Menin Reduces Parvalbumin Expression and is Required for the Anti-Depressant Function of Ketamine

Dysfunction of parvalbumin (PV) neurons is closely involved in depression, however, the detailed mechanism remains unclear. Based on the previous finding that multiple endocrine neoplasia type 1 (Protein: Menin; Gene: Men1) mutation (G503D) is associated with a higher risk of depression, a Menin-G503D mouse model is generated that exhibits heritable depressive-like phenotypes and increases PV expression in brain. This study generates and screens a serial of neuronal specific Men1 deletion mice, and found that PV interneuron Men1 deletion mice (PcKO) exhibit increased cortical PV levels and depressive-like behaviors. Restoration of Menin, knockdown PV expression or inhibition of PV neuronal activity in PV neurons all can ameliorate the depressive-like behaviors of PcKO mice. This study next found that ketamine stabilizes Menin by inhibiting protein kinase A (PKA) activity, which mediates the anti-depressant function of ketamine. These results demonstrate a critical role for Menin in depression, and prove that Menin is key to the antidepressant function of ketamine. Parvalbumin (PV) increases in several depression mice models. Men1 deficiency in PV interneurons (PcKO) increases pvalb transcription and PV expression by H3K27me3 modification and leading to depression-like behaviors in mice. The depressive-like behaviors in PcKO mice can be rescued by PV knockdown or Menin restoring. Ketamine stabilizes Menin protein to contribute its's anti-depressant function.image