REDUCTION OF TENEURIN-4 IN THE PREFRONTAL CORTEX INDUCES DEPRESSIVE BEHAVIORS IN MICE
Authors: Arakida *Yuki , Asano Takashi , Tokoro Kazuki , Horita Tomoya , Izuo Naotaka , Muramatsu Shin-Ichi , Nitta Atsumi 
Published: February 2025

Abstract

In recent years, the number of patients with depression disorders has increased. New stratagem should be established for the recovery of depression. The gene encoding Teneurin-4 (Tenm-4), ODZ4, has been identified as a risk gene for many psychiatric disorders1,2,3. However, it is still unclear how Tenm-4 affects the pathogenesis of psychiatric disorders. Prefrontal cortex (PFC) contributes emotion regulation, cognitive function, and social behaviors4,5. Importantly, a reduced volume of the PFC region has been reported in depressed patients6. Therefore, the PFC is thought to be involved in the pathogenesis of depression. We hypothesized that Tenm-4 in the PFC influences depression and other psychiatric disorders. In this study, we generated mice with Tenm-4 knockdown specifically in the PFC of mice, to clarify the involvement of Tenm-4 in psychiatric disorders in the PFC, We investigated their behavioral phenotype by conducting various behavioral experiments. Mice with reduced Tenm-4 expression in the PFC were generated using genetic modification technology incorporating the CRISPER- Cas9 system in an adeno-associated virus vector (AAV)(Tenm-4 KD, and Mock as control), and we used these mice for the behavioral experiments. We performed various behavioral experiments by using the mice. In the forced swimming test and tail suspension test, Tenm-4 KD mice group showed significantly increased immobility time compared with Mock mice group. In the sucrose preference test, Tenm-4 KD mice group showed significantly decreased sucrose preference compared with Mock mice group.
Furthermore, a single intraperitoneal dose of aripiprazole significantly decreased immobility time in the tail suspension test and restored sucrose preference in the sucrose preference test in mice accompanied with reducion Tenm-4 expression. These results suggest that reduction of Tenm-4 in the PFC would cause depression-like behaviors. Further, we revealed that depression-like behaviors induced by reduction of the Tenm-4 in the PFC was recovered by the administration of aripiprazole. Aripiprazole functions as a partial agonist of dopamine D2,3 receptors, a partial agonist of serotonin 5-HT1A receptors, and an antagonist of serotonin 5-HT2Areceptors. Therefore, this result suggests that the dopaminergic and/or Serotonergic neurons, especially in the PFC, would be involved in depression-like behaviors induced by reduction of the Tenm-4 in the PFC. The relationship between depression and Tenm-4 is still not well understood. However, we have successfully generated a new mouse model of depression induced by decreased Tenm-4 in the PFC. These results could provide a pathomechanism involving Tenm-4 in depression. Our study successfully identified a new therapeutic target for depressed patients.

References
1.Yi, X., Li, M., He, G., Du, H., Li, X., Cao, D., Wang, L., Wu, X., Yang, F., Chen, X., He, L., Ping, Y., &Zhou, D. (2021). Genetic and functional analysis reveals TENM4 contributes to schizophrenia. iScience, 24. doi: 10.1016/j.isci.2021.103063
2.Xue, B, C., Xu, H, Z., Zhu, J., Wu, Y., Zhuang, H, X., Chen, L, Q., Wu, R, C., Hu, T, J., Zhou, S, H., Xie, H, W., Yi, X., Yu, S, S., Peng, Y, Z., Yang, M, H., Hong, H, X.,& Chen, H, J. (2019). Exome Sequencing Identifies TENM4 as a Novel Candidate Gene for Schizophrenia in the SCZD2 Locus at 11q14-21. Front Genet, 9.doi: 10.3389/fgene.2018.00725
3.Psychiatric GWAS Consortium Bipolar Disorder Working Group. (2011). Large-scale genome-wide association analysis of bipolar disorder identifies a new susceptibility locus near ODZ4. Nat Genet, 43, 977-983. doi: 10.1038/ng.943
4.Hiser, J., &Koenigs, M. (2018). The Multifaceted Role of the Ventromedial Prefrontal Cortex in Emotion, Decision Making, Social Cognition, and Psychopathology. Biol Psychiatry, 83, 638-647. doi: 10.1016/j.biopsych.2017.10.030
5.Merre, L, P., Ä hrlund-Richter, S., &Carlé n, M. (2021). The mouse prefrontal cortex: Unity in diversity. Neuron, 109, 1925-1944. doi: 10.1016/j.neuron.2021.03.035
6.Schmaal, L. Hibar, P, D., Sä mann, G, P., Hall, B, G., Baune, T, B., Jahanshad, N., Cheung, J, W., Erp, G, M van, T., Bos, D., Ikram, A, M., Vernooij, N., Niessen, J, W., Tiemeir, H. Hofman, A., Wittfeld, K., Grabe, J, H., Janowitz, D., Bü low, R., Selonke, M., Vö lzke, M., Grotegerd, D., Dannlowski, U., Arolt, V., Opel, N., Heindel, W., Kugel, H., Hoehn, D., Czisch, M., Couvy-Duchesene, B., Renterí a, E, M., Strike, T, L., Wright, J, M., Mills, T, N., Zubicaray, I de, G., McMahon, L, K., Medlamd, E, S., Martin, G, N., Gillespie, A, N., Goya- Maldonado, R., Grubar, O., Krä mer B., Hatton, N, S., Lagopoulos, L., Hickie, B, I., Frodl, T., Carballedo, A., Frey, M, E., Velzen, S van, L., Penninx, W, J, H, B., Tol van M-J., Wee, J van der, N., Davey, G, C., Harrison, J, B., Mwangi, B., Cao, B., Soares, C, J., Veer, M, I., Walter, H., Schopef, D., Zurowski, B., Konrad, C., Schramm, E., Normann, C., Schnell, K., Sacchet, D, M., Gotlib, H, I., MacQueen, M, G., Godlewska, R, B., Nickson, T., Mclntosh, D, M., Papmeyer, M., Whalley, C, H., Hall, J., Sussmann, E, J., Li, M., Walter, M., Aftanas, L., Brack, I., Bokhan, A, N., Thompson, M, P., Veltmen, J, D. (2017). Cortical abnormalities in adults and adolescents with major depression based on brain scans from 20 cohorts worldwide in the ENIGMA Major Depressive Disorder Working Group. Mol Psychiatry, 22, 900-909. doi: 10.1038/mp.2016.60