Memory Susceptibility To Retroactive Interference Is Developmentally Regulated By NMDA Receptors

Retroactive interference(RI)refers to the phenomenon that learning new information can attenuate previously stored memory,which is one of the major sources of forgetting.It has been proposed that memory is encoded by modification of synaptic strengths through cellular mechanisms such as long term potentiation(LTP),and long-term storage of information demands maintenance of LTP.In this way,the erosion of memory is related to the reversal of LTP.Furthermore,depotentiation is likely to be the mechanism of RI.The ability of learning and memory decline during development,even appear in early adulthood.That presumably occurr because long-term memory is becoming difficult to form as time goes by,or in the reason of memory have not yet had a chance to consolidate as forgetting arises.Traditional studies in the neuroscience of learning and memory have emphasized aspects of the memory forming during development.However,forgetting and its cellular mechanisms in the process of time were rarely studied.We decided to focus on the changes and underlying mechanisms of retroactive inhibitory in DG during development.Behavior: 1.RI brought forgetting of newly acquired memory in adults,but not young,animals.2.RI produced forgetting of newly acquired memory in adults through GluN2A-containing NMDARs.3.Overexpression of GluN2 A in DG enhanced vulnerability to RI,the same as the downregulation of GluN2 B.Electrophysiology: 1.Depotentiation which was induced by low frequency stimulation(LFS)occured in adults,but not young,animals.2.Novelty exploration reversed LTP in adults,but not adolescent mice.3.NMDAR blocker MK-801 prevented LTP reversal in adult slices.4.The decay time constant of NMDAR-mediated excitatory postsynaptic currents(NMDA-EPSC)decreased during development.5.Ifenprodil blocked a greater portion of NMDA-EPSCs in young slices than in adult slices.6.Application of GluN2 A blocker PEAQX during LFS blocked depotentiation in adults.7.After receiving intra-DG infusion of ifenprodil 1h after LTP induction in adolescent mice,depotentiation occured if the mice wereallowed to explore novel enrichment(NE).8.Both GluN2 A overexpression and GluN2 B downregulation in the DG promoted the depotentiation of young animals.Western Blot: The GluN2 A protein in DG increased obviously from juvenile to adulthood,but the expression of GluN2 B decreased dramatically.In addition,GluN2A/ GluN2 B ratio elevated greatly during development.In conclusion,the developmental enhancement of RI and depotentiation are controlled by the ratio of GluN2A/GluN2 B.The results of the experiments demonstrated that RI was developmentally regulated by composition of NMDA receptors.These finds helped to provide new ideas for the maintenance and erosion of memory,also contributed to understand the cognitive function of brain and neural circuit function.