Maternal Stress Primes Adolescent Stress Susceptibility via Microglial Complement-Dependent Synaptic Phagocytosis.

Adolescence represents a critical neurodevelopmental transition marked by profound reorganization of brain circuitry, emotional regulation, and social cognition [,]. During this period, individuals encounter diverse psychosocial stressors, including academic demands, peer competition, and evolving social hierarchies. While many adolescents demonstrate resilience in navigating these challenges, a substantial proportion exhibit heightened vulnerability to stress-related mood disorders, particularly depression [–]. This inter-individual variability in stress susceptibility is thought to reflect underlying differences in neurobiological programming, yet the mechanisms governing this differential vulnerability remain incompletely understood. Given the rising global prevalence of adolescent depression and its profound societal burden, elucidating the neurobiological substrates of stress vulnerability has become an urgent priority. The “2-hit” hypothesis offers a tractable framework for dissecting this question, proposing that early-life adversity (the first hit) induces latent neurobiological alterations that shape individuals’ responses to subsequent challenges (the second hit) encountered later in life [–]. The prenatal period is particularly relevant in this context, as the foundational architecture of the nervous system is laid down during gestation through tightly orchestrated programs of neurogenesis, neuronal migration, and synaptic assembly [–]. Notably, psychological distress during pregnancy is remarkably prevalent: the World Health Organization estimates that approximately 10% of pregnant women worldwide experience mental health disorders, with rates reaching 15.6% in low- and middle-income countries []. Maternal stress has been causally linked to fetal hypothalamic–pituitary–adrenal (HPA) axis dysregulation, epigenetic reprogramming, and perturbation of the neuroimmune microenvironment [,], disruptions that may fundamentally alter trajectories of brain development. Because adolescence itself constitutes a second sensitive window of synaptic remodeling and heightened plasticity, prenatal perturbations may preconfigure an individual’s stress-response phenotype during this later stage. Nevertheless, the cellular and molecular mechanisms underpinning these effects remain to be fully elucidated. Among brain regions implicated in stress reactivity, the hippocampus—and the dentate gyrus (DG) in particular—has emerged as a critical node of stress susceptibility. Hippocampal volume reductions in major depressive disorders are most pronounced in the DG, paralleled by postmortem losses in granule cell number and dendritic complexity [,]. Unlike CA1 and CA3, which achieve mature connectivity by weaning, DG granule cells continue synaptic remodeling throughout adolescence, leaving their excitatory connectivity uniquely open to activity-dependent reshaping. Functionally, the DG transforms entorhinal inputs into sparse, decorrelated representations through pattern separation, a computation exquisitely sensitive to glutamatergic drive onto granule cells [–]. This convergence of adolescent-extended plasticity, stress sensitivity, and glutamatergic dependence positions the DG as a plausible locus at which a prenatal “first hit” may be latently encoded and subsequently unmasked by adolescent stress. We therefore hypothesize that the DG constitutes a key anatomical node linking early-life adversity to adolescent stress susceptibility.