TAAR9 knockout increases hippocampal serotonin and alters grooming behavior in rats

Ilya S. Zhukov^1,2*Inessa V Karpova²Ramilya Z Murtazina¹Yazen Alnefeesi¹Olga M Korenkova¹Ilia Yu Tissen²Svetlana A Palchikova²Lydia A Tokareva¹Sarng S Pyurveev²Petr D Shabanov²Larisa G Kubarskaya^2,3Mikhail A Rozhko³Ekaterina B Zernova³Ekaterina A Zolotoverkhaja³Anna B. Volnova¹Allan V Kalueff^1,4Natalia Alenina⁵Raul R Gainetdinov^1,6*

• ¹Saint Petersburg State University, Saint Petersburg, Russia
• ²Institute of Experimental Medicine, St. Petersburg, Russia
• ³Institute of Toxicology of Federal Medical-Biological Agency, Saint Petersburg, Russia
• ⁴Xi'an Jiaotong University Suzhou Academy, Xi'an, China
• ⁵Max-Delbruck-Centrum fur Molekulare Medizin in der Helmholtz-Gemeinschaft Experimental and Clinical Research Center, Berlin, Germany
• ⁶Saint Petersburg State University Hospital, Saint Petersburg State University, Saint Petersburg, Russia

Introduction: Despite their association with brain disorders, the neurophysiological roles of the trace amine-associated receptors (TAARs) remain poorly understood. In humans, the genomic TAAR cluster comprises nine consecutive genes, six of which code for functional proteins (TAAR1, TAAR2, TAAR5, TAAR6, TAAR8, TAAR9). While homologues of the former three are known to regulate classical monoamines and neurogenesis, the functions of the latter three remain largely unknown. In this exploratory study, we demonstrate for the first time that TAAR9 plays a significant regulatory role in the monoaminergic systems of the rat. Methods: We used qPCR to measure TAAR9 mRNA expression throughout the rat brain. Serotonin, dopamine, and their metabolite levels were assessed by HPLC in brain tissues from TAAR9-KO and WT littermates. We applied fast-scan cyclic voltammetry to measure mesolimbic dopamine release. Behavioral analysis included assessment of grooming, anxiety-like, and sexual behaviors. A battery of hematological/hormone assays was also applied. Results & Discussion: We detected TAAR9 mRNA in the brainstem and midbrain – regions that include key monoaminergic nuclei such as the locus coeruleus, raphe nuclei, and the ventral tegmental area. The TAAR9-KO rats exhibited increased hippocampal serotonin levels and a slight shift in dopamine turnover, but not mesolimbic dopamine release. Although hippocampal serotonin is commonly implicated in mood and anxiety regulation, behaviorally, no genotype differences were detected in the elevated plus maze, suggesting that basal anxiety-like behavior remained unaffected under the test conditions. However, changes in grooming microstructure indicated subtle alterations in behavioral organization, which may reflect the neurochemical changes observed in the hippocampus. No changes were evident in a battery of hematological assays. Conclusion: Together, these findings suggest that TAAR9 deletion selectively modulates central monoaminergic systems and related behavioral patterns, without altering systemic physiological parameters.