Social isolation primes anxiety via a hippocampal iron-a-synuclein cascade

This study reveals a novel mechanism linking social isolation to anxiety through a glucocorticoid (GC)-driven, ventral hippocampal (vHip)-specific iron-a-synuclein (a-Syn) axis. Social isolation activates glucocorticoid receptors (GRs) in vHip pyramidal neurons, which upregulate transferrin receptor 1 (TfR1) to promote iron accumulation. Elevated iron induces a-Syn overexpression, thereby enhancing presynaptic glutamate release and neuronal hyperexcitability in the vHip; this ultimately drives anxiety-like behaviors. Gain-of-function/loss-of-function experiments confirm that TfR1 and a-Syn are essential for this pathway, while intranasal iron chelation or a-Syn inhibition rescues both neural and behavioral abnormalities. These findings establish the GR-TfR1-a-Syn axis as a therapeutic target for social stress-related anxiety, which bridges metallobiology and psychiatric pathophysiology. Overall design: RNA-seq profiles were generated from the ventral hippocampus tissues of (Camk2a-Cre, C57BL/6) mice following 28 days of housing under three conditions: group housing, social isolation, and neuronal-specific Nr3c1 knockdown combined with social isolation.