Regulation of serotonin (5-HT) function by a VGLUT1 dependent glutamate pathway

Unraveling the mechanisms of 5-HT neuron control might provide new insights into depression pathophysiology. In addition to the inhibitory 5-HT1A autoreceptors, cortico-raphe glutamatergic descending pathways are suggested to modulate 5-HT activity in the DRN. Here we studied how decreased VGLUT1 levels in the brain stem affect glutamate regulation of 5-HT function.VGLUT1+/− mice (C57BL/6) and wild type (WT) littermates were used. VGLUT1 expression in the DRN, 5-HT turnover and immuno histochemical analysis of neuronal activity in different areas was studied. Moreover, the functionality of the inhibitory 5-HT1A autoreceptor was assessed using electrophysiological, biochemical and pharmacological approaches.VGLUT1 immunoreactivity was markedly lower in the DRN of the VGLUT1+/− mice and specifically, in the surroundings of GABA and 5-HT cell bodies. These mice showed decreased induced neuronal activity in 5-HT cells bodies and in different forebrain areas, as well as decreased hippocampal cell proliferation and 5-HT turnover. Further, 5-HT1A autoreceptor desensitization was evidenced by electrophysiological studies, GTP-γ-S coupling to 5-HT1A autoreceptor and a lower hypothermic response to 5-HT1A activation.This study shows first time that VGLUT1 dependent glutamate innervation of the DRN could modulate 5-HT function.

► We study mechanisms of 5-HT neuron control related to depression pathophysiology. ► Decreased VGLUT1 in the brain stem affects glutamate regulation of 5-HT function. ► VGLUT1+/− mice show decreased neuronal activity and cell proliferation. ► These mice show decreased 5-HT turnover and 5-HT1A autoreceptor desensitization. ► Here we show first time that VGLUT1 innervation of the DRN modulates 5-HT function.