Glycogen synthase kinase‐3 inhibition rescues sex‐dependent contextual fear memory deficit in human immunodeficiency virus‐1 transgenic mice

Background and Purpose A significant number of HIV‐1 patients on antiretroviral therapy develop HIV‐associated neurocognitive disorders (HAND). Evidence indicate that biological sex may regulate HAND pathogenesis, but the mechanisms remain unknown. We investigated synaptic mechanisms associated with sex differences in HAND, using the HIV‐1‐transgenic 26 (Tg26) mouse model. Experimental Approach Contextual‐ and cue‐dependent memories of male and female Tg26 mice and littermate wild type mice were assessed in a fear conditioning paradigm. Hippocampal electrophysiology, immunohistochemistry, western blot, qRT‐PCR and ELISA techniques were used to investigate cellular, synaptic and molecular impairments. Key Results Cue‐dependent memory was unaltered in male and female Tg26 mice, when compared to wild type mice. Male, but not female, Tg26 mice showed deficits in contextual fear memory. Consistently, only male Tg26 mice showed depressed hippocampal basal synaptic transmission and impaired LTP induction in area CA1. These deficits in male Tg26 mice were independent of hippocampal neuronal loss and microglial activation but were associated with increased HIV‐1 long terminal repeat mRNA expression, reduced hippocampal synapsin‐1 protein, reduced BDNF mRNA and protein, reduced AMPA glutamate receptor (GluA1) phosphorylation levels and increased glycogen synthase kinase 3 (GSK3) activity. Importantly, selective GSK3 inhibition using 4‐benzyl‐2‐methyl‐1,2,4‐thiadiazolidine‐3,5‐dione increased levels of synapsin‐1, BDNF and phosphorylated‐GluA1 proteins, restored hippocampal basal synaptic transmission and LTP, and improved contextual fear memory in male Tg26 mice. Conclusion and Implications Sex‐dependent impairments in contextual fear memory and synaptic plasticity in Tg26 mice are associated with increased GSK3 activity. This implicates GSK3 inhibition as a potential therapeutic strategy to improve cognition in HIV‐1 patients.