HUMAN NEURONS UNDERGO PROTRACTED FUNCTIONAL MATURATION INTO ADULTHOOD

Human cognitive development is uniquely prolonged, reflecting extended postnatal maturation of the cerebral cortex. However, when human cortical neurons reach functional electrophysiological maturity and how their developmental trajectory compares to other species remains unknown. Here, through patch-clamp recordings of human temporal cortex from infancy to adulthood (n=584 cells, 80 subjects, 10 months to 55 years), we show that supragranular pyramidal neurons exhibit pronounced neoteny of their functional properties, with physiological maturation continuing well into adulthood. Comparing human and mouse developmental trajectories (n=562 cells, 242 mice) reveals that while the nature and sequence of developmental changes is conserved, human neurons mature physiologically hundreds of times slower than mouse and 2-6 times slower than predicted from anatomical brain growth differences between species. This reflects fundamentally different allometric relationships between physiological and anatomical maturation: while mouse neuronal physiology closely tracks brain growth, human physiological development follows its own extended timeline. The slow maturation results in different stages of cognitive development being supported by functionally distinct neuronal populations, with the progression from infancy to middle age characterized by specific electrophysiological profiles. Notably, a burst-firing neuronal subtype thought to be human-specific, with electrophysiological traits that enhance computational capacity, appears only in late adolescence or early adulthood. Our findings establish neuronal physiological neoteny as a fundamental evolutionary adaptation in human brain development and provide a quantitative framework for selecting appropriate rodent ages to model specific human developmental stages and understanding the age-specific emergence of neurodevelopmental disorders.