Raphe-driven glutamate co-transmission shapes hippocampal function via modulation of cholecystokinin expressing inhibitory neurons

Abstract

Theraphenucleiconsistofheterogeneousneuronalpopulations,includingserotonergic,dopaminergic,glutamatergic,andGABAergicneurons.Whilemostresearchontheraphehasfocusedonthemodulatoryroleofserotonergicslowsynaptictransmission—giventhepredominanceofserotonergicneurons—growingevidencehighlightsthesignificanceoffastsynaptictransmissionmediatedbyGABAandglutamate.Inparticular,serotonergicneuronsintheraphenucleihavebeenshowntoco-releaseglutamateinmultiplebrainregions,includingthehippocampus,amygdala,andventraltegmentalarea.Notably,thisglutamatergicco-transmissionoftentargetsinhibitoryinterneuronsratherthanexcitatorycells,especiallywithintheamygdalaandhippocampus.Suchfindingssuggestthatfastexcitatorysignalingfromrapheneuronsmaypreferentiallymodulatelocalinhibitorycircuits,therebyshapingtheactivityofdownstreamnetworks.Inthisstudy,weexaminedthefunctionalroleofraphe-drivenfastsynaptictransmissioninmajorprojectionareasofserotonergicneurons.Bycombiningoptogenetics,immunohistochemistry,andconfocalimaging,weidentifiedthatmultiplebrainregionsreceivedi-synapticinputsfromrapheserotonergicneurons,withthehippocampusshowingthemostsignificantfunctionalconnection.Withinthehippocampus,wediscoveredthatglutamateco-releasefromrapheserotonergicneuronsselectivelyenhancestheexcitabilityofCCK-positiveinhibitoryinterneurons.ThismodulationofCCK-expressingneuronshadadownstreameffectontheexcitabilityofCA1pyramidalneuronsandsignificantlyfacilitatedsynapticplasticityatSchaffercollateral–CA1synapses.Ourfindingsunderscorethefunctionalimportanceofraphe-mediatedglutamateco-transmissionandprovidenewinsightsintotheintricatesynapticmodulationexertedbyrapheserotonergicneuronsinthebrain.