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MeCP2 gates spatial learning-induced alternative splicing events in the mouse hippocampus
David V C Brito1, Kubra Gulmez Karaca1,2,3, Janina Kupke1
1Department of Neurobiology, Interdisciplinary Centre for Neurosciences (IZN), Heidelberg University, Im Neuenheimer Feld 366, 69120, Heidelberg, Germany.
Molecular Brain
|November 18, 2020
Summary
Methyl CpG binding domain protein 2 (MeCP2) fine-tunes neuronal alternative splicing for memory formation. This protein is crucial for regulating gene expression in the hippocampus following spatial learning experiences.
Area of Science:
- Neuroscience
- Molecular Biology
- Genetics
Background:
- Long-term memory relies on neuronal network changes driven by gene transcription and protein synthesis.
- Transcriptional and post-transcriptional mechanisms modulate neuronal gene expression during learning.
- DNA methylation regulators, including Methyl CpG binding domain protein 2 (MeCP2), are involved in memory consolidation.
Purpose of the Study:
- To investigate the role of MeCP2 in regulating alternative splicing in the mouse hippocampus during spatial learning.
- To identify alternative splicing events associated with memory formation and the impact of MeCP2 on these processes.
Main Methods:
- Analysis of the mouse hippocampal alternative splicing profile under basal and post-spatial learning conditions.
- Virus-mediated knockdown of MeCP2 to assess its requirement for learning-dependent splicing.
- Comparative analysis of MeCP2-regulated transcriptome and alternatively spliced mRNA pools.
Main Results:
- Spatial learning induces widespread alternative splicing in hippocampal transcripts related to neuronal remodeling.
- MeCP2 knockdown impairs learning-dependent post-transcriptional regulation in mature hippocampal neurons.
- MeCP2 influences intron retention and exon skipping, affecting specific gene sets in basal and learning states.
- MeCP2 disruption alters the abundance of alternatively spliced isoforms without changing overall mRNA levels.
Conclusions:
- Adult hippocampal MeCP2 is essential for fine-tuning alternative splicing in both resting states and upon spatial learning.
- These findings offer insights into MeCP2's regulation of cognitive functions and the pathophysiology of Rett syndrome.
