Tcf4 Regulates Synaptic Plasticity, DNA Methylation, and Memory Function

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

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.

MeSH terms

  • Animals
  • Autistic Disorder / complications
  • Autistic Disorder / pathology
  • Autistic Disorder / physiopathology
  • CpG Islands / genetics
  • DNA Methylation / drug effects
  • DNA Methylation / genetics*
  • Disease Models, Animal
  • Facies
  • Gene Expression Profiling
  • Gene Knockdown Techniques
  • Hippocampus / metabolism
  • Histone Deacetylase 2 / metabolism
  • Histone Deacetylase Inhibitors / pharmacology
  • Hydroxamic Acids / pharmacology
  • Hyperventilation / complications
  • Hyperventilation / genetics
  • Hyperventilation / pathology
  • Hyperventilation / physiopathology
  • Intellectual Disability / complications
  • Intellectual Disability / genetics
  • Intellectual Disability / pathology
  • Intellectual Disability / physiopathology
  • Long-Term Potentiation / drug effects
  • Male
  • Memory* / drug effects
  • Mice
  • Motor Activity / drug effects
  • Neuronal Plasticity / drug effects
  • Neuronal Plasticity / genetics*
  • Prepulse Inhibition / drug effects
  • Transcription Factor 7-Like 2 Protein / genetics
  • Transcription Factor 7-Like 2 Protein / metabolism*
  • Transcription, Genetic / drug effects
  • Vorinostat

Substances

  • Histone Deacetylase Inhibitors
  • Hydroxamic Acids
  • Transcription Factor 7-Like 2 Protein
  • Vorinostat
  • Hdac2 protein, mouse
  • Histone Deacetylase 2

Supplementary concepts

  • Pitt-Hopkins syndrome