Maternal separation stress through triggering of the neuro-immune response in the hippocampus induces autistic-like behaviors in male mice

Autism spectrum disorder (ASD) is the fastest-growing neurodevelopmental disease throughout the world. Neuro-immune responses from prenatal to adulthood stages of life induce developmental defects in synaptic signaling, neurotransmitter imbalance, and even structural changes in the brain. In this study, we aimed to focus on the possible role of neuroinflammatory response in the hippocampus in development of the autistic-like behaviors following maternal separation (MS) stress in mice. To do this, mice neonates daily separated from their mothers from postnatal day (PND) 2 to PND 14 for 3 h. During PND45-60, behavioral tests related to autistic-like behaviors including three-chamber sociability, Morris water maze (MWM), shuttle box, resident-intruder, and marble burying tests were performed. Then, hippocampi were dissected out, and the gene expression of inflammatory mediators including TNF-alpha, IL-1 beta, TLR4, HMGB1, and NLRP3 was assessed in the hippocampus using RT-PCR. Results showed that MS mice exerted impaired sociability preference, repetitive behaviors, impaired passive avoidance, and spatial memories. The gene expression of inflammatory mediators significantly increased in the hippocampi of MS mice. We concluded that MS stress probably via activating of the HMGB1/TLR4 signaling cascade in the hippocampus induced autistic-like behaviors in mice. Maternal separation (MS), in part at least, through activation of the HMGB1/TLR4 signaling cascade in the hippocampus provokes autistic-like behaviors in mice as impaired sociability preference, repetitive behaviors as well as impaired passive avoidance and spatial memories.