THE MECHANISM OF PATHOGENESIS OF AN AUTISM RISK FACTOR: ACTIVATION OF THE MATERNAL IMMUNE SYSTEM ALTERS FETAL BRAIN DEVELOPMENT VIA IL-6

Maternal infection is associated with increased autism and 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 these mental disorders. 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. 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. Thus, the cytokine IL-6 is a key mediator of the effects of MIA on fetal brain development. Additional new findings with the adult offspring of MIA mothers that are relevant for autism and schizophrenia include abnormalities in eyeblink conditioning, hippocampal CA1 neuron responses to dopamine, and a delay in the migration of late-born cortical neurons.