Prenatal immune activation interacts with stress and corticosterone exposure later in life to modulate N-methyl-D-aspartate receptor synaptic function and plasticity.

Prenatal infection is an environmental risk factor for schizophrenia while later in life, stressful events have been associated with the onset and severity of psychosis. Recent findings on the impact of stress on the N-methyl-d-aspartate receptor (NMDAR), of which hypofunctioning is implicated in schizophrenia, suggest changes in stress-induced regulation of the glutamatergic system may be related to the pathogenesis of schizophrenia. Our study aimed to test whether prenatal immune activation could interact with stress at adolescence to alter NMDAR function. We used offspring from rat dams administered bacterial lipopolysaccharide (LPS) during pregnancy (gestational days 15 and 16), an animal model expressing schizophrenia-related behavioural phenotypes. Using electrophysiological techniques, we investigated effects of stress and the stress hormone corticosterone (Cort) on NMDAR-mediated synaptic function and long-term depression (LTD) in hippocampal CA1 slices from these adolescent (aged 28-39 d) male offspring. In prenatal LPS offspring, NMDAR-mediated synaptic function and LTD were reduced and abolished, respectively, compared to prenatal saline controls. Notably, in vivo stress and in vitro Cort treatment facilitated LTD in slices from prenatal LPS rats but not prenatal saline controls. Finally, Cort enhanced NMDAR-mediated synaptic function in slices from prenatal LPS rats only. We conclude that prenatal immune activation results in NMDAR hypofunction in the hippocampus of adolescent rats but also increases responsiveness of NMDAR-mediated synaptic function and LTD towards stress. Prenatal infection could confer susceptibility to schizophrenia through modification of hippocampal NMDAR function, with hypofunction in resting conditions and heightened responsiveness to stress, thus impacting the development of the disorder.