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- W2520004809 abstract "Neuralpathways within thehippocampus undergo use-dependent changes insynaptic efficacy, andthese changes aremediated byanumberofsignaling mechanisms, including cAMP-dependent protein kinase (PKA). ThePKA holoenzyme iscomposed ofregulatory andcatalytic (C) subunits, bothofwhichexist asmultiple isoforms. Thereare twoCsubunit genes inmice, CaandC,B, andtheCf3genegives rise toseveral splice variants that arespecifically expressed in discrete regions ofthebrain. We haveusedhomologous recombination inembryonic stemcells tointroduce aninac- tivating mutation intothemouseC1gene, specifically tar- geting theCj81-subunit isoform. Homozygous mutants showed normalviability andnoobvious pathological defects, despite acomplete lackofCfJ1. Themicewereanalyzed inelectro- physiological paradigms totesttheroleofthisisoform in long-term modulation ofsynaptic transmission intheSchaffer collateral-CAl pathwayofthehippocampus. A high- frequency stimulus produced potentiation inbothwild-type andCI38-/- mice, butthemutants wereunable tomaintain thepotentiated response, resulting inalate phase oflong-term potentiation thatwasonly30%ofcontrols. Paired pulse facilitation wasunaffected inthemutantmice. Low-frequency stimulation produced long-term depression anddepotentia- tioninwild-type micebutfailed toproduce lasting synaptic depression intheCf13/- mutants. Thesedataprovide direct genetic evidence thatPKA,andmorespecifically theCf81 isoform, isrequired forlong-term depression anddepoten- tiation, aswellasthelate phase oflong-term potentiation in theSchaffer collateral-CAl pathway. A large bodyofevidence, bothinhumansandexperimental animals, hasrevealed thatthehippocampus issingularly important intheability tousespatial, olfactory, auditory, and other contextual cuestolearn newtasks andtocommit those experiences tomemory.Significantly, neuronsofthehip- pocampus demonstrate theremarkable capacity toundergo persistent increases anddecreases insynaptic transmission in response toelectrical stimuli. Long-term potentiation (LTP)is anenhanced synaptic responsiveness thatiselicited byhigh- frequency stimulation oftheafferent neurons (1,2). LTPcan last forhours inaninvitro hippocampal slice preparation and forweeks whenperformed invivo. Mostneural pathways ofthe hippocampus also exhibit asecond formofsynaptic plasticity, long-term depression (LTD), inwhichlow-frequency stimu- lation produces adecrease insynaptic responsiveness (3-5). BothLTDandLTPintheCAIregion ofthehippocampus aredependent uponN-methyl-D-aspartate" @default.
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- W2520004809 date "1996-01-01" @default.
- W2520004809 modified "2023-09-26" @default.
- W2520004809 title "Impaired hippocampal plasticity inmicelacking theCf31catalytic subunit ofcAMP-dependent protein kinase" @default.
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