Ferroplasticity drives social isolation-induced anxiety via a ventral hippocampal iron-α-synuclein axis

Social isolation is a major environmental driver of anxiety disorders, yet its neurobiological underpinnings remain elusive. We report here that social isolation triggers "ferroplasticity"-a novel form of experience-dependent synaptic remodeling-in ventral hippocampus (vHip) pyramidal neurons via a glucocorticoid-initiated iron-α-synuclein (α-Syn) axis. Psychosocial stress specifically engages this pathway. Mechanistically, isolation-induced glucocorticoid receptor activation upregulates transferrin receptor 1 (TfR1), leading to neuronal iron accumulation, which boosts α-Syn expression via translational derepression. α-Syn then enhances glutamate release and spine density, driving vHip hyperexcitability and anxiety. Interventions targeting the TfR1-iron-α-Syn axis at any node prevent or reverse anxiety-like behaviors, establishing necessity and causality. Translationally, intranasal delivery of an iron chelator or α-Syn-targeting antisense oligonucleotide (ASO) normalizes vHip neural activity and alleviates anxiety, highlighting a direct and viable path to clinical translation. Our findings define ferroplasticity as a core mechanism in social stress pathology, bridging brain iron metabolism with affective disorders.