Exposure to Prenatal Stress Is Associated With an Excitatory/Inhibitory Imbalance in Rat Prefrontal Cortex and Amygdala and an Increased Risk for Emotional Dysregulation

Abstract

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 regulation of synapse formation promoting higher PV-dependent inhibitory transmission and increased overall circuit inhibition in the PFC of males. In the AMY, PNS more evidently affects the transcription of GABAergic-related genes, shifting the balance toward inhibition. Collectively, our findings suggest that the E/I dysregulation of the PFC-to-AMY transmission may be a long-term signature of PNS and may contribute to increase the risk for mood disorder upon further stress.

Autistic-like behavioral effects of prenatal stress in juvenile Fmr1 mice: the relevance of sex differences and gene–environment interactions

“…One possible explanation lies in the prosocial effects of increased oxytocin, since this has been described in hypothalamic and limbic brain regions following exposure to a variety of stressors 63 . A second possible interpretation may consider the increased social interaction of WT stressed mice as a reflection of a the altered excitatory/inhibitory(E/I) imbalance induced by stress especially in brain circuits involving the prefrontal cortex 15 , 64 , known to critically control social behaviors in rodents 65 , 66 . Our findings suggest that these potential changes in oxytonergic or E/I systems are in any case induced by stress only in WT mice, perhaps because of a reduced functionality of these adaptive mechanisms of stress response in our Fmr1 mutant animals.…”

Integrating the Neurodevelopmental and Dopamine Hypotheses of Schizophrenia and the Role of Cortical Excitation-Inhibition Balance

“…Rodent studies show a range of stressors affect frontal E/I balance. Prenatal stress exposure (123), social instability stress (124) and stress during adolescence are all associated with altered excitability of the prefrontal cortex (PFC) and changes in E/I molecular markers (125). Acute stress has also been shown to decrease synchronous activity of both excitatory and inhibitory neurons (126).…”

“…Interestingly, numerous rodent studies show effects on E/I balance and enhanced microglial pruning and resultant synaptic loss are more marked in males (137,138). For example, PFC E/I imbalance due to prenatal stress was shown in male but not female rodents (123). Chronic unpredictable stress causing synapse elimination by glia was also shown in males only (129,130).…”

Impact of stress on inhibitory neuronal circuits, our tribute to Bruce McEwen

“…Gestational restraint stress in rats (from E14 to E21) also promoted excitation/inhibition (E/I) imbalances in the rat adult PFC (in males but not females) and amygdala (in both sexes). In the PFC the balance was shifted towards excitation, while in the amygdala the shift was towards inhibition ( Marchisella et al, 2021 ). A decreased density of PV + neurons and PV + neurons surrounded by PNNs was also observed in the PFC of P21 male mice exposed to prenatal stress (from E15 to E17.5).…”