Microglia-mediated neurogenesis is linked to cognitive deficits in a two-hit model of maternal immune activation and juvenile stress

Maternal immune activation (MIA), combined with exposure to a second environmental stressor, contributes to neurodevelopmental disorders in offspring. Immune-challenged microglial cells play a crucial role in the pathogenesis of these disorders. However, the mechanisms through which microglia mediate cognitive impairments in individuals exposed to dual stresses remain poorly understood. In this research, pregnant rat dams were subjected to viral mimetic, poly(I:C), and their young male offspring were either exposed to a second stressor or not during juvenile age. The results showed that a pathological microglial phenotype was accompanied by impairments in hippocampal neurogenesis and deficits in hippocampus-dependent spatial learning and memory in the MIA offspring exposed to the second stressor during juvenile age. Minocycline shifts pathological microglial cells to a neuroprotective state, alleviating neurogenesis impairments and spatial learning and memory deficits in these “two-hit” animals. However, the cognitive improvements induced by minocycline were blocked by temozolomide treatment, as evidenced by the inhibition of neurogenesis. Our findings highlight the important role of hippocampal neurogenesis in inflammatory-mediated cognitive abnormalities and provide insights into the roles of microglia underlying neurodevelopmental disorders.