Interaction between maternal immune activation and postpartum immune stress in neuropsychiatric phenotypes.

Epidemiological evidence has shown that maternal infection is a notable risk factor for developmental psychiatric disorders. Animal models have corroborated this link and demonstrated that maternal immune activation (MIA) induces long-term behavioural deficits and neuroimmunological responses to subsequent immune stress in offspring. However, it is unclear whether MIA offspring are more sensitive or more tolerant to immunological challenges from postnatal infections. Pregnant mice were weighed and injected with a single dose of polyinosinic-polycytidylic acid (poly I:C) or saline at gestational day 9.5, and their male offspring were exposed to poly I:C or saline again during adolescence, adulthood, and middle life. After a two-week recovery from the last exposure to poly I:C, the mice underwent behavioural and neuroendophenotypic evaluations. Finally, the mice were sacrificed, and the expression levels of inflammatory factors and the activation levels of glial cells in the cerebral cortex and hippocampus were evaluated. We found MIA mice have lifelong behavioural deficits and glial activation abnormalities. Postpartum infection exposure at different ages has different consequences. Adolescent and middle life exposure prevents sensorimotor gating deficiency, but adult exposure leads to increased sensitivity to MK-801. Moreover, MIA imposed a lasting impact on the neuroimmune profile, resulting in an enhanced cytokine-associated response and diminished microglial reactivity to postnatal infection. Our results reveal an intricate interplay between prenatal and postpartum infection in neuropsychiatric phenotypes, which identify potential windows where preventive or mitigating measures could be applied.

Non-neutralizing antibodies to SARS-Cov-2-related linear epitopes induce psychotic-like behavior in mice.

Objective: An increasing number of studies have reported that numerous patients with coronavirus disease 2019 (COVID-19) and vaccinated individuals have developed central nervous system (CNS) symptoms, and that most of the antibodies in their sera have no virus-neutralizing ability. We tested the hypothesis that non-neutralizing anti-S1-111 IgG induced by the spike protein of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) could negatively affect the CNS. Methods: After 14-day acclimation, the grouped ApoE-/- mice were immunized four times (day 0, day 7, day 14, day 28) with different spike-protein-derived peptides (coupled with KLH) or KLH via subcutaneous injection. Antibody level, state of glial cells, gene expression, prepulse inhibition, locomotor activity, and spatial working memory were assessed from day 21. Results: An increased level of anti-S1-111 IgG was measured in their sera and brain homogenate after the immunization. Crucially, anti-S1-111 IgG increased the density of microglia, activated microglia, and astrocytes in the hippocampus, and we observed a psychomotor-like behavioral phenotype with defective sensorimotor gating and impaired spontaneity among S1-111-immunized mice. Transcriptome profiling showed that up-regulated genes in S1-111-immunized mice were mainly associated with synaptic plasticity and mental disorders. Discussion: Our results show that the non-neutralizing antibody anti-S1-111 IgG induced by the spike protein caused a series of psychotic-like changes in model mice by activating glial cells and modulating synaptic plasticity. Preventing the production of anti-S1-111 IgG (or other non-neutralizing antibodies) may be a potential strategy to reduce CNS manifestations in COVID-19 patients and vaccinated individuals.