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

Abstract

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 GABA_B receptor subunit levels were decreased after HI, but unrelated to later seizure susceptibility. In contrast, Hp GABA_A receptor α1 subunit (GABA_ARα1) levels were increased after HI. Adjusting the number of PV⁺ INs for their GABA_ARα1 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.

Keywords: GABA receptor; Hypoxic-ischemic brain injury; Neonatal brain injury; Neonatal seizure; Parvalbumin; Sex-dimorphism; Somatostatin.