Depression-Associated Negr1 Gene-Deficiency Induces Alterations in the Monoaminergic Neurotransmission Enhancing Time-Dependent Sensitization to Amphetamine in Male Mice

Maria Kaare; Mohan Jayaram; Toomas Jagomäe; Katyayani Singh; Kalle Kilk; Kaie Mikheim; Marko Leevik; Este Leidmaa; Jane Varul; Helis Nõmm; Kristi Rähn; Tanel Visnapuu; Mario Plaas; Kersti Lilleväli; Michael K E Schäfer; Mari-Anne Philips; Eero Vasar

doi:10.3390/brainsci12121696

Depression-Associated Negr1 Gene-Deficiency Induces Alterations in the Monoaminergic Neurotransmission Enhancing Time-Dependent Sensitization to Amphetamine in Male Mice

Brain Sci. 2022 Dec 10;12(12):1696. doi: 10.3390/brainsci12121696.

Authors

Maria Kaare^{1

2}, Mohan Jayaram^{1

2}, Toomas Jagomäe^{1

2

3}, Katyayani Singh^{1

2}, Kalle Kilk^{1

4}, Kaie Mikheim^{1

2}, Marko Leevik^{1

2}, Este Leidmaa⁵, Jane Varul^{1

2}, Helis Nõmm^{1

2}, Kristi Rähn⁴, Tanel Visnapuu^{1

2}, Mario Plaas^{1

2

3}, Kersti Lilleväli^{1

2}, Michael K E Schäfer^{6

7

8}, Mari-Anne Philips^{1

2}, Eero Vasar^{1

2}

Affiliations

¹ Institute of Biomedicine and Translational Medicine, Department of Physiology, University of Tartu, 19 Ravila Street, 50411 Tartu, Estonia.
² Centre of Excellence in Genomics and Translational Medicine, University of Tartu, 50411 Tartu, Estonia.
³ Institute of Biomedicine and Translational Medicine, Laboratory Animal Centre, University of Tartu, 14B Ravila Street, 50411 Tartu, Estonia.
⁴ Institute of Biomedicine and Translational Medicine, Department of Biochemistry, University of Tartu, 19 Ravila Street, 50411 Tartu, Estonia.
⁵ Institute of Molecular Psychiatry, Medical Faculty, University of Bonn, 53129 Bonn, Germany.
⁶ Department of Anesthesiology, Focus Program Translational Neurosciences, Research Center for Immunotherapy, University Medical Center of the Johannes Gutenberg-University, 55131 Mainz, Germany.
⁷ Focus Program Translational Neurosciences, Johannes Gutenberg University Mainz, 55131 Mainz, Germany.
⁸ Research Center for Immunotherapy, Johannes Gutenberg University Mainz, 55131 Mainz, Germany.

Abstract

In GWAS studies, the neural adhesion molecule encoding the neuronal growth regulator 1 (NEGR1) gene has been consistently linked with both depression and obesity. Although the linkage between NEGR1 and depression is the strongest, evidence also suggests the involvement of NEGR1 in a wide spectrum of psychiatric conditions. Here we show the expression of NEGR1 both in tyrosine- and tryptophan hydroxylase-positive cells. Negr1^-/- mice show a time-dependent increase in behavioral sensitization to amphetamine associated with increased dopamine release in both the dorsal and ventral striatum. Upregulation of transcripts encoding dopamine and serotonin transporters and higher levels of several monoamines and their metabolites was evident in distinct brain areas of Negr1^-/- mice. Chronic (23 days) escitalopram-induced reduction of serotonin and dopamine turnover is enhanced in Negr1^-/- mice, and escitalopram rescued reduced weight of hippocampi in Negr1^-/- mice. The current study is the first to show alterations in the brain monoaminergic systems in Negr1-deficient mice, suggesting that monoaminergic neural circuits contribute to both depressive and obesity-related phenotypes linked to the human NEGR1 gene.

Keywords: Negr1; depression; dopamine; genetic models; serotonin.

Grants and funding

PRG 685/Estonian Research Council