A Truncated Receptor TrkB Isoform (TrkB.T1) in Mechanisms of Genetically Determined Depressive-like Behavior of Mice

Overview

Journal Biomedicines

Specialty Biomedical Engineering

Date 2023 Sep 28

PMID 37761014

Authors

Marah Alsalloum

Tatiana Ilchibaeva

Anton Tsybko

Dmitry Eremin

Vladimir Naumenko

Affiliations

Soon will be listed here.

Abstract

Depression is a mental disorder that significantly reduces quality of life, and the discovery of new drug targets is an urgent problem for modern neuroscience. Brain-derived neurotrophic factor (BDNF) and its receptors have been found to participate in mechanisms of depression and antidepressant drugs' action. In this study, we focused on a less-studied truncated isoform of receptor TrkB: TrkB.T1. Initially, we noticed that the level of TrkB.T1 is low in the hippocampus of Antidepressant-Sensitive Cataleptics (ASC) mice, which are characterized by genetically determined depressive-like behavior in contrast to "normal" C57BL/6J mice. Next, overexpression of TrkB.T1 receptor in hippocampal neurons of ACS mice was induced to clarify the role of this receptor in mechanisms of depressive-like behavior. TrkB.T1 overexpression lowered BDNF protein concentration in the hippocampus. On the behavioral level, TrkB.T1 overexpression severely decreased aggression and enhanced social behavior. Additionally, this excess of receptor TrkB.T1 slightly promoted anxiety and depressive-like behavioral traits without affecting learning and memory. Our results show that this TrkB isoform participates in the control of aggression, anxiety, and depressive-like behavior and in the regulation of BDNF system functioning in ASC mice (genetically predisposed to depressive-like behavior). Considering our findings, we believe that hippocampal receptor TrkB.T1 can be a drug target for the correction of behavioral pathologies.

References

Guyon N, Rakauskas Zacharias L, van Lunteren J, Immenschuh J, Fuzik J, Martin A . Adult trkB Signaling in Parvalbumin Interneurons is Essential to Prefrontal Network Dynamics. J Neurosci. 2021; 41(14):3120-3141. PMC: 8026352. DOI: 10.1523/JNEUROSCI.1848-20.2021. View

Abe Y, Nishimura Y, Nakamura K, Tamura S, Honsho M, Udo H . Peroxisome Deficiency Impairs BDNF Signaling and Memory. Front Cell Dev Biol. 2020; 8:567017. PMC: 7591468. DOI: 10.3389/fcell.2020.567017. View

Bazovkina D, Kulikova A, Kondaurova E, Popova N . [Selection for the predisposition to catalepsy enhances depressive-like traits in mice]. Genetika. 2005; 41(9):1222-8. View

Mikics E, Guirado R, Umemori J, Toth M, Biro L, Miskolczi C . Social Learning Requires Plasticity Enhanced by Fluoxetine Through Prefrontal Bdnf-TrkB Signaling to Limit Aggression Induced by Post-Weaning Social Isolation. Neuropsychopharmacology. 2017; 43(2):235-245. PMC: 5635971. DOI: 10.1038/npp.2017.142. View

Kulikov A, Morozova M, Kulikov V, Kirichuk V, Popova N . Automated analysis of antidepressants' effect in the forced swim test. J Neurosci Methods. 2010; 191(1):26-31. DOI: 10.1016/j.jneumeth.2010.06.002. View

Yamaura K, Bi Y, Ishiwatari M, Oishi N, Fukata H, Ueno K . Sex differences in stress reactivity of hippocampal BDNF in mice are associated with the female preponderance of decreased locomotor activity in response to restraint stress. Zoolog Sci. 2013; 30(12):1019-24. DOI: 10.2108/zsj.30.1019. View

Fenner B . Truncated TrkB: beyond a dominant negative receptor. Cytokine Growth Factor Rev. 2012; 23(1-2):15-24. DOI: 10.1016/j.cytogfr.2012.01.002. View

Yacoubian T, Lo D . Truncated and full-length TrkB receptors regulate distinct modes of dendritic growth. Nat Neurosci. 2000; 3(4):342-9. DOI: 10.1038/73911. View

Ilchibaeva T, Tsybko A, Kozhemyakina R, Kondaurova E, Popova N, Naumenko V . Genetically defined fear-induced aggression: Focus on BDNF and its receptors. Behav Brain Res. 2018; 343:102-110. DOI: 10.1016/j.bbr.2018.01.034. View

10.

Papp G, Witter M, Treves A . The CA3 network as a memory store for spatial representations. Learn Mem. 2007; 14(11):732-44. DOI: 10.1101/lm.687407. View

11.

Michaelsen K, Zagrebelsky M, Berndt-Huch J, Polack M, Buschler A, Sendtner M . Neurotrophin receptors TrkB.T1 and p75NTR cooperate in modulating both functional and structural plasticity in mature hippocampal neurons. Eur J Neurosci. 2010; 32(11):1854-65. DOI: 10.1111/j.1460-9568.2010.07460.x. View

12.

Banerjee R, Ghosh A, Ghosh B, Bhattacharyya S, Mondal A . Decreased mRNA and Protein Expression of BDNF, NGF, and their Receptors in the Hippocampus from Suicide: An Analysis in Human Postmortem Brain. Clin Med Insights Pathol. 2013; 6:1-11. PMC: 3767649. DOI: 10.4137/CMPath.S12530. View

13.

Ramos A . Animal models of anxiety: do I need multiple tests?. Trends Pharmacol Sci. 2008; 29(10):493-8. DOI: 10.1016/j.tips.2008.07.005. View

14.

Kesner R . An analysis of dentate gyrus function (an update). Behav Brain Res. 2017; 354:84-91. DOI: 10.1016/j.bbr.2017.07.033. View

15.

Sun D, Mei L, Xiong W . Dorsal Dentate Gyrus, a Key Regulator for Mood and Psychiatric Disorders. Biol Psychiatry. 2023; 93(12):1071-1080. DOI: 10.1016/j.biopsych.2023.01.005. View

16.

Pitts E, Li D, Gourley S . Bidirectional coordination of actions and habits by TrkB in mice. Sci Rep. 2018; 8(1):4495. PMC: 5852142. DOI: 10.1038/s41598-018-22560-x. View

17.

Tikhonova M, Kulikov A . Antidepressant-Like Effects of Central BDNF Administration in Mice of Antidepressant Sensitive Catalepsy (ASC) Strain. Chin J Physiol. 2013; 55(4):284-93. DOI: 10.4077/CJP.2012.BAA041. View

18.

Naumenko V, Kondaurova E, Bazovkina D, Tsybko A, Tikhonova M, Kulikov A . Effect of brain-derived neurotrophic factor on behavior and key members of the brain serotonin system in genetically predisposed to behavioral disorders mouse strains. Neuroscience. 2012; 214:59-67. DOI: 10.1016/j.neuroscience.2012.04.031. View

19.

Kulikov A, Osipova D, Naumenko V, Popova N . Association between Tph2 gene polymorphism, brain tryptophan hydroxylase activity and aggressiveness in mouse strains. Genes Brain Behav. 2005; 4(8):482-5. DOI: 10.1111/j.1601-183X.2005.00145.x. View

20.

Wirth A, Chen-Wacker C, Wu Y, Gorinski N, Filippov M, Pandey G . Dual lipidation of the brain-specific Cdc42 isoform regulates its functional properties. Biochem J. 2013; 456(3):311-22. DOI: 10.1042/BJ20130788. View