Tcf4 Regulates Synaptic Plasticity, DNA Methylation, and Memory Function

David J Ecker,J David Sweatt,S Timothy Motley,Jing Wang,Jessica Posey,Sarah K Strange,Todd P Michael,Eric E Swayze,Scott E Phillips,Brynna S Paulukaitis,John W Lewis,Kyle Decker,Jeremy J Day,Andrew J Kennedy,Mikael C Guzman-Karlsson,Holly B Kordasiewicz,Katherine E Savell,Elizabeth J Rahn

doi:10.1016/j.celrep.2016.08.004

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, weobserved that Hdac2 isoform-selective knockdown was sufficient to rescue memory deficits in Tcf4(+/-) mice.

Highlights

Transcription factor 4 (Tcf4 aka E2-2, ITF-2, and SEF-2) is necessary for neurodevelopment and plays an important role in cognition, being associated with both schizophrenia and autism-spectrum intellectual disability (ID) (Forrest et al, 2014; Sweatt, 2013)
To further understanding of the neurobiological consequences of Tcf4 haploinsufficiency, we assessed a Tcf4(+/−) mouse with a deletion of the exons that code for the basic helix-loop-helix (bHLH) domain as a potential model for Pitt-Hopkins syndrome (PTHS) (Grubišić et al, 2015; Zhuang et al, 1996)
Seven out of ten PTHS cases are caused by SNPs that generate a premature stop codon or a point mutation in the bHLH domain of Tcf4 protein (Sepp et al, 2012), disrupting either transcription factor dimerization or mutating one of the basic residues required for DNA backbone association (Figure 1A)

Summary

Introduction

Transcription factor 4 (Tcf aka E2-2, ITF-2, and SEF-2) is necessary for neurodevelopment and plays an important role in cognition, being associated with both schizophrenia and autism-spectrum intellectual disability (ID) (Forrest et al, 2014; Sweatt, 2013). Tcf has an intimate relationship with verbal memory and language development. A series of intronic SNPs in the Tcf locus have been identified by genome-wide association studies as highly correlative with schizophrenia. The Tcf rs9960767 SNP disrupts sensory-motor gating in both schizophrenia-spectrum and healthy volunteers alike and enhances verbal memory in schizophrenic patients that carry the rs9960767 risk allele without measurably affecting attention and executive function (Lennertz et al, 2011; Quednow et al, 2011). It is likely that Tcf regulation of CNS gene transcription is an underlying process in language comprehension, production, and recall

Results

Discussion

Conclusion