IMMUNE INVOLVEMENT IN AUTISM & SCHIZOPHRENIA: ETIOLOGY AND AN ANIMALMODEL

Abstract

Introduction: Maternal infection is associated with increased schizophrenia in the offspring. In a mouse model of this risk factor, infection with influenza virus at mid-gestation leads to post-pubertal onset of behavioral abnormalities in the offspring that are consistent with abnormalities seen in schizophrenia, and which are corrected by anti-psychotic drugs. There is also neuropathology that is consistent with that seen in schizophrenia and autism. The cause of these abnormalities is maternal immune activation (MIA), as treatment of uninfected, pregnant mice with the dsRNA, polyI:C, which evokes an anti-viral-like immune response, mimics the effects of infection on the offspring. Since infection and polyI:C induce cytokines, we asked whether these proteins mediate the effects of MIA on the fetal brain. Methods: Pregnant mice were injected with either interleukin-6 (IL-6), or with polyI:C +/- anti-cytokine antibodies. Pregnant IL-6 knockoutmice were also injected with polyI:C. The adult offspring were behaviorally tested, and their gene expression in the frontal cortex analyzed by microarray. Results: After testing a variety of cytokines, we found that injection of IL-6 in normal pregnant mice causes behavioral deficits in the offspring similar to those caused by MIA. In the converse experiment, co-injection of anti-IL-6 antibody (but not anti-IFN) with polyI:C in pregnant mice strongly attenuates the effects of MIA on the behavior of the offspring. Moreover, maternal anti-IL-6 blocks the changes in gene expression in the brains of adult offspring that are caused by maternal polyI:C treatment. Finally, the offspring of polyI:C-treated IL-6 knockout mice do not display behavioral abnormalities. Conclusions: Thus, the cytokine IL-6 is a key mediator of the effects of MIA on fetal brain development. Our new findings with the adult offspring of MIA mothers that are relevant for schizophrenia include abnormalities in eyeblink conditioning and water maze performance, hippocampal CA1 neuron responses to dopamine, and a delay in the migration of late-born cortical neurons.