Can prenatal infection contribute to psychiatric disease in offspring?

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Science Translational Medicine  24 Feb 2016:
Vol. 8, Issue 327, pp. 327ec33
DOI: 10.1126/scitranslmed.aaf3846

While it may seem incredible that environmental factors experienced in utero can contribute to the onset of a disease more than two decades later, epidemiologists have long suspected that a wide variety of maternal infections during pregnancy could increase the risk of schizophrenia and bipolar disorder in adult offspring. Although animal models of maternal immune activation have consistently reproduced behavioral deficits in offspring, the functional mechanisms underlying these effects have been unclear.

Now, Canetta et al. report reduced functional GABAergic transmission specifically by the parvalbumin (PV)-positive subclass of interneurons in the medial prefrontal cortex of adult offspring exposed prenatally to maternal immune activation. This deficit occurred prior to any loss of PV neuron cell number and could not be explained by anatomical deficits or alterations in the intrinsic excitability of PV interneurons. Instead, reduced GABAergic release probability was consistent with a decrease in the amount of presynaptic GABA available for release, resulting from a strong trend in reduced levels of the GABA synthesizing enzyme (GAD67) in the PV neurons of these mice. This is consistent with findings of decreased GAD67 in PV neurons in postmortem brain tissue from patients with schizophrenia.

The authors used an optogenetics approach to demonstrate that decreased PV to pyramidal neuron functional connectivity was sufficient to reproduce the cognitive deficits and anxiety-related behavior they observed in mice exposed prenatally to maternal immune activation. Using optogenetics, they decreased PV interneuron activity with green light stimulation in healthy mice and replicated the cognitive deficits and anxiety-related behavior found in mice exposed prenatally to maternal immune activation. Together, these findings are convergent with those from a number of studies using genetic mouse models of schizophrenia, which have also hinted that abnormal PV interneuron function can contribute to this disorder.

S. Canetta et al., Maternal immune activation leads to selective functional deficits in offspring parvalbumin interneurons. Mol. Psychiatry 10.1038/mp.2015.222 (2016). [Abstract]

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