2. Academic Validation
  3. Disfunction of dorsal raphe nucleus-hippocampus serotonergic-HTR3 transmission results in anxiety phenotype of Neuroplastin 65-deficient mice

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

  • Acta Pharmacol Sin. 2024 Mar 25. doi: 10.1038/s41401-024-01252-5.
Jie Cheng 1 2,  Ling Chen 1 2,  Ya-Ni Zheng 1 2,  Juan Liu 3,  Lei Zhang 1 2,  Xiao-Ming Zhang 1 2,  Liang Huang 1 2,  Qiong-Lan Yuan 4 5
Affiliations

Affiliations

  • 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.
  • 4 Department of Neurology, Shanghai Tongji Hospital, Tongji University School of Medicine, Shanghai, 200065, China. yqiongl@tongji.edu.cn.
  • 5 Department of Human Anatomy, Histology and Embryology, Tongji University School of Medicine, Shanghai, 200092, China. yqiongl@tongji.edu.cn.
PMID: 38528118 DOI: 10.1038/s41401-024-01252-5
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.

Keywords

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

Figures
Products