Vol. 62, Issue 6, 1332-1338, December 2002

Mss4 Gene Is Up-Regulated in Rat Brain after Chronic Treatment with Antidepressant and Down-Regulated When Rats Are Anhedonic

Christian Andriamampandry, Claude Muller, Catherine Schmidt-Mutter, Serge Gobaille, Michael Spedding, Dominique Aunis, and Michel Maitre

Institut de Chimie Biologique and Institut National de la Santé et de la Recherche Médicale U-338, Faculty of Medicine, Strasbourg, France (C.A., C.M., C.S.-M., S.G., D.A., M.M.) and Institut de Recherche International Servier, Neuilly-sur-Seine, France (M.S.)

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 Ca²⁺-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.