Biphasic Impact of Prenatal Inflammation and Macrophage Depletion on the Wiring of Neocortical Inhibitory Circuits Thion, Morgane Sonia et al. Cell Reports, Volume 28, Issue 5, 1119 - 1126.e4
The etiology of neurodevelopmental disorders is linked to defects in parvalbumin (PV)-expressing cortical interneurons and to prenatal immune challenges. Mouse models of maternal immune activation (MIA) and microglia deficits increase the postnatal density of PV interneurons, raising the question of their functional integration. Here, we show that MIA and embryonic depletion of macrophages including microglia have a two-step impact on PV interneurons wiring onto their excitatory target neurons in the barrel cortex. In adults, both challenges reduced the inhibitory drive from PV interneurons, as reported in neurodevelopmental disorders. In juveniles, however, we found an increased density of PV neurons, an enhanced strength of unitary connections onto excitatory cells, and an aberrant horizontal inhibition with a reduced lateral propagation of sensory inputs in vivo. Our results provide a comprehensive framework for understanding the impact of prenatal immune challenges onto the developmental trajectory of inhibitory circuits that leads to pathological brain wiring.
We are grateful to members of the Garel and Audinat labs for discussions and critical comments on the manuscript. We thank the IBENS Imaging Facility (France BioImaging, supported by ANR-10-INBS-04, ANR-10-LABX-54 MEMO LIFE, and ANR-11-IDEX-000-02 PSL Research University, ‘‘Investments for the future’’). We are grateful to C. Auger, A. Delecourt, E. Touzalin, D. Valera, C. Le Moal, A. David, and M. Omnes, for excellent technical assistance. This work was supported by grants from INSERM, CNRS, the ERC Consolidator Grant NImO 616080 to S.G., and by grants from INSERM, the Fondation pour la Recherche Me´ dicale (FRM: DEQ20140329488), European Commission (H2020-MSCA-722053 EU-GliaPhD) to E.A. C.-A.M. was supported by the Re´ gion ^Ile-de-France (DIM Cerveau et Pense´ e) and by the FRM (FDT20170739030). F.G. is an EMBO YIP awardee and is supported by Singapore Immunology Network (SIgN) core funding as well as a Singapore National Research Foundation Senior Investigatorship (NRFI; NRF2016NRFNRFI001-02).