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Tcf4 Regulates Synaptic Plasticity, DNA Methylation, and Memory Function
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DOI：10.1016/j.celrep.2016.08.004.png)
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Abstract
En 中文
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 haploin-sufficient 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:
PITT-HOPKINS SYNDROME
LONG-TERM-MEMORY
ULTRASONIC VOCALIZATION
HISTONE ACETYLATION
GENE-TRANSCRIPTION
GAIT ANALYSIS
MOUSE MODEL
EXPRESSION
SCHIZOPHRENIA
DISEASE
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