同济大学Qiong-lan Yuan课题组发现，中缝背核-海马血清素能-HTR3传导功能失调导致neuroplastin 65缺失小鼠的焦虑表型。2024年3月25日，国际学术期刊《中国药理学报》在线发表了这一成果。

研究人员表示，焦虑症是最常见的精神疾病，但焦虑症的病因在很大程度上仍不清楚。研究人员之前的研究表明，neuroplastin 65缺失（NP65^-/-）小鼠表现出异常的社交和精神行为，并且色氨酸羟化酶 2（TPH2）蛋白的表达量减少。然而，TPH2的减少与焦虑症之间是否存在因果关系尚待确定。

研究人员发现，补充中缝背核（DRN）中的TPH2可提高海马中的5-HT水平，缓解焦虑样行为。此外，在DRN中注射AAV-NP65能显著增加TPH2在DRN和海马中的表达，并减少焦虑样行为。在海马中急性给予外源性5-HT或HTR3激动剂SR57227A可减轻NP65^-/-小鼠的焦虑样行为。此外，DRN中TPH2的补充部分修复了NP65^-/-小鼠海马中长期电位（LTP）维持的损伤。

最后，研究人员发现NP65的缺失降低了转录因子Lmx1b在小鼠出生后的表达，而DRN中NP65的补充逆转了NP65^-/-小鼠Lmx1b表达的下降。

综上所述，这些研究结果表明，NP65的缺失会通过下调DRN-海马血清素能-HTR3的传递而诱发焦虑表型。这些研究为NP65的功能提供了一个新颖而有洞察力的观点，并为治疗焦虑症提供了一个有吸引力的潜在靶点。

附：英文原文

Title: Disfunction of dorsal raphe nucleus-hippocampus serotonergic-HTR3 transmission results in anxiety phenotype of Neuroplastin 65-deficient mice

Author: Cheng, Jie, Chen, Ling, Zheng, Ya-ni, Liu, Juan, Zhang, Lei, Zhang, Xiao-ming, Huang, Liang, Yuan, Qiong-lan

Issue&Volume: 2024-03-25

Abstract: Anxiety disorders are the most common psychiatric condition, but the etiology of anxiety disorders remains largely unclear. Our previous studies have shown that neuroplastin 65 deficiency (NP65/) mice exhibit abnormal social and mental behaviors and decreased expression of tryptophan hydroxylase 2 (TPH2) protein. However, whether a causal relationship between TPH2 reduction and anxiety disorders exists needs to be determined. In present study, we found that replenishment of TPH2 in dorsal raphe nucleus (DRN) enhanced 5-HT level in the hippocampus and alleviated anxiety-like behaviors. In addition, injection of AAV-NP65 in DRN significantly increased TPH2 expression in DRN and hippocampus, and reduced anxiety-like behaviors. Acute administration of exogenous 5-HT or HTR3 agonist SR57227A in hippocampus mitigated anxiety-like behaviors in NP65/ mice. Moreover, replenishment of TPH2 in DRN partly repaired the impairment of long-term potentiation (LTP) maintenance in hippocampus of NP65/ mice. Finally, we found that loss of NP65 lowered transcription factors Lmx1b expression in postnatal stage and replenishment of NP65 in DRN reversed the decrease in Lmx1b expression of NP65/ mice. Together, our findings reveal that NP65 deficiency induces anxiety phenotype by downregulating DRN-hippocampus serotonergic-HTR3 transmission. These studies provide a novel and insightful view about NP65 function, suggesting an attractive potential target for treatment of anxiety disorders.

DOI: 10.1038/s41401-024-01252-5

Source: https://www.nature.com/articles/s41401-024-01252-5