Hypersynchronicity in the default mode-like network in a neurodevelopmental animal model with relevance for schizophrenia

Background: Immune activation during pregnancy is an important risk factor for schizophrenia. Brain dysconnectivity and NMDA receptor (NMDAR) hypofunction have been postulated to be central to schizophrenia pathophysiology. The aim of this study was to investigate resting-state functional connectivity (resting-state functional MRI-rsfMRI), microstructure (diffusion tension imaging-DTI) and response to NMDAR antagonist (pharmacological fMRI-phMRI) using multimodal MRI in offspring of pregnant dams exposed to immune challenge (maternal immune activation-MIA model), and determine whether these neuroimaging readouts correlate with schizophrenia-related behaviour. Methods: Pregnant rats were injected with Poly I:C or saline on gestational day 15. The maternal weight response was assessed. Since previous research has shown behavioural deficits can differ between MIA offspring dependent on the maternal response to immune stimulus, offspring were divided into three groups: controls (saline, n = 11), offspring of dams that gained weight (Poly I:C WG, n = 12) and offspring of dams that lost weight post-MIA (Poly I:C WL, n = 16). Male adult offspring were subjected to rsfMRI, DTI, phMRI with NMDAR antagonist, behavioural testing and histological assessment. Results: Poly I:C WL offspring exhibited increased functional connectivity in default mode-like network (DMN). Poly I:C WG offspring showed the most pronounced attenuation in NMDAR antagonist response versus controls. DTI revealed no differences in Poly I:C offspring versus controls. Poly I:C offspring exhibited anxiety. Conclusions: MIA offspring displayed a differential pathophysiology depending on the maternal response to immune challenge. While Poly I:C WL offspring displayed hypersynchronicity in the DMN, altered NMDAR antagonist response was most pronounced in Poly I:C WG offspring.