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

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.