Major urinary protein 1 modulates neuronal excitability in the medial prefrontal cortex in a male mouse model of affective empathy

Affective empathy describes the capacity to share others’ emotions, yet the molecular mechanisms governing individual differences in empathic sensitivity remain poorly understood. Using a male mouse model of social transmission of depression (STD), we demonstrated that STD‑sensitive observer mice exhibit heightened neuronal excitability and upregulated major urinary protein 1 (MUP1) expression in the medial prefrontal cortex (mPFC) compared with STD‑insensitive observer mice. Mechanistically, MUP1 drives the STD‑sensitive phenotype by modulating astrocytic glutamate transporter 1 (GLT1) to augment mPFC neuronal excitability. Via virtual screening, we identified two small‑molecule compounds (C25 and C11) that bidirectionally modulate STD‑related behaviors. In summary, our work establishes MUP1 as a master modulator of STD vulnerability, deciphers mechanisms driving heterogeneous affective empathy across individuals, and unveils actionable therapeutic candidates for empathy-related psychiatric illnesses. Individual differences in affective empathy lack defined molecular mechanisms. Here, the authors show that major urinary protein 1 in the medial prefrontal cortex increases neuronal excitability by modulating astrocytic glutamate transporter 1 in male mice, thereby promoting sensitivity in empathy-like behaviors.