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.
Subject(s)
DNA Methylation/genetics , Memory , Neuronal Plasticity/genetics , Transcription Factor 7-Like 2 Protein/metabolism , Animals , Autistic Disorder/complications , Autistic Disorder/pathology , Autistic Disorder/physiopathology , CpG Islands/genetics , DNA Methylation/drug effects , 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 , Prepulse Inhibition/drug effects , Transcription Factor 7-Like 2 Protein/genetics , Transcription, Genetic/drug effects , VorinostatABSTRACT
Memory formation is a multi-stage process that initially requires cellular consolidation in the hippocampus, after which memories are downloaded to the cortex for maintenance, in a process termed systems consolidation. Epigenetic mechanisms regulate both types of consolidation, but histone variant exchange, in which canonical histones are replaced with their variant counterparts, is an entire branch of epigenetics that has received limited attention in the brain and has never, to our knowledge, been studied in relation to cognitive function. Here we show that histone H2A.Z, a variant of histone H2A, is actively exchanged in response to fear conditioning in the hippocampus and the cortex, where it mediates gene expression and restrains the formation of recent and remote memory. Our data provide evidence for H2A.Z involvement in cognitive function and specifically implicate H2A.Z as a negative regulator of hippocampal consolidation and systems consolidation, probably through downstream effects on gene expression. Moreover, alterations in H2A.Z binding at later stages of systems consolidation suggest that this histone has the capacity to mediate stable molecular modifications required for memory retention. Overall, our data introduce histone variant exchange as a novel mechanism contributing to the molecular basis of cognitive function and implicate H2A.Z as a potential therapeutic target for memory disorders.
