Reversible Inhibition of CREBATF Transcription Factors in 在crebatf转录因子的可逆抑制.ppt

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2018-04-17 发布于江西
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Reversible Inhibition of CREBATF Transcription Factors in 在crebatf转录因子的可逆抑制.ppt

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Reversible Inhibition of CREB/ATF Transcription Factors in Region CA1 of the Dorsal Hippocampus Disrupts Hippocampus-Dependent Spatial Memory Pittenger C, Huang YY, Paletzki RF, Bourtchouladze R, Scanlin H, Vronskaya S, and Kandel ER BackgroundCREB (cAMP response element-binding) CREB Leucine zipper Leu residue at every seventh position DNA-binding domain has high concentration of Lys and Arg Complications of previous research Compensation of CREB inhibition by CREM/ATF-1 Little or no spatial restriction of mutation Lack of temporal regulation for expression of mutation KCREB Binds to wild-type CREB, CREM, and ATF-1 K304A CREB: Mg2+ interaction ? high affinity DNA binding Heterodimerized CREB/ATF ? lower affinity Repressor of CREB-mediated transcription How they made the transgenic mice How did they solve the complications of previous studies? Compensation of CREM/ATF-1: KCREB Spatial restriction: forebrain-specific CamKIIα promoter Temporal regulation: tetracycline-regulated tTA transactivator (Doxycycline) Expression of KCREB transgene CREB immunoreactivity in KCREB transgenic mice Proenkephalin and Substance P expression in transgenic mice Proenkephalin: CREB regulated ResultsDoes expression of KCREB in hippocampus… Impair spacial memory? Impair fear conditioning? Impair object recognition? Impair LTP maintenance with tetanus? Forskolin? Dopamine agonist? Spatial Memory Test - Morris Water Maze (A) Normal acquisition of control task (B) Slight difference at end of training Dorsal hippocampus impairment is responsible for deficient probe trial performance str-KCREB performance = wild-type performance Poor performance of dCA1-KCREB due to KCREB expression in hippocampus Spatial learning impairment is alleviated by doxycycline Doxycycline for two weeks Does expression of KCREB in hippocampus… Impair spacial memory? Impair fear conditioning? Fear conditioning is not impaired by dorsal hippocampus KCREB expression (A) fear conditioning not affec