Activity-induced histone modifications govern Neurexin-1 mRNA splicing and memory preservation

Abstract

Epigenetic mechanisms regulate the formation, consolidation and reconsolidation of memories. However, the signaling path from neuronal activation to epigenetic modifications within the memory-related brain circuit remains unknown. We report that learning induces long-lasting histone modifications in hippocampal memory-activated neurons to regulate memory stability. Neuronal activity triggers a late-onset shift in Nrxn1 splice isoform choice at splicing site 4 by accumulating a repressive histone marker, H3K9me3, to modulate the splicing process. Activity-dependent phosphorylation of p66α via AMP-activated protein kinase recruits HDAC2 and Suv39h1 to establish repressive histone markers and changes the connectivity of the activated neurons. Removal of Suv39h1 abolished the activity-dependent shift in Nrxn1 splice isoform choice and reduced the stability of established memories. We uncover a cell-autonomous process for memory preservation in which memory-related neurons initiate a late-onset reduction of their rewiring capacities through activity-induced histone modifications.

Genomic Dissection of Bipolar Disorder and Schizophrenia, Including 28 Subphenotypes

“…Their members, including GATAD2A , display preferential expression in fetal brain development(Li et al, 2015) and in recent work has been implicated in SCZ through open chromatin(Fullard et al, n.d.). Further, p66α (mouse GATAD2A ) was recently shown to participate in memory preservation through long-lasting histone modification in hippocampal memory-activated neurons(Ding et al, 2017). SNP-heritability appears to be consistently shared across regions and chromosomes between these two disorders.…”

Synaptic Neurexin Complexes: A Molecular Code for the Logic of Neural Circuits

“…Pioneering studies by Zisapel and colleagues showed that activation of cultured cortical neurons causes a dramatic, Ca 2+ -dependent exclusion of the Nrxn2 SS3 insert that depends on specific sequence motifs associated with the alternatively spliced exon (Rozic-Kotliroff and Zisapel, 2007; Rozic et al, 2013), consistent with the high degree of regional regulation of SS3 alternative splicing (Ullrich et al, 1995). Subsequent more extensive studies showed that SS4 is also regulated by neuronal activity (Ding et al, 2017). The regulation of neurexin alternative splicing at SS3 and SS4 by activity appears to be physiologically important since it can be observed in vivo, both as a consequence of fear learning (Rozic et al, 2011; Ding et al, 2017) and as a diurnally regulated process (Shapiro-Reznik et al, 2012).…”

“…Subsequent more extensive studies showed that SS4 is also regulated by neuronal activity (Ding et al, 2017). The regulation of neurexin alternative splicing at SS3 and SS4 by activity appears to be physiologically important since it can be observed in vivo, both as a consequence of fear learning (Rozic et al, 2011; Ding et al, 2017) and as a diurnally regulated process (Shapiro-Reznik et al, 2012). …”

“…Ding et al (2017) showed that neuronal activity induces increases in the repressive histone marker H3K9me3 at the SS4 exon of Nrxn1 , which is mediated at least in part by the histone methyl-transferase Suv39h1. Strikingly, suppression of Suv39h1 blocked the activity-dependent exclusion of SS4 in Nrxn1 (Ding et al, 2017). Thus, both STAR-domain RNA-binding proteins and histone modifications may control neurexin SS4 alternative splicing.…”

Neuron-specific increase in lamin B1 disrupts nuclear function in Huntington’s disease

“…MACS was run with the default parameters but with the shift size adjusted to 100 bp to perform peak calling 67 Biotechnology Information Gene Expression Omnibus (NCBI GEO) 72 repository under the accession number GSE139884. Additionally, public datasets for hippocampal H3K9me3 (GSM2460430) 73 , H3K9ac (GSM2415914) 74 and CTCF (GSM2228526) 75 ChIP-seq experiments were retrieved for integrated data analysis.…”