Adolescent environmental enrichment prevents early-life stress-induced schizophrenia-like phenotypes via restoration of CREB-BDNF-TrkB signaling

Early-life stress (ELS) is a major environmental risk factor for schizophrenia, yet effective preventive strategies targeting its neurodevelopmental consequences remain limited. Here, we show that adolescent environmental enrichment (EE) prevents the emergence of schizophrenia-like behavioral and cognitive deficits induced by maternal separation (MS), a validated ELS model. Mechanistically, MS induced oxidative stress, mitochondrial dysfunction, neuroinflammation, neuronal apoptosis, and synaptic deficits in the hippocampus, accompanied by suppression of the CREB-BDNF-TrkB (cAMP response element-binding protein-brain-derived neurotrophic factor-tropomyosin receptor kinase B) signaling. Adolescent EE robustly reversed these abnormalities and restored neuroplasticity-related signaling. Importantly, we provide evidence supporting a causal role of TrkB signaling in these protective effects within the experimental framework used here: pharmacological activation of TrkB rescued oxidative stress-induced synaptic deficits in vitro, whereas pharmacological inhibition of TrkB abolished the behavioral and cognitive benefits of EE in vivo. To establish translational relevance, we further show that TrkB levels are significantly reduced in neuron-derived exosomes (NDEs) from patients with schizophrenia, with moderate diagnostic performance (AUC = 0.784). Together, these findings support CREB-BDNF-TrkB signaling as a key mechanistic node linking ELS to schizophrenia-related phenotypes and suggest adolescent EE as a developmentally timed, non-pharmacological intervention with translational relevance within the experimental framework used here.