Tcf4 Regulates Synaptic Plasticity, DNA Methylation, and Memory Function

Abstract

SUMMARY 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.

WNT/β-Catenin Pathway and Epigenetic Mechanisms Regulate the Pitt-Hopkins Syndrome and Schizophrenia Risk Gene TCF4

“…4c). Moreover, consistent with our identification that class I HDAC inhibition through CI-994 is sufficient to enhance TCF4 expression, this study also demonstrated that selective inhibition of the class I HDAC2 using antisense oligonucleotides infused into the brain is sufficient to rescue memory deficits in the TCF4 haploinsufficient mice [69]. While HDAC2 inhibition is likely to affect multiple genes and proteins critical to neuroplasticity based upon our and others' published findings [78,79,80,81], given its critical role in and cognition, these results provide critical in vivo evidence of the potential for targeting the epigenetic regulation of TCF4 as novel therapeutics for PTHS and other cognitive disorders involving dysfunction of TCF4.…”

“…During preparation of this paper, the Sweatt laboratory [69] reported that chronic (11-day) systemic administration of SAHA, the HDAC inhibitor we show here enhances expression of multiple TCF4 transcripts, was able to normalize deficits in hippocampal long-term potentiation and memory in a mouse model of TCF4 haploinsufficiency. Correlated with these functional effects of HDAC inhibition in the TCF4 haploinsufficient mouse, SAHA administration significantly increased the expression of multiple TCF4 transcripts (Tcf4-004, Tcf4-007, Tcf4-011, and Tcf4-014) in the hippocampal CA1 region.…”

“…Likewise, at the cellular level, it is unclear whether TCF4 haploinsufficiency causes dysfunction in NPCs, neurons, both, or other cell types. Indeed, TCF4 has been shown to play roles in all of these developmental stages and brain cell types: e.g., in neuronal migration in the developing cortex [68]; in synaptic plasticity during memory formation in the mature brain [69]; in neurogenesis [70]; and in excitability of mature cortical neurons [15]. Our data suggest that it may be possible to reverse TCF4 haploinsufficiency by drug therapy during development or in brain regions with continual production of NPCs (i.e., in the hippocampus).…”

“…Future work will be required to determine whether expression of any of these novel TCF4 neuronal target genes are dysregulated in the context of PTHS and schizophrenia patients, and much additional work will be required to comprehensively catalog the full set of TCF4 target genes in a brain cell type-specific manner. Ultimately, these efforts when integrated with findings emerging from other model systems [15,69] will lead to the elucidation of pathological mechanisms due to altered TCF4 function and help identify pharmacological therapies for treatment and ideally prevention of neuropsychiatric disorders. …”

Learning and Age-Related Changes in Genome-wide H2A.Z Binding in the Mouse Hippocampus

“…Under steady-state conditions (i.e., in naïve mice), H2A.Z is positively associated with basal gene expression, such that genes with the highest H2A.Z occupancy also have the highest expression (Figure 4c). To determine how learning-induced H2A.Z eviction relates to the expression of memory-related genes, we assessed whether H2A.Z eviction occurred on genes that are altered 30 min (data presented) and 1hr (Kennedy et al, 2016) after fear conditioning. Compared to all genes, H2A.Z peaks were significantly more associated with genes that are upregulated, but not genes that are downregulated 30 min after fear conditioning (Figure 4e).…”