Sex specific correlation between GABAergic disruption in the dorsal hippocampus and flurothyl seizure susceptibility after neonatal hypoxic-ischemic brain injury

Charles R. Lechner; Melanie A. McNally; Mark St. Pierre; Ryan J. Felling; Frances J. Northington; Carl E. Stafstrom; Raul Chavez-Valdez

Neurobiology of Disease (Jan 2021)

Sex specific correlation between GABAergic disruption in the dorsal hippocampus and flurothyl seizure susceptibility after neonatal hypoxic-ischemic brain injury

Charles R. Lechner,
Melanie A. McNally,
Mark St. Pierre,
Ryan J. Felling,
Frances J. Northington,
Carl E. Stafstrom,
Raul Chavez-Valdez

Affiliations

Charles R. Lechner: Division of Neonatology, Department of Pediatrics, Johns Hopkins University School of Medicine, 600 North Wolf Street, Baltimore, MD 21287, USA
Melanie A. McNally: Department of Neurology, Johns Hopkins University School of Medicine, 600 North Wolf Street, Baltimore, MD 21287, USA
Mark St. Pierre: Division of Neonatology, Department of Pediatrics, Johns Hopkins University School of Medicine, 600 North Wolf Street, Baltimore, MD 21287, USA
Ryan J. Felling: Department of Neurology, Johns Hopkins University School of Medicine, 600 North Wolf Street, Baltimore, MD 21287, USA
Frances J. Northington: Division of Neonatology, Department of Pediatrics, Johns Hopkins University School of Medicine, 600 North Wolf Street, Baltimore, MD 21287, USA
Carl E. Stafstrom: Department of Neurology, Johns Hopkins University School of Medicine, 600 North Wolf Street, Baltimore, MD 21287, USA
Raul Chavez-Valdez: Division of Neonatology, Department of Pediatrics, Johns Hopkins University School of Medicine, 600 North Wolf Street, Baltimore, MD 21287, USA; Corresponding author at: Department of Pediatrics, Division of Neonatology, Johns Hopkins Hospital. 600 N. Wolfe Street, CMSC 6-104 Baltimore, MD 21287, USA.

Journal volume & issue: Vol. 148
p. 105222

Abstract

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Since neonatal hypoxia-ischemia (HI) disrupts the hippocampal (Hp) GABAergic network in the mouse and Hp injury in this model correlates with flurothyl seizure susceptibility only in male mice, we hypothesized that GABAergic disruption correlates with flurothyl seizure susceptibility in a sex-specific manner. C57BL6 mice were exposed to HI (Vannucci model) versus sham procedures at P10, randomized to normothermia (NT) or therapeutic hypothermia (TH), and subsequently underwent flurothyl seizure testing at P18. Only in male mice, Hp atrophy correlated with seizure susceptibility. The number of Hp parvalbumin positive interneurons (PV+INs) decreased after HI in both sexes, but TH attenuated this deficit only in females. In males only, seizure susceptibility directly correlated with the number of PV+INs, but not somatostatin or calretinin expressing INs. Hp GABAB receptor subunit levels were decreased after HI, but unrelated to later seizure susceptibility. In contrast, Hp GABAA receptor α1 subunit (GABAARα1) levels were increased after HI. Adjusting the number of PV+ INs for their GABAARα1 expression strengthened the correlation with seizure susceptibility in male mice. Thus, we identified a novel Hp sex-specific GABA-mediated mechanism of compensation after HI that correlates with flurothyl seizure susceptibility warranting further study to better understand potential clinical translation.

Published in Neurobiology of Disease

ISSN: 0969-9961 (Print); 1095-953X (Online)
Publisher: Elsevier
Country of publisher: United States
LCC subjects: Medicine: Internal medicine: Neurosciences. Biological psychiatry. Neuropsychiatry
Website: https://www.journals.elsevier.com/neurobiology-of-disease

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