Behavioral as well as hippocampal transcriptomic and microglial responses differ across sexes in adult mouse offspring exposed to a dual genetic and environmental challenge

• Published in: Brain, behavior, and immunity behavior, and immunity, 2024-02, Vol.116, p.126-139
• Main Authors: Carrier, Micaël, Hui, Chin W., Watters, Valérie, Šimončičová, Eva, Picard, Katherine, González Ibáñez, Fernando, Vernoux, Nathalie, Droit, Arnaud, Desjardins, Michèle, Tremblay, Marie-Ève
• Format: Article
• Language: English
• Subjects: CX3CR1 knockout; GABA; Hippocampus; Maternal immune activation; Microglia; Mood disorders; Mouse model; Schizophrenia; Viral infection
• ISSN: 0889-1591; 1090-2139
• DOI: 10.1016/j.bbi.2023.11.025

•Dual-challenged males had schizophrenia-like behavioral alterations at adulthood.•Dual-challenged females instead displayed anxious-like behavior at adulthood.•Dual-challenged females reduced GABAergic transmission genes at adulthood.•Dual-challenged male microglia presented a blunted morphology at adulthood.•Dual-challenged female microglia instead adopted a hypertrophic morphology. A wide range of positive, negative, and cognitive symptoms compose the clinical presentation of schizophrenia. Schizophrenia is a multifactorial disorder in which genetic and environmental risk factors interact for a full emergence of the disorder. Infectious challenges during pregnancy are a well-known environmental risk factor for schizophrenia. Also, genetic variants affecting the function of fractalkine signaling between neurons and microglia were linked to schizophrenia. Translational animal models recapitulating these complex gene-environment associations have a great potential to untangle schizophrenia neurobiology and propose new therapeutic strategies. Given that genetic variants affecting the function of fractalkine signaling between neurons and microglia were linked to schizophrenia, we compared the outcomes of a well-characterized model of maternal immune activation induced using the viral mimetic polyinosinic:polycytidylic acid (Poly I:C) in wild-type versus fractalkine receptor knockout mice. Possible behavioral and immune alterations were assessed in male and female offspring during adulthood. Considering the role of the hippocampus in schizophrenia, microglial analyses and bulk RNA sequencing were performed within this region to assess the neuroimmune dynamics at play. Males and females were examined separately. Offspring exposed to the dual challenge paradigm exhibited symptoms relevant to schizophrenia and unpredictably to mood disorders. Males displayed social and cognitive deficits related to schizophrenia, while females mainly presented anxiety-like behaviors related to mood disorders. Hippocampal microglia in females exposed to the dual challenge were hypertrophic, indicative of an increased surveillance, whereas those in males showed on the other end of the spectrum blunted morphologies with a reduced phagocytosis. Hippocampal bulk-RNA sequencing further revealed a downregulation in females of genes related to GABAergic transmission, which represents one of the main proposed causes of mood disorders. Building on previous results, we identified in the cu