title: Tcf4 Regulates Synaptic Plasticity, DNA Methylation, and Memory Function.
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.
authors: 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.
authors: Andrew J
authors: AJ
authors: Kennedy
authors: Department of Neurobiology and Evelyn F. McKnight Brain Institute, University of Alabama at Birmingham, Birmingham, AL 35294, USA.
authors: Elizabeth J
authors: EJ
authors: Rahn
authors: 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.
authors: Brynna S
authors: BS
authors: Paulukaitis
authors: Department of Neurobiology and Evelyn F. McKnight Brain Institute, University of Alabama at Birmingham, Birmingham, AL 35294, USA.
authors: Katherine E
authors: KE
authors: Savell
authors: Ionis Pharmaceuticals, Carlsbad, CA 92010, USA.
authors: Holly B
authors: HB
authors: Kordasiewicz
authors: Department of Neurobiology and Evelyn F. McKnight Brain Institute, University of Alabama at Birmingham, Birmingham, AL 35294, USA.
authors: Jing
authors: J
authors: Wang
authors: Department of Neurobiology and Evelyn F. McKnight Brain Institute, University of Alabama at Birmingham, Birmingham, AL 35294, USA.
authors: John W
authors: JW
authors: Lewis
authors: Department of Neurobiology and Evelyn F. McKnight Brain Institute, University of Alabama at Birmingham, Birmingham, AL 35294, USA.
authors: Jessica
authors: J
authors: Posey
authors: Department of Neurobiology and Evelyn F. McKnight Brain Institute, University of Alabama at Birmingham, Birmingham, AL 35294, USA.
authors: Sarah K
authors: SK
authors: Strange
authors: Department of Neurobiology and Evelyn F. McKnight Brain Institute, University of Alabama at Birmingham, Birmingham, AL 35294, USA.
authors: Mikael C
authors: MC
authors: Guzman-Karlsson
authors: Department of Neurobiology and Evelyn F. McKnight Brain Institute, University of Alabama at Birmingham, Birmingham, AL 35294, USA.
authors: Scott E
authors: SE
authors: Phillips
authors: Department of Neurobiology and Evelyn F. McKnight Brain Institute, University of Alabama at Birmingham, Birmingham, AL 35294, USA.
authors: Kyle
authors: K
authors: Decker
authors: Ibis Biosciences, Carlsbad, CA 92008, USA.
authors: S Timothy
authors: ST
authors: Motley
authors: Ionis Pharmaceuticals, Carlsbad, CA 92010, USA.
authors: Eric E
authors: EE
authors: Swayze
authors: Ibis Biosciences, Carlsbad, CA 92008, USA.
authors: David J
authors: DJ
authors: Ecker
authors: Ibis Biosciences, Carlsbad, CA 92008, USA.
authors: Todd P
authors: TP
authors: Michael
authors: Department of Neurobiology and Evelyn F. McKnight Brain Institute, University of Alabama at Birmingham, Birmingham, AL 35294, USA.
authors: Jeremy J
authors: JJ
authors: Day
authors: 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.
authors: J David
authors: JD
authors: Sweatt
mesh_terms: D000818:Animals; D001321:Autistic Disorder / Q000150:complications / Q000473:pathology / Q000503:physiopathology; D018899:CpG Islands / Q000235:genetics; D019175:DNA Methylation / Q000187:drug effects / Q000235:genetics*; D004195:Disease Models, Animal; D019066:Facies; D020869:Gene Expression Profiling; D055785:Gene Knockdown Techniques; D006624:Hippocampus / Q000378:metabolism; D056464:Histone Deacetylase 2 / Q000378:metabolism; D056572:Histone Deacetylase Inhibitors / Q000494:pharmacology; D006877:Hydroxamic Acids / Q000494:pharmacology; D006985:Hyperventilation / Q000150:complications / Q000235:genetics / Q000473:pathology / Q000503:physiopathology; D008607:Intellectual Disability / Q000150:complications / Q000235:genetics / Q000473:pathology / Q000503:physiopathology; D017774:Long-Term Potentiation / Q000187:drug effects; D008297:Male; D008568:Memory / Q000187:drug effects; D051379:Mice; D009043:Motor Activity / Q000187:drug effects; D009473:Neuronal Plasticity / Q000187:drug effects / Q000235:genetics*; D065808:Prepulse Inhibition / Q000187:drug effects; D058118:Transcription Factor 7-Like 2 Protein / Q000235:genetics / Q000378:metabolism*; D014158:Transcription, Genetic / Q000187:drug effects; D000077337:Vorinostat
chemical_list: D056572:Histone Deacetylase Inhibitors; D006877:Hydroxamic Acids; D058118:Transcription Factor 7-Like 2 Protein; D000077337:Vorinostat; C533424:Hdac2 protein, mouse; D056464:Histone Deacetylase 2
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