NRG1-ErbB4 signaling in the mPFC mediates adolescent social isolation-induced depressive-like behaviors.

Major depressive disorder (MDD) is one of the most common neuropsychiatric conditions worldwide, with an increasing number of cases originating early in life, particularly during adolescence. However, the underlying mechanisms of depression arising during this critical developmental stage remain poorly understood. In this study, we established a mouse model of depression that was induced by 4-week social isolation immediately after weaning, which fulfilled the key criteria of the etiologic, face and predictive validity. Meanwhile, social isolation during adolescence also resulted in impaired GABAergic neurotransmission in the medial prefrontal cortex (mPFC). Furthermore, downregulation of neuregulin 1 (NRG1), a susceptibility gene for depression, in the mPFC mediated social isolation-induced depressive-like behaviors by ErbB4 receptors in PV interneuron. Importantly, a clinical anti-epileptic drug clonazepam (CZP), which is a positive allosteric modulator of GABAA receptor, reversed depressive-like behaviors in these isolated mice. Our findings thus establish an animal model of depression in adolescence and shed new light on the mechanisms underlying adolescent depression, which provide potential targets for its treatment.