Sex-dependent sensitivity to positive allosteric modulation of GABA action in an APP knock-in mouse model of Alzheimer's disease: Potential epigenetic regulation

Conflicting evidence suggest that perturbations of GABAergic neurotransmission play crucial roles in disrupting cortical neuronal network oscillations, memory, and cognitive deficits in Alzheimer's disease (AD). However, the role and impact of sex differences on GABAergic transmission in AD are not well understood. Using an APP knock-in mouse model of AD, APP^NLGF mice, we studied the effects of acute diazepam administration on memory and anxiety-like behavior to unveil sex-dependent dysregulation of GABAergic neurotransmission. We also examined sex differences in GABA_A receptor subunit mRNA and protein expression and the role of epigenetic regulation in hippocampus of APP^NLGF mice. We found that diazepam elicited dose-dependent suppression of locomotion in wildtype and APP^NLGF mice. However, a low dose, which had no significant effect in both male and female wildtype as well as female APP^NLGF mice, significantly suppressed locomotion in male APP^NLGF mice. Furthermore, this low dose of diazepam was more efficacious at eliciting anxiolytic-like effects in male than female APP^NLGF mice. The same low dose of diazepam disrupted recognition memory exclusively in male APP^NLGF mice. Biochemical analyses revealed that hippocampal α1 and α5 GABA_A receptor subunits mRNA and protein expression were significantly higher in male than female APP^NLGF mice and were regulated by histone H3 tri-methylation (H3K4me3) but not histone H3 acetylation. The higher sensitivity of APP^NLGF males to diazepam-induced behavioral effects may potentially be due to epigenetic-dependent upregulation of hippocampal α1 and α5 GABA_A receptor subunits expression compared to female APP^NLGF mice. These findings suggest that dysregulation of GABAergic neurotransmission plays a significant role in memory and affective behavior, particularly in male APP^NLGF mice.