Optimalrefinementofneuralcircuitsduringdevelopmentisahighlycontrolledprocessthatdependscriticallyon experience.Amplegeneticevidenceinmentaldisorderspointsspecificallytodefectsinmoleculartargetsrelated toexperience-dependentdevelopmentalplasticityofexcitatorysynapses,anddysregulationofthisfundamental developmentalprocess resultsinavarietyofneuropsychiatricdiseases.This projectseekstoelucidate mechanismsbywhichexperiencesculptsthefunctionalconnectionofexcitatorysynapsesduringdevelopment andhowperturbationsinthisprocesscanderailthenormaldevelopmentaltrajectory.Wefoundthatduringthe criticalperiodoftheirfunctionalmaturation,excitatorysynapsesofthemouseprimaryvisualcortex(V1)maintain adynamicequilibriumintheirAMPAreceptor-mediatedtransmission.Thisequilibriumrequiresneurogranin(Ng), a postsynapticcalmodulin-bindingprotein important for synaptic plasticity,which ishasbeenimplicatedin schizophreniaandmentalretardation.Ourpreliminarystudiesshowthatinadditiontocontrollingincorporation of AMPA receptors into AMPA receptor-lacking(silent)synapsesandsynapticpruning, Nglevelsalso control thetimingofthedevelopmentalswitchinNMDAreceptorsubunits,andchangethephosphorylationprofilesof severalpostsynapticproteinsincludingNMDAreceptorandPSD-93/95.Thisprojectinvestigatesthehypothesis thatNglevelsinfluencetheexperience-dependentreorganizationofexcitatorysynapticconnectivitybyaltering Ca/CaM-dependent signaling pathways,including PP2B and NMDA receptors,usingacombinationofvirus- mediatedgenemanipulation,synapticphysiology,channelbiophysics,morphologicalanalysis,andbehavioral interrogation.Theresultswillelucidatethemolecularpathwaysgoverningexperience-dependentrefinementof excitatorysynapticconnectivityduringdevelopmentandwillhelptoidentifypotentialtargetsforpharmacologic interventionsinpatientwithneurodevelopmentaldisorders.
Experience-dependent refinement of excitatory synaptic connectivity is a fundamental developmental mechanism whose dysregulation leads to neuropsychiatric disorders. We found that neurogranin (Ng), apostsynapticcalmodulin(CaM)-bindingproteinandschizophrenia-associatedgenetarget,regulatesconstructive synapticrefinementinvisualcortexduringthecriticalperiod.Thisstudywilluseacombinationofvirus-mediated gene manipulation,electrophysiology,high-throughput and high-resolutionchannel biophysics,morphological analysis,andbehavioralinterrogationtobetterunderstandmolecularmechanismsthatcontroltheorganization of excitatorycircuitsduringdevelopment,andthushelp identifytherapeuticapproachestoaddressmentaldisorders.
