Adolescent Astrocyte Dysregulation Impairs Prefrontal Interneuron Maturation and Adult Cognition

Abstract

The prefrontal cortex (PFC), a brain region critical for executive and cognitive functions, is characterized by its protracted maturation extending through adolescence until early adulthood. During adolescence, the PFC undergoes substantial rearrangements, creating a window of heightened plasticity allowing experience-dependent refinement of neural networks. While this extended plasticity supports the development of higher-order cognitive functions, it also confers increased vulnerability to environmental and biological perturbations that can disrupt circuit development and contribute to cognitive and behavioral impairments relevant to psychiatric disorders. Astrocytes are central regulators of brain homeostasis and actively participate in developmental processes that shape postnatal brain maturation. Although astrocyte dysfunction has been increasingly linked to psychiatric pathophysiology, it remains unknown whether aberrant astrocyte activity can directly influence PFC development and cognitive maturation. Here, using selective modulation of astrocyte activity during defined developmental windows in the PFC, we show that abnormal astrocyte activity during adolescence induces transient synaptic loss through enhanced microglial phagocytosis, produces long-lasting alterations in fast-spiking parvalbumin (PV) interneurons, and results in persistent deficits in PFC-dependent behaviors. Together, these findings provide causal evidence that disrupted astrocyte function during adolescent PFC maturation can lead to persistent neuronal and cognitive deficits with relevance to major psychiatric disorders.