Mechanisms Underlying The Function Of PKC?/? In Learning And Memory

Learning and memory is one of the important brain functions and a prerequisite for survival and reproduction.Long-term potentiation(LTP)is an important cellular model of synaptic plasticity and is wildly considered to share many molecular and cellular mechanisms.The mechanism of LTP formation is a complex process involving numerous signaling pathways and function proteins.Protein kinase C(PKC)also plays a very important role.There are at least 10 members of the PKC family,which can be divided into three sub-group:traditional PKC(conventional PKC,cPKC),novel PKC(novel PKC,nPKC),and atypical PKC(atypical PKC,aPKC)Hippocampal CA1 region which expresses PKC?/? and PKM? is widely used for LTP research.Our recent study has demonstrated the critical of PKC?/? in hippocampal LTP.Activation of PKC?/? via the signaling pathway CaMK?-Ras-PI3K regulates the phosphorylation GluA1 subunit S818 site of AMPA receptors to postsynaptic.In the present study,we employed a conditional PKC?/? KO mice to further in-depth study the function of PKC?/? in synaptic plasticity,learning and memoryIn the first part of this thesis,PKC?/? was knocked out in the excitatory pyramidal neurons of the hippocampal CA1 region by constructing PKC?/? conditional knockout(cKO)mice.It was found that PKC?/? cKO mice exhibited normal hippocampal LTP.Subsequently,we detected the expression of aPKC in hippocampus at different time after LTP induction and fear conditioning training.It was found that PKM?significantly increased at the time of p-PKC?/? increasing in the wild type group,suggesting that the function of PKC?/? might be replaced by PKM? in PKC?/? cKO mice.To test the idea,we firstly used the PKM? function induced GluA2/NSF interaction inhibitor pep2m to inhibit the late stage of LTP.But pep2m inhibited the early stage of LTP suggesting that PKC?/? might be replaced by PKM? in PKC?/?cKO mice;Second,we found that membrane trafficking blocker TeTX couldn't inhibit LTP of PKC?/? cKO mice,suggesting that PKC?/? cKO mice LTP didn't depend on AMPA membrane trafficking.It may depend on APMA receptor lateral transition into postsynaptic membrane and stabilized by the PKM? mediated mechanism;Finally,AMAP receptor subunit A3 significantly increased 10 minutes after LTP induction in PKC?/? cKO mice,suggesting that PKM? dependent GluA3 mechanism replace the PKC?/? dependent GluA1 mechanism;The results explained that the mechanism of the PKC?/? cKO LTP is dependent on the function of PKM?.When cKO mice were challenged with more difficult hippocampus-dependent learning tasks,moderate learning deficits were detected,suggesting a suboptimal compensation for PKC?/?'s function in PKC?/? cKO miceWe know that the hippocampal learning and memory depends not only on the formation of LTP,but also on the memory consolidation through several brain regions In the second part of this thesis,we investigate the system consolidation on several brain regions and neural circuit level.We explore the methods of multi-site grid multi-channel recording and record the local field potential of several key brain regions of contextual fear memory:hippocampus,anterior cingulate cortex,medial prefrontal cortex,and posterior parietal cortex to study the change of functional connection between key brain regions in remote memory consolidation.In the recent memory stage,the Gamma band power-power coupling is increasing between the hippocampus and several cortex regions.In the remote memory stage,the Theta band power-power coupling is increasing between cortex regions.The Gamma band power-power coupling and Theta band power-power coupling is increasing between hippocampus and mPFC during remote memory recall.It suggested that the hippocampus and the cortex have functional connections and transformations to help the memory formation and consolidation.There may be two sets of memory recall system,which are dependent on hippocampus and independent on hippocampus,during the remote memory recall stageIn subsequent studies,we will investigate the function of PKC?/? by multi-channel recording PKC?/? cKO transgenic mice,chemical genetics methods to block PKC?/?activity during the remote memory consolidation and recall.So we can deeply understand the further function of PKC?/? on neural circuit level during the memory consolidation and recall.