Resolving and Rescuing Developmental Miswiring in a Mouse Model of Cognitive Impairment

Abstract

Cognitive deficits, core features of mental illness, largely result from dysfunction of prefrontal networks. This dysfunction emerges already 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 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 layer II/III 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. Transient administration of minocycline, potentially acting via microglial cells, rescues morphological, synaptic and functional neuronal deficits, and restores pre-juvenile cognitive abilities. Elucidation of the cellular substrate of developmental miswiring related to later cognitive deficits opens new perspectives for identification of neurobiological targets, amenable to therapies.