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Cell Rep. 2016 Sep 6;16(10):2666-2685. doi: 10.1016/j.celrep.2016.08.004. Epub 2016 Aug 25.

Tcf4 Regulates Synaptic Plasticity, DNA Methylation, and Memory Function.

Author information

1
Department of Neurobiology and Evelyn F. McKnight Brain Institute, University of Alabama at Birmingham, Birmingham, AL 35294, USA; Department of Chemistry, Bates College, Lewiston, ME 04240, USA.
2
Department of Neurobiology and Evelyn F. McKnight Brain Institute, University of Alabama at Birmingham, Birmingham, AL 35294, USA.
3
Department of Neurobiology and Evelyn F. McKnight Brain Institute, University of Alabama at Birmingham, Birmingham, AL 35294, USA; Department of Pharmacology, Vanderbilt University, Nashville, TN 37232, USA.
4
Ionis Pharmaceuticals, Carlsbad, CA 92010, USA.
5
Ibis Biosciences, Carlsbad, CA 92008, USA.
6
Department of Neurobiology and Evelyn F. McKnight Brain Institute, University of Alabama at Birmingham, Birmingham, AL 35294, USA; Department of Pharmacology, Vanderbilt University, Nashville, TN 37232, USA. Electronic address: david.sweatt@vanderbilt.edu.

Abstract

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.

KEYWORDS:

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

PMID:
27568567
PMCID:
PMC5710002
DOI:
10.1016/j.celrep.2016.08.004
[Indexed for MEDLINE]
Free PMC Article

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