The Effects And Mechanism Of Rapl1 On Fear Conditioning&Extinction

Rap1,a member of small GTPase Ras superfamily,is ubiquitously expressed in numerous tissues as a crucial molecular swith.It takes part in regulating cell adhesion,polarity,proliferation and so on.Rap1 has been implicated in neuronal exciatbily,AMPARs trafficking and synaptic plasticity.However,little is known when it comes to its role in regulating specific brain advanced founction such as learning and memory.Fear conditioning associates neutral environmental cues with predicted dangers.It protects animals from damage through making animals to respond to these pontential dangerous cues adequately.It is critical for survial of animals.Recent research found forebrain restricted rap1a/rap1 b double knockout increased basal synaptic transmission in cortical-amygdala pathway and impaired fear learning.However,it did not distinguish the two isoforms of Rap1 —— Rap1 A and Rap1 B,which share 95% amino acid identity.In order to dissect the individual or common contribution of each isoform to fear conditioning,I breded forebrain restricted rap1 a,rap1b and double knockout mice.Subsquently,I investigated their fear conditioning and found rap1 b knockout mimicking rap1a/rap1 b double knockout imparied the fear memory.Pulldown assay also revealed fear conditioning could activate Rap1 in mPFC.Then,c-Fos immunostaining and patch clamp showed that rap1 b knockout and rap1a/rap1 b double knockout,inhibited the neurons in PL after fear conditioning.Therefore,Rap1 B primarily mediates fear conditioning by regulating the activity of mPFC.Meanwhile,we investigated the effects of Rap1 on fear extinction.Fear extinction refers to the gradual decline of conditioned fear responses occurring with repeated presentation of the unreinforced conditioned fear stimulus.This article found forebrain restricted rap1a/rap1 b double knockout could facilitate the acquisition of fear extinction,but not alterd the consolidation and retrival of extinction memory.Subsequent c-Fos staining and eletrophysiological techniques revealed that it signif-icantly activated the PL after fear extinction.Finally,locally deleting rap1a/rap1 b by infusing with adeno-associated virus(AAV)expressing Cre into the mPFC of rap1a/rap1b-floxed mice generated the same behavioral phenotype as forebrain restricted rap1a/rap1 b double knockout.In addition,the phenotype could be rescued by re-expression of rap1a/rap1 b with AAV injected into the mPFC of forebrain restricted rap1a/rap1 b double knockout mice.In conclusion,(1)the effects of Rap1 on fear conditioning were primarily induced by Rap1B;(2)Rap1 would affect the acquisition of fear extinction;(3)Rap1 infulence the fear conditioning and extinction by regulating the activity of mPFC.