Sex-Dependent Modulation of AMPA and GABAA Receptors in Response to Perinatal Stress: Implications for Cognitive and Emotion-related Behaviors

Background: Early-life stress can severely impact brain health and neuronal plasticity, potentially leading to psychiatric disorders, with excitatory and inhibitory neurotransmission changes being key to understanding and mitigating these effects. Objective: We investigated the effects of Perinatal Stress (PRS) on the balance of excitatory and inhibitory neurotransmission, particularly focusing on AMPA and GABAA receptor protein levels and their relationship with cognition and risk-taking behavior in male and female Sprague-Dawley rats. Methods: Adult PRS offspring of dams exposed to 10 days of gestational restraint stress, which led to reduced maternal care, were evaluated at 3-4 months for behavioral responses to novelty, adverse environments, and recognition memory, with biochemical analyses conducted in the prefrontal cortex and the ventral and dorsal hippocampus. Results: PRS and sex notably affected behavior and AMPA/GABAA receptor subunit expression. PRS males showed reduced risk-taking behavior when exposed to novel and adverse environments and impaired recognition memory, while PRS females demonstrated better behavioral performance compared to both PRS males and control females. In the dorsal hippocampus, PRS increased the GluA2:GluA1 ratio and GABAA-α1 subunit in females but reduced them in males, modulating the AMPA/GABAA balance to enhance synaptic GABAergic inhibition and behavioral resilience in PRS females and control males. Conclusion: Our findings indicate that increased synaptic inhibition and reduced excitatory noise may underlie enhanced recognition memory and risk-taking behavior. The sex differences in PRS rats suggest that targeting AMPA or GABAA receptors could help treat early-life stress-related disorders and underscore the need for developing gender-specific therapies.