; Mice, Knockout ; Receptors, GABA-A/genetics ; Receptors, GABA-A/metabolism ; gamma-Aminobutyric Acid/metabolism
مستخلص: Pentameric GABA A 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 GABA A 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.
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معلومات مُعتمدة: R01 GM108580 United States GM NIGMS NIH HHS; R21 MH111461 United States MH NIMH NIH HHS; U54 HD087011 United States HD NICHD NIH HHS; T32 GM007200 United States GM NIGMS NIH HHS; R21 MH104506 United States MH NIMH NIH HHS; R21 MH114866 United States MH NIMH NIH HHS; T32GM007200 International U.S. Department of Health & Human Services | NIH | National Institute of General Medical Sciences (NIGMS); R21 AA026753 United States AA NIAAA NIH HHS
المشرفين على المادة: 0 (Biomarkers)
0 (Receptors, GABA-A)
56-12-2 (gamma-Aminobutyric Acid)
Q3JTX2Q7TU (Diazepam)
تواريخ الأحداث: Date Created: 20191113 Date Completed: 20201106 Latest Revision: 20240721
رمز التحديث: 20240721
مُعرف محوري في PubMed: PMC6848214
DOI: 10.1038/s41598-019-52851-w
PMID: 31712706
قاعدة البيانات: MEDLINE
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