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

Jie Cheng1,2, Ling Chen1,2, Ya-ni Zheng1,2, Juan Liu3, Lei Zhang1,2, Xiao-ming Zhang1,2, Liang Huang1,2, Qiong-lan Yuan1,2
1 Department of Neurology, Shanghai Tongji Hospital, Tongji University School of Medicine, Shanghai 200065, China
2 Department of Human Anatomy, Histology and Embryology, Tongji University School of Medicine, Shanghai 200092, China
3 Chinese Institute for Brain Research, Beijing 102206, China
Correspondence to: Qiong-lan Yuan:,
DOI: 10.1038/s41401-024-01252-5
Received: 10 November 2023
Accepted: 26 February 2024
Advance online: 25 March 2024


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.

Keywords: neuroplastin 65; dorsal raphe nucleus; tryptophan hydroxylase 2; Lmx1b; serotonergic transmission; anxiety disorders

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