Raphe-driven feed-forward inhibition of the hippocampus by glutamate co-transmission

Abstract

Raphe nuclei are clusters of heterogeneous cell populati ons comprised of serotonergic, dopaminergic, glutamatergic, and GABAergic neurons.Investi gati ons about the modulati on by raphe nuclei have primarily concentrated on their serotonergic slow synapti c transmission since the majorityof the neuronal populati on in the raphe nuclei is serotonergic. However, accumulati ng evidence suggests the emerging role of GABA- or glutamate-mediated fast synapti c transmission by raphe neurons. Especially, glutamate is co-transmitt ed by serotonergic neurons in the diverse brain regionsincluding the hippocampus, amygdala, and VTA. Interesti ngly, glutamatergic transmission mediated by the raphe nuclei tends to modulate inhibitoryneurons rather than excitatory neurons in the amygdala and hippocampus. This evidence suggests that raphe-mediated fast excitatory transmissionmay be mainly converted to inhibitory tone in the target regions. In this study, we focused on the inhibitory eff ect of raphe-mediated fast synapti ctransmission in the major targets of the raphe nuclei. Using optogeneti c approaches, immunohistochemistry, and enhanced confocal imaging, wefound that multi ple brain regions receive disynapti c inhibitory inputs from raphe serotonergic neurons, among which the hippocampus is functi onallythe most impacted region by raphe-mediated feed-forward inhibiti on. In additi on, we discovered that this feed-forward inhibiti on is mediated by theglutamatergic transmission of the raphe neurons. Most notably, raphe-driven feed-forward inhibiti on was able to modulate synapti c transmission atSchaff er collateral-CA1 synapses in the hippocampus. Our fi ndings demonstrate the functi onal signifi cance of raphe-mediated fast synapti ctransmission and provide new insights into the complex synapti c connecti vity of raphe serotonergic neurons.