Cognitive deficits, core features of mental illness, largely result from dysfunction of prefrontal networks. This dysfunction emerges during early development, before a detectable behavioral readout, yet the cellular elements controlling the abnormal maturation are still unknown. Here, we address this open question by combining in vivo electrophysiology, optogenetics, neuroanatomy, and behavioral assays during development in mice mimicking the dual genetic-environmental etiology of psychiatric disorders. We report that pyramidal neurons in superficial layers of the prefrontal cortex are key elements causing disorganized oscillatory entrainment of local circuits in beta-gamma frequencies. Their abnormal firing rate and timing relate to sparser dendritic arborization and lower spine density. Administration of minocycline during the first postnatal week, potentially acting via microglial cells, rescues the neuronal deficits and restores pre-juvenile cognitive abilities. Elucidation of the cellular substrate of developmental miswiring causing later cognitive deficits opens new perspectives for identification of neurobiological targets amenable to therapies.

Despite inherent difficulties to translate human cognitive phenotype into animals, a large number of animal models for psychiatric disorders, such as schizophrenia, have been developed over the last decades. To which extent they reproduce common patterns of dysfunction related to mental illness and abnormal processes of maturation is still largely unknown. While the devastating symptoms of disease are firstly detectable in adulthood, they are considered to reflect profound miswiring of brain circuitry as result of abnormal development. To reveal whether different disease models share common dysfunction early in life, we investigate the prefrontal–hippocampal communication at neonatal age in (a) mice mimicking the abnormal genetic background (22q11.2 microdeletion, DISC1 knockdown), (b) mice mimicking the challenge by environmental stressors (maternal immune activation during pregnancy), (c) mice mimicking the combination of both aetiologies (dual‐hit models) and pharmacological mouse models. Simultaneous extracellular recordings in vivo from all layers of prelimbic subdivision (PL) of prefrontal cortex (PFC) and CA1 area of intermediate/ventral hippocampus (i/vHP) show that network oscillations have a more fragmented structure and decreased power mainly in neonatal mice that mimic both genetic and environmental aetiology of disease. These mice also show layer‐specific firing deficits in PL. Similar early network dysfunction was present in mice with 22q11.2 microdeletion. The abnormal activity patterns are accompanied by weaker synchrony and directed interactions within prefrontal–hippocampal networks. Thus, only severe genetic defects or combined genetic environmental stressors are disruptive enough for reproducing the early network miswiring in mental disorders.

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Up to five percent of human infants are exposed to maternal antidepressant medication by serotonin reuptake inhibitors (SRI) during pregnancy, yet the SRI effects on infants’ early neurodevelopment are not fully understood. Here, we studied how maternal SRI medication affects cortical frequency-specific and cross-frequency interactions estimated, respectively, by phase-phase correlations (PPC) and phase-amplitude coupling (PAC) in electroencephalographic (EEG) recordings. We examined the cortical activity in infants after fetal exposure to SRIs relative to a control group of infants without medical history of any kind. Our findings show that the sleep-related dynamics of PPC networks are selectively affected by in utero SRI exposure, however, those alterations do not correlate to later neurocognitive development as tested by neuropsychological evaluation at two years of age. In turn, phase-amplitude coupling was found to be suppressed in SRI infants across multiple distributed cortical regions and these effects were linked to their neurocognitive outcomes. Our results are compatible with the overall notion that in utero drug exposures may cause subtle, yet measurable changes in the brain structure and function. Our present findings are based on the measures of local and inter-areal neuronal interactions in the cortex which can be readily used across species, as well as between different scales of inspection: from the whole animals to in vitro preparations. Therefore, this work opens a framework to explore the cellular and molecular mechanisms underlying neurodevelopmental SRI effects at all translational levels.