Prefrontal spine loss in neuropsychiatric disorders: circuit consequences for cognition

Dendritic spine loss on superficial layer pyramidal neurons in the prefrontal cortex (PFC) has emerged as a central neuropathological feature across a range of neuropsychiatric disorders. This is particularly significant as the PFC serves as a critical hub for higher-order cognitive functions such as working memory, attention regulation, and decision-making, which are often disrupted in neuropsychiatric disorders. These cognitive functions rely on the integration of local and global inputs within prefrontal microcircuits, with dendritic spines acting as key structural substrates underlying this integration. Consequently, spine loss in the PFC might compromise functional connectivity within local prefrontal circuits as well as brain-wide networks, ultimately cascading into circuit dysfunction and impaired cognitive performance. By integrating findings across molecular, circuit, and behavioral levels as well as across species, we highlight why, despite disparate etiologies, this shared pathological feature of prefrontal spine loss may act as a mechanistic link between cellular pathology and the complex cognitive symptoms observed in neuropsychiatric disorders.