Neuralcircuitassemblyrequirestheorchestrationofmultiplemolecularprocesses,includingaxonalpathfinding, targetrecognition,synapsespecification,andmolecularorganizationofthepre-andpostsynapticcompartment. However,themolecularnetworksandsignalingpathwaysunderlyingsynapseformationandspecificationwithin neural circuits remain poorly understood. Cell adhesion molecules are emerging as essential regulators of synapse formation, organization, and specificity. The adhesion-class GPCR Latrophilins (Lphn) are candidate synaptic cell adhesion molecules with putative cAMP-mediated GPCR signaling capabilities. We found that Lphn3ishighlyexpressedinhippocampalneuronsandlocalizedtothepostsynapticcompartment.Conditional KO(cKO)ofLphn3inhippocampalneuronsdiminishedexcitatorysynapticstrengthinamannerthatrequired GPCRfunction.ExpressionanalysisinvivorevealedthatLphn2andLphn3exhibitdistinctexpressionpatterns along the hippocampal CA1 pyramidal cell dendritic arbor, with Lphn2 enriched in the stratum lacunosum- moleculare(s.l.m.),andLphn3enrichedinthestratumoriens(s.o.)andstratumradiatum(s.r.)oftheCA1.Cell- autonomous cKO of Lphn2 or Lphn3 in CA1 pyramidal cells resulted in synapse loss and reduced excitatory synapticstrengthinthes.l.mors.o./s.r.,respectively.Thus,Lphn2andLphn3functionaspostsynapticadhesion moleculesthatregulatesynapsespecificationfromPerforantpathinputsintothes.l.m.andSchaffercollateral inputs into the s.o./s.r., respectively. Our results define a novel cell adhesion and signaling pathway mediated byLphnsthatregulatessynapseformationandspecificityinthehippocampalCA1.Currenteffortsarefocused on assessing the role of Lphn2/3 GPCR function in hippocampal CA1 synapse specificity, and the behavioral consequencesofLphn3cKOintheCA1.Mycareergoalistoleadaresearchprogramasaprincipalinvestigator in academia focused on advancing our understanding of the cellular and molecular basis of neural circuit development and function, how circuits generate behavior, and how aberrant neural circuit function underlies neurologicaldisorders.Toobtainthisgoal,Iamcurrentlyfocusedonpublishingmyongoingpostdoctoralstudies, andwillcompleteadditionalpostdoctoralintellectualandtechnicaltraining,includinginoptogeneticsandmouse behavioralassays.Theseskillswillcomplementmycurrenttraining,andallowmetoinvestigatethequestionsI will pursue during my independent career, which will span from molecular mechanisms to behavior. Future researchduringtheindependentphasewillstudytheneuronalfunctionoftheadhesion-classGPCRCELSRs (cadherinEGFLAGseven-passG-typereceptor),whicharerelatedtoLphnsandexhibitsynapticlocalization. CELSRs, together with Lphns, are the only adhesion GPCRs conserved from invertebrates to vertebrates, suggestingtheymaymediateuniversalfunctions.ThesestudieswillfocusoninvestigatingtheGPCRsignaling pathwaysutilizedbyLphnsandCELSRs,andtheroleofCELSRsinneuralcircuitassemblyandfunction.
Aberrationsinsynapticdevelopmentandphysiologyunderlienumerousneuropsychiatricdisorders.Ourstudies are examining a novel synaptic adhesion and GPCR signaling pathway mediated by adhesion-class GPCR Latrophilinproteins,whichhavebeenassociatedwithseveralneurologicaldisorders,includingADHD.
