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Cell Rep. 2019 Jul 30;28(5):1119-1126.e4. doi: 10.1016/j.celrep.2019.06.086.

Biphasic Impact of Prenatal Inflammation and Macrophage Depletion on the Wiring of Neocortical Inhibitory Circuits.

Author information

1
Institut de Biologie de l'École Normale Supérieure (IBENS), Département de Biologie, École Normale Supérieure, CNRS, INSERM, Université PSL, 75005 Paris, France. Electronic address: thion@biologie.ens.fr.
2
Neurophysiologie et Nouvelles Microscopies, INSERM U1128, Université Paris Descartes, 75006 Paris, France.
3
Institut des Neurosciences Paris-Saclay (NeuroPSI), Département de Neurosciences Intégratives et Computationnelles (ICN), CNRS, Université Paris Sud, UMR9197, 91190 Gif-sur-Yvette, France.
4
Institut de Biologie de l'École Normale Supérieure (IBENS), Département de Biologie, École Normale Supérieure, CNRS, INSERM, Université PSL, 75005 Paris, France.
5
Singapore Immunology Network (SIgN), Agency for Science, Technology and Research (A(∗)STAR), Singapore 138648, Singapore.
6
Institut de Biologie de l'École Normale Supérieure (IBENS), Département de Biologie, École Normale Supérieure, CNRS, INSERM, Université PSL, 75005 Paris, France. Electronic address: garel@biologie.ens.fr.
7
Neurophysiologie et Nouvelles Microscopies, INSERM U1128, Université Paris Descartes, 75006 Paris, France; Institut de Génomique Fonctionnelle (IGF), CNRS, INSERM, Université de Montpellier, 34094 Montpellier, France. Electronic address: etienne.audinat@igf.cnrs.fr.

Abstract

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.

KEYWORDS:

barrel; cortex; inhibition; interneurons; macrophages; maternal immune activation; microglia; optogenetics; parvalbumin; somatosensory; voltage-sensitive dye imaging

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