5-HT4 receptor agonist RS67333 increases hippocampal neurogenesis and BDNF after only 3 days of treatment

Abstract

It has been described that certain hippocampal neuroplastic changes induced by classical antidepressants, as the increase in hippocampal BDNF levels or in the number of new neurons generated in the dentate gyrus, occur only after several weeks of treatment. A three-day regimen with the 5-HT4 receptor agonist RS67333 has been reported to be enough to show antidepressant-like properties in several behavioural tests. This result suggests a new strategic therapy for depressive disorders with a short onset of action. In order to verify if a short treatment with this 5-HT4 receptor agonist induces neuroplastic changes comparable to those observed after several weeks of treatment with typical antidepressants, immunohistochemical and in situ hybridization studies have been carried out. RS67333 (1.5 mg/kg/day) was delivered s.c. through 3-days osmotic minipumps to male Sprague-Dawley rats. RS67333 administration for 3 days increases the expression of the neurotrophic factor BDNF mRNA in hippocampus measured by in situ hybridization. BrdU immunohistochemistry revealed that a 3-days treatment with RS67333 upregulates the proliferation rate of adult hippocampal progenitors a 19 % and the number of U-catenin-immunopositive cells in the dentate gyrus around a 25%. Moreover, when the identity of U-catenin positive neural progenitors was analyzed by colocalization with Sox2 and GFAP, it was found that RS67333 increased specifically the number of hippocampal amplifying adult progenitors expressing U-catenin, suggesting that this treatment could be targeting the same type of neural progenitors that the classical antidepressants. These findings suggest that a 3-day treatment with RS67333 induces the same type of neuroplastic changes that require several weeks for classical antidepressants. They support the relevance of 5-HT4 receptor agonists as candidates for a new class of antidepressant response with a short onset of action.