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Maternal immune activation leads to selective functional deficits in offspring parvalbumin interneurons

Abstract

Abnormalities in prefrontal gamma aminobutyric acid (GABA)ergic transmission, particularly in fast-spiking interneurons that express parvalbumin (PV), are hypothesized to contribute to the pathophysiology of multiple psychiatric disorders, including schizophrenia, bipolar disorder, anxiety disorders and depression. While primarily histological abnormalities have been observed in patients and in animal models of psychiatric disease, evidence for abnormalities in functional neurotransmission at the level of specific interneuron populations has been lacking in animal models and is difficult to establish in human patients. Using an animal model of a psychiatric disease risk factor, prenatal maternal immune activation (MIA), we found reduced functional GABAergic transmission in the medial prefrontal cortex (mPFC) of adult MIA offspring. Decreased transmission was selective for interneurons expressing PV, resulted from a decrease in release probability and was not observed in calretinin-expressing neurons. This deficit in PV function in MIA offspring was associated with increased anxiety-like behavior and impairments in attentional set shifting, but did not affect working memory. Furthermore, cell-type specific optogenetic inhibition of mPFC PV interneurons was sufficient to impair attentional set shifting and enhance anxiety levels. Finally, we found that in vivo mPFC gamma oscillations, which are supported by PV interneuron function, were linearly correlated with the degree of anxiety displayed in adult mice, and that this correlation was disrupted in MIA offspring. These results demonstrate a selective functional vulnerability of PV interneurons to MIA, leading to affective and cognitive symptoms that have high relevance for schizophrenia and other psychiatric disorders.

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Acknowledgements

We would like to thank Bhavani Ramesh, Mariya Shegda and Lindsay Kenney for their assistance with genotyping of mice and Heather Perusini, Kafi Friday and Katherine Yao for their assistance with behavioral and electrophysiological studies. Confocal images were collected in the Confocal and Specialized Microscopy Shared Resource of the Herbert Irving Comprehensive Cancer Center at Columbia University, supported by NIH grant #P30 CA013696 (National Cancer Institute). This work was supported by a Schaefer Research Scholar Award (CK), a NIMH T32 Training Grant (MH16434-31, SC), NARSAD Young Investigator Award (SC), a Sackler Institute for Developmental Psychobiology Fellowship (SC), a K02 MH065422 (AB) and AA19801 and AA023531 to NLH.

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SC, SB, AB, NLH, JAG and CK designed the experiments and wrote the manuscript. SC, SB, NP, LJS and RS performed the experiments.

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Canetta, S., Bolkan, S., Padilla-Coreano, N. et al. Maternal immune activation leads to selective functional deficits in offspring parvalbumin interneurons. Mol Psychiatry 21, 956–968 (2016). https://doi.org/10.1038/mp.2015.222

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