Protein Phosphatase 1 Regulates the Histone Code for Long-Term Memory

Abstract

Chromatin remodeling through histone posttranslational modifications (PTMs) and DNA methylation has recently been implicated in cognitive functions, but the mechanisms involved in such epigenetic regulation remain poorly understood. Here, we show that protein phosphatase 1 (PP1) is a critical regulator of chromatin remodeling in the mammalian brain that controls histone PTMs and gene transcription associated with long-term memory. Our data show that PP1 is present at the chromatin in brain cells and interacts with enzymes of the epigenetic machinery including HDAC1 (histone deacetylase 1) and histone demethylase JMJD2A (jumonji domaincontaining protein 2A). The selective inhibition of the nuclear pool of PP1 in forebrain neurons in transgenic mice is shown to induce several histone PTMs that include not only phosphorylation but also acetylation and methylation. These PTMs are residue-specific and occur at the promoter of genes important for memory formation like CREB (cAMP response element-binding protein) and NF-B (nuclear factor-B). These histone PTMs further co-occur with selective binding of RNA polymerase II and altered gene transcription, and are associated with improved long-term memory for objects and space. Together, these findings reveal a novel mechanism for the epigenetic control of gene transcription and long-term memory in the adult brain that depends on PP1.

Dynamic histone marks in the hippocampus and cortex facilitate memory consolidation

“…The data also show that these marks occur at the zif268 promoter and correlate with a shift of zif268 expression from the hippocampus to the PFC as the memory matures, suggesting an important functional role of these histone PTMs in memory consolidation. The results are in line with several recent findings showing that enhancing histone acetylation favours memory, including object 13,31 , fear 10,12,14,15,17,[32][33][34] , spatial 13,34 and taste 19,35 memory. They significantly extend these findings by showing that in addition to histone acetylation, histone phosphorylation and methylation (on H3K36) are activated in a temporally and spatially regulated manner during memory consolidation in both the hippocampus and the cortex.…”

“…The novel object-recognition task was conducted essentially as described 13 . Training consisted in exposing the animals five times for 5 min to the objects, with either a 5 min or a 15 min intertrial interval (see Figs 1a and 3a).…”

“…We focused on PTMs previously associated with the formation of longterm associative memory 10,[12][13][14][15]19 , specifically phosphorylation of S10, acetylation of K14 and trimethylation of K36 on histone 3 (H3), and acetylation of K5 on H4. As the formation and storage of object memory depend on a temporally regulated interplay between hippocampal and cortical areas, in particular the PFC 20,21 , we postulated that PTMs occur in both brain regions but may be differentially regulated over time.…”

“…In this model, PP1 is selectively inhibited in forebrain neurons, in particular in the hippocampus and PFC ( Supplementary Fig. S3) 13,14,22 . When tested on the object recognition task, the transgenic mice (Transgenic) had memory performance comparable to control mice (Control) 10 min after training but had improved memory both 1 and 7 days after training (Fig.…”

“…For histones, several PTMs have been unequivocally linked to memory formation and storage, in particular, phosphorylation of histone (H) 3 serine (S) 10 (refs 12-14); acetylation of H2B lysine (K) 5, H3K9, H3K14, H4K5 and H4K12 (refs 10,12-17); and methylation of H3K36 (ref. 13), all of which are marks of transcriptional activation 18 . However, the spatiotemporal dynamics of these histone PTMs in the hippocampus and cortex in relation to memory consolidation remain poorly characterized.…”