Depression-Associated Gene Negr1-Fgfr2 Pathway Is Altered by Antidepressant Treatment.

Lucia Carboni,Mario Lauria,Francesca Pischedda,Laura Musazzi,Enrico Domenici,Maurizio Popoli,Aleksander A Mathé,Giovanni Piccoli

doi:10.3390/cells9081818

Abstract

The Negr1 gene has been significantly associated with major depression in genetic studies. Negr1 encodes for a cell adhesion molecule cleaved by the protease Adam10, thus activating Fgfr2 and promoting neuronal spine plasticity. We investigated whether antidepressants modulate the expression of genes belonging to Negr1-Fgfr2 pathway in Flinders sensitive line (FSL) rats, in a corticosterone-treated mouse model of depression, and in mouse primary neurons. Negr1 and Adam10 were the genes mostly affected by antidepressant treatment, and in opposite directions. Negr1 was down-regulated by escitalopram in the hypothalamus of FSL rats, by fluoxetine in the hippocampal dentate gyrus of corticosterone-treated mice, and by nortriptyline in hippocampal primary neurons. Adam10 mRNA was increased by nortriptyline administration in the hypothalamus, by escitalopram in the hippocampus of FSL rats, and by fluoxetine in mouse dorsal dentate gyrus. Similarly, nortriptyline increased Adam10 expression in hippocampal cultures. Fgfr2 expression was increased by nortriptyline in the hypothalamus of FSL rats and in hippocampal neurons. Lsamp, another IgLON family protein, increased in mouse dentate gyrus after fluoxetine treatment. These findings suggest that Negr1-Fgfr2 pathway plays a role in the modulation of synaptic plasticity induced by antidepressant treatment to promote therapeutic efficacy by rearranging connectivity in corticolimbic circuits impaired in depression.

Highlights

Recent genome-wide association studies (GWAS) have identified Negr1 as one of the most significant risk genes for major depressive disorder (MDD) [1,2], and by integratingGWAS with gene expression information across multiple human tissues, including brain, the association has been confirmed [3]
We aimed to investigate whether antidepressant treatment affected the expression of Negr1 and other genes belonging to the same pathway in the hypothalamus, a brain region involved both in the regulation of feeding behaviour and in neuro-vegetative symptoms of MDD
We subjected rats belonging to the Flinders sensitive line (FSL) strain to the experience of maternal separation to model the early-life stress exposure experience that is deemed to be a causative factor for triggering MDD

Summary

Introduction

Recent genome-wide association studies (GWAS) have identified Negr (neuronal growth regulator1) as one of the most significant risk genes for major depressive disorder (MDD) [1,2], and by integratingGWAS with gene expression information across multiple human tissues, including brain, the association has been confirmed [3]. Recent genome-wide association studies (GWAS) have identified Negr 1) as one of the most significant risk genes for major depressive disorder (MDD) [1,2], and by integrating. The involvement of Negr in the molecular neurobiology of MDD is suggested by reports showing changes in protein expression patterns in cerebrospinal fluid of depressed patients [6], and in response to antidepressant treatments [7]. Different polymorphisms in the Negr locus are known to be associated with risk for body mass index and obesity [10,11]. The biological mechanism is unknown, but available data suggest that Negr effects on energy balance are mediated at least in part by genes in the rodent hypothalamus, in the periventricular hypothalamic areas [12,13]

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