Tcf4 Regulates Synaptic Plasticity, DNA Methylation, and Memory Function

Cell Reports

Sarah K. Strange¹  Andrew J. Kennedy¹  Katherine E. Savell¹  Jing Wang¹  J. David Sweatt¹  Scott E. Phillips¹  John W. Lewis¹  Mikael C. Guzman-Karlsson¹  Brynna S. Paulukaitis¹  Kyle Decker¹  Jeremy J. Day¹  Elizabeth J. Rahn¹  Jessica Posey¹  Todd P. Michael²  David J. Ecker²  S. Timothy Motley²  Eric E. Swayze³  Holly B. Kordasiewicz³ 

[1] Department of Neurobiology and Evelyn F. McKnight Brain Institute, University of Alabama at Birmingham, Birmingham, AL 35294, USA;Ibis Biosciences, Carlsbad, CA 92008, USA;Ionis Pharmaceuticals, Carlsbad, CA 92010, USA;

关键词: epigenetics;    Pitt-Hopkins syndrome;    transcription factor 4;    E2-2;    neuroepigenetics;    DNA methylation;    learning and memory;    next-generation sequencing;    HDAC inhibitor;    schizophrenia;    language;    transcription;    autism;    social interactions;    autism spectrum disorder;   

DOI  :  10.1016/j.celrep.2016.08.004

来源: DOAJ

【 摘 要 】

Human haploinsufficiency of the transcription factor Tcf4 leads to a rare autism spectrum disorder called Pitt-Hopkins syndrome (PTHS), which is associated with severe language impairment and development delay. Here, we demonstrate that Tcf4 haploinsufficient mice have deficits in social interaction, ultrasonic vocalization, prepulse inhibition, and spatial and associative learning and memory. Despite learning deficits, Tcf4(+/−) mice have enhanced long-term potentiation in the CA1 area of the hippocampus. In translationally oriented studies, we found that small-molecule HDAC inhibitors normalized hippocampal LTP and memory recall. A comprehensive set of next-generation sequencing experiments of hippocampal mRNA and methylated DNA isolated from Tcf4-deficient and WT mice before or shortly after experiential learning, with or without administration of vorinostat, identified “memory-associated” genes modulated by HDAC inhibition and dysregulated by Tcf4 haploinsufficiency. Finally, we observed that Hdac2 isoform-selective knockdown was sufficient to rescue memory deficits in Tcf4(+/−) mice.

【 授权许可】

Unknown