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.

Previous studies have revealed a specific role of the prefrontal-parietal network in rapid goal-directed chunking (RGDC), which dissociates prefrontal activity related to chunking from parietal working memory demands. However, it remains unknown how the prefrontal and parietal cortices collaborate to accomplish RGDC. To this end, a novel experimental design was used that presented Chinese characters in a chunking task, testing eighteen undergraduate students (9 females, mean age = 22.4 years) while recoding the electroencephalogram (EEG). In the experiment, radical-level chunking was accomplished in a timely stringent way (RT = 1485 ms, SD = 371 ms), whereas the stroke-level chunking was accomplished less coherently (RT = 3278 ms, SD = 1083 ms). By comparing the differences between radical-level chunking vs. stroke-level chunking, we were able to dissociate the chunking processes in the radical-level chunking condition within the analyzed time window (-200 to 1300 ms). The chunking processes resulted in an early increase of gamma band synchronization over parietal and occipital cortices, followed by enhanced power in the beta-gamma band (25-38 Hz) over frontal areas. We suggest that the posterior rhythmic activities in the gamma band may underlie the processes that are directly associated with perceptual manipulations of chunking, while the subsequent beta-gamma activation over frontal areas appears to reflect a post-evaluation process such as reinforcement of the selected rules over alternative solutions, which may be an important characteristic of goal-directed chunking.