ROLE OF TAAR1 IN THE DENTATE GYRUS IN MEDIATING CHRONIC STRESS-INDUCED IMPAIRED HIPPOCAMPAL NEURONAL PLASTICITY IN MICE

Abstract Background Accumulating evidences suggest that trace amine-associated receptor 1 (TAAR1) is a new promising target for psychiatric disorders since TAAR1 was discovered in 2001[1, 2]. Stressful life events are a key environmental risk factor to develop major depressive disorder (MDD) [3]. Studies in humans and animals have demonstrated that depression and stress induced pathologies are implicated in the dentate gyrus (DG), one of the key regions for HPA axis glucocorticoid feedback [4]. TAAR1 exhibits widespread expression in the hippocampus and the data gained in transcriptomic data that indicate an important role of TAARs in the regulation of adult neurogenesis [5]. However, the role of TAAR1 in dentate gyrus (DG) mediating the negative outcomes induced by chronic stress remains unknown. Aims & Objectives In this study, we aimed to investigate the role of TAAR1 involved in stress-induced structural and functional impairments of the DG. Methods Firstly, chronic social defeat stress model (21 days) in mice was established. Via behavioral measurement and molecular biology techniques, hippocampus-related behaviors, adult neurogenesis, the expression levels of TAAR1 induced by chronic social defeat stress were investigated. Secondly, we explored whether selective knockout TAAR1 in the dentate gyrus (DG) can mimic the chronic stress induced impaired adult neurogenesis and cognitive function deficits. A Cre recombinase-responsive adeno-associated virus (AAV) was bilaterally stereotactically microinjected into the DG of TAAR1 CKO mice. Lastly, we investigated whether and how activating TAAR1 during stress exposure could block the negative outcomes of chronic stress exposure. RO5263397, a TAAR1 agonist, prior to each stress exposure were systematically administered. Results Male C57BL/6N mice subjected to chronic social defeat stress exhibited significant reduction in the TAAR1 mRNA level in the DG, impaired social approach behavior, social memory and spatial object recognition memory, and impaired proliferation and maturation of adult-born dentate granule cells. Furthermore, selective knockout TAAR1 in the DG can mimic the chronic stress induced hippocampus- dependent cognitive function deficits and damage of neurogenesis. Lastly, Systemic TAAR1 agonist RO5263397 administration during chronic stress exposure prevented stress-induced deficits of hippocampus-dependent cognitive ability. RO5263397 reversed the inhibitory effects on adult neurogenesis induced by chronic stress and alleviated chronic stress-evoked morphological changes of dental granule cells, including dendrite retraction, shrinkage of apical branches and spine loss. Discussion & Conclusion Taken together, our findings indicate TAAR1 is an important molecular mediating chronic stress-induced deficit of hippocampal morphology and function. The TAAR1 agonist RO5263397 has the potential role towards the treatment of patients with MDD-related cognitive impairments. References Alnefeesi, Y., et al., Trace amine-associated receptor 1 (TAAR1): Potential application in mood disorders: A systematic review. Neurosci Biobehav Rev, 2021. 131: p. 192-210. Halff, E.F., et al., Trace amine- associated receptor 1 (TAAR1) agonism as a new treatment strategy for schizophrenia and related disorders. Trends Neurosci, 2023. 46(1): p. 60-74. Kendler, K.S., L.M. Karkowski, and C.A. Prescott, Causal relationship between stressful life events and the onset of major depression. Am J Psychiatry, 1999. 156(6): p. 837-41. Gould, E. and P. Tanapat, Stress and hippocampal neurogenesis. Biol Psychiatry, 1999. 46(11): p. 1472-9. Katolikova, N.V., et al., Expression of Trace Amine-Associated Receptors in the Murine and Human Hippocampus Based on Public Transcriptomic Data. Cells, 2022. 11(11).