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Published on: October 24, 2018
Mss4 gene is up-regulated in rat brain after chronic treatment with antidepressant and down-regulated when rats are
Christian Andriamampandry1, Claude Muller, Catherine Schmidt-Mutter
1Institut de Chimie Biologique, U-338, Faculty of Medicine, Strasbourg, France.
Abstract:
Differential display reverse transcription-polymerase chain reaction was used to identify mRNAs that are differentially expressed in the brain of rats treated chronically with the reference tricyclic antidepressant, imipramine, in comparison with control rats. The gene encoding for a mutation suppressor for Sec4-8 yeast (Mss4) transcript is overexpressed in the amygdala of treated rats after 3 weeks of daily administration. This overexpression is also found in the hippocampus of rats treated chronically with either tianeptine or fluoxetine. Mss4 protein has the properties of a guanine nucleotide exchange factor, interacting with several members of the Rab family implicated in Ca(2+)-dependent exocytosis of neurotransmitters. Mss4 was also overexpressed in other brain structures as judged by in situ hybridization. The kinetics of the up-regulation of Mss4 gene expression measured by Northern blot during the imipramine, tianeptine, or fluoxetine treatments are consistent with an antidepressant effect that occurs after 3 weeks. In rats in which anhedonia was induced by chronic mild stress during 3 weeks, Mss4 transcripts were specifically down-regulated in hippocampus and amygdala compared with control rats. It is proposed that Mss4 protein, which stimulates exocytosis in vivo, participates in the potentiation of the activity of neurotransmitter pathways implicated in the action of several antidepressants and constitutes one of the common functional molecules induced after chronic antidepressant treatment.
Insights
Chronic antidepressant treatment, including imipramine, tianeptine, and fluoxetine, upregulates the Mss4 gene in rat brains. This suggests Mss4 protein plays a role in antidepressant action and neurotransmitter pathway potentiation.
Area of Science:
- Neuroscience
- Molecular Biology
- Pharmacology
Background:
- Antidepressant medications are crucial for treating mood disorders.
- The precise molecular mechanisms underlying antidepressant efficacy remain incompletely understood.
- Identifying common molecular targets of various antidepressants can elucidate therapeutic pathways.
Purpose of the Study:
- To identify genes differentially expressed in the rat brain following chronic treatment with the antidepressant imipramine.
- To investigate the role of the identified genes in the mechanisms of action of different classes of antidepressants.
- To explore the involvement of these genes in stress-induced anhedonia.
Main Methods:
- Differential display reverse transcription-polymerase chain reaction (DD-RT-PCR) was employed to screen for differentially expressed mRNAs.
- Northern blot analysis and in situ hybridization were used to quantify and localize gene expression.
- Anhedonia was induced in rats using a chronic mild stress model.
Main Results:
- The mutation suppressor for Sec4-8 yeast (Mss4) transcript was found to be significantly overexpressed in the amygdala and hippocampus of rats treated with imipramine, tianeptine, or fluoxetine.
- Mss4 protein functions as a guanine nucleotide exchange factor, interacting with Rab proteins involved in neurotransmitter exocytosis.
- Mss4 transcripts were downregulated in the hippocampus and amygdala of rats subjected to chronic mild stress, a model of anhedonia.
Conclusions:
- Mss4 gene expression is upregulated by chronic administration of multiple antidepressants, suggesting it is a common molecular target.
- Mss4 protein's role in stimulating exocytosis indicates its involvement in potentiating neurotransmitter pathways crucial for antidepressant action.
- Mss4 may represent a key functional molecule induced by chronic antidepressant treatments and implicated in mood regulation.
