Chen Zhenlei, Yang Shangchen, Leng Lige, Ding Jinjun, Yuan Ziqi, Zhuang Kai, Can Dan, Zou Tingting, Wang Ya, Li Huifang, Yuan Ti-Fei, Zhang Jie
Fujian Provincial Key Laboratory of Neurodegenerative Disease and Aging Research, Institute of Neuroscience, College of Medicine, Xiamen University, Xiamen, Fujian, China.
Department of Pediatrics, Xiamen Maternity and Child Health Hospital affiliated to Xiamen University, Xiamen, Fujian, China.
Mol Psychiatry. 2025 May 27. doi: 10.1038/s41380-025-03061-6.
Alcohol use disorder (AUD) is commonly associated with depression, which may exacerbate the clinical outcome and increase treatment difficulty. The neural substrates underlying such comorbid symptoms are unclear. Here, we identify the regulatory role of amygdala Menin (multiple endocrine neoplasia type 1) signaling in orchestrating local GABAergic inhibition, which modulates the emotional state following alcohol use. Alcohol intake reduces Menin expression in the amygdala, decreasing GAT1 transcription. Restoring Menin signaling or overexpressing GAT1 in the amygdala could suppress alcohol preference and prevent depressive-like behaviors in these animals. Notably, knocking-in mice expressing a human MEN1 variant (Menin-G503D) that associates with MDD exhibit strong alcohol preference. These findings uncover a previously unknown mechanism for a common clinical element of alcohol addiction and point to a novel candidate therapeutic target against depression.
酒精使用障碍（AUD）通常与抑郁症相关，这可能会加剧临床结果并增加治疗难度。这种共病症状背后的神经基础尚不清楚。在这里，我们确定了杏仁核中Menin（多发性内分泌肿瘤1型）信号在协调局部GABA能抑制中的调节作用，该抑制作用调节饮酒后的情绪状态。酒精摄入会降低杏仁核中Menin的表达，减少GAT1转录。恢复Menin信号或在杏仁核中过表达GAT1可以抑制这些动物的酒精偏好并预防类似抑郁的行为。值得注意的是，敲入表达与重度抑郁症相关的人类MEN1变体（Menin-G503D）的小鼠表现出强烈的酒精偏好。这些发现揭示了酒精成瘾常见临床因素的一种先前未知的机制，并指出了一个针对抑郁症的新型候选治疗靶点。
