Abstract
Long-term memory formation is supported by functional and structural changes of neuronal networks, which rely on de novo gene transcription and protein synthesis. The modulation of the neuronal transcriptome in response to learning depends on transcriptional and post-transcriptional mechanisms. DNA methylation writers and readers regulate the activity-dependent genomic program required for memory consolidation. The most abundant DNA methylation reader, the Methyl CpG binding domain protein 2 (MeCP2), has been shown to regulate alternative splicing, but whether it establishes splicing events important for memory consolidation has not been investigated. In this study, we identified the alternative splicing profile of the mouse hippocampus in basal conditions and after a spatial learning experience, and investigated the requirement of MeCP2 for these processes. We observed that spatial learning triggers a wide-range of alternative splicing events in transcripts associated with structural and functional remodeling and that virus-mediated knockdown of MeCP2 impairs learning-dependent post-transcriptional responses of mature hippocampal neurons. Furthermore, we found that MeCP2 preferentially affected the splicing modalities intron retention and exon skipping and guided the alternative splicing of distinct set of genes in baseline conditions and after learning. Lastly, comparative analysis of the MeCP2-regulated transcriptome with the alternatively spliced mRNA pool, revealed that MeCP2 disruption alters the relative abundance of alternatively spliced isoforms without affecting the overall mRNA levels. Taken together, our findings reveal that adult hippocampal MeCP2 is required to finetune alternative splicing events in basal conditions, as well as in response to spatial learning. This study provides new insight into how MeCP2 regulates brain function, particularly cognitive abilities, and sheds light onto the pathophysiological mechanisms of Rett syndrome, that is characterized by intellectual disability and caused by mutations in the Mecp2 gene.
Highlights
It is well established that long-term memory formation requires de novo gene transcription and protein synthesis
Spatial learning induces alternative splicing events that are altered in Methyl CpG binding domain protein 2 (MeCP2) knockdown mice In this study, we sought to investigate whether MeCP2 regulates alternative splicing events in the adult hippocampus in basal conditions as well as after spatial learning
In this study, we showed that adult hippocampal MeCP2 is required for the regulation of alternative splicing events during memory consolidation
Summary
It is well established that long-term memory formation requires de novo gene transcription and protein synthesis. Selective expression of alternative splice variants functionally impacts cells through the remodeling of the transcriptome which may modify protein interaction, function and localization [10, 14,15,16] These findings strongly suggest that the coordinated regulation of gene transcription and alternative splicing is vital to determine neuronal activity-dependent changes required for memory consolidation. In mouse models of RTT, MeCP2 was shown to control alternative splicing events in the cortex during basal conditions [25, 28] and in the hippocampus in basal state and in a seizure model [8] These studies have attributed a role for MeCP2 in the regulation of alternative splicing. It remains unclear whether MeCP2 establishes alternative splicing events important for memory consolidation in response to a physiological learning stimulus
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