ORIGINAL RESEARCH published: 01 June 2021 doi: 10.3389/fcell.2021.653384 Edited by: James A. Coffman, Mount Desert Island Biological Laboratory, United States Reviewed by: Melissa J. Glenn, Colby College, United States Laurence Coutellier, The Ohio State University, United States *Correspondence: Marco Andrea Riva m.riva@unimi.it Specialty section: This article was submitted to Developmental Epigenetics, a section of the journal Frontiers in Cell and Developmental Biology Received: 14 January 2021 Accepted: 07 April 2021 Published: 01 June 2021 Citation: Marchisella F, Creutzberg KC, Begni V, Sanson A, Wearick-Silva LE, Tractenberg SG, Orso R, Kestering-Ferreira É, Grassi-Oliveira R and Riva MA (2021) Exposure to Prenatal Stress Is Associated With an Excitatory/Inhibitory Imbalance in Rat Prefrontal Cortex and Amygdala and an Increased Risk for Emotional Dysregulation. Front. Cell Dev. Biol. 9:653384. doi: 10.3389/fcell.2021.653384 Exposure to Prenatal Stress Is Associated With an Excitatory/Inhibitory Imbalance in Rat Prefrontal Cortex and Amygdala and an Increased Risk for Emotional Dysregulation Francesca Marchisella 1 , Kerstin Camile Creutzberg 1 , Veronica Begni 1 , Alice Sanson 1 , Luis Eduardo Wearick-Silva 2 , Saulo Gantes Tractenberg 2 , Rodrigo Orso 2 , Érika Kestering-Ferreira 2 , Rodrigo Grassi-Oliveira 2,3 and Marco Andrea Riva 1,4 * 1 Laboratory of Psychopharmacology and Molecular Psychiatry, Department of Pharmacological and Biomolecular Sciences, University of Milan, Milan, Italy, 2 Developmental Cognitive Neuroscience Lab, Brain Institute, Pontifical Catholic University of Rio Grande do Sul, Porto Alegre, Brazil, 3 Translational Neuropsychiatry Unit, Department of Clinical Medicine, Aarhus University, Aarhus, Denmark, 4 Biological Psychiatry Unit, IRCCS Istituto Centro San Giovanni di Dio Fatebenefratelli Brescia, Brescia, Italy Epidemiological studies have shown that environmental insults and maternal stress during pregnancy increase the risk of several psychiatric disorders in the offspring. Converging lines of evidence from humans, as well as from rodent models, suggest that prenatal stress (PNS) interferes with fetal development, ultimately determining changes in brain maturation and function that may lead to the onset of neuropsychiatric disorders. From a molecular standpoint, transcriptional alterations are thought to play a major role in this context and may contribute to the behavioral phenotype by shifting the expression of genes related to excitatory and inhibitory (E/I) transmission balance. Nevertheless, the exact neurophysiological mechanisms underlying the enhanced vulnerability to psychopathology following PNS exposure are not well understood. In the present study, we used a model of maternal stress in rats to investigate the distal effects of PNS on the expression of genes related to glutamatergic and GABAergic neurotransmissions. We inspected two critical brain regions involved in emotion regulation, namely, the prefrontal cortex (PFC) and the amygdala (AMY), which we show to relate with the mild behavioral effects detected in adult rat offspring. We observed that PNS exposure promotes E/I imbalance in the PFC of adult males only, by dysregulating the expression of glutamatergic-related genes. Moreover, such an effect is accompanied by increased expression of the activity-dependent synaptic modulator gene Npas4 specifically in the PFC parvalbumin (PV)-positive interneurons, suggesting an altered Frontiers in Cell and Developmental Biology | www.frontiersin.org 1 June 2021 | Volume 9 | Article 653384