MSK1 mediates BDNF-dependent MeCP2-S421 phosphorylation in postnatal striatal development and psychiatric-relevant...

Area of Science:

• Neuroscience
• Molecular Biology
• Developmental Biology

Background:

• Brain-derived neurotrophic factor (BDNF) is crucial for neuronal development and circuit maturation.
• Downstream mediators of BDNF signaling in specific neuronal populations are not fully understood.
• Understanding these mediators is key to addressing neurodevelopmental disorders.

Purpose of the Study:

• To identify downstream mediators of BDNF signaling in postnatal striatal development.
• To investigate the role of mitogen- and stress-activated kinase 1 (MSK1) in striatal development.
• To explore the mechanistic link between MSK1, MeCP2, and striatal circuit function.

Main Methods:

• Utilized a novel Msk1 exon IV knockout (Msk1^IV KO) mouse model.
• Analyzed striatal volume, medium spiny neuron (MSN) dendritic complexity, and gene expression.
• Investigated MSK1-MeCP2 interactions and signaling pathways (MAPK/ERK).
• Assessed behavioral phenotypes in Msk1^IV KO mice.

Main Results:

• MSK1 is predominantly expressed in GABAergic neurons, with persistent expression in striatal MSNs.
• Msk1^IV KO mice exhibited reduced striatal volume and MSN dendritic complexity.
• MSK1 mediates BDNF-induced MeCP2 phosphorylation, impacting transcriptional regulation.
• Dysregulated GABAergic and dopaminergic gene expression was observed in Msk1^IV KO striata.
• Msk1^IV KO mice displayed behavioral deficits including hypersociability and depressive-like behavior.

Conclusions:

• MSK1 is a critical striatal-specific mediator of BDNF signaling during postnatal development.
• MSK1-MeCP2 signaling pathway is essential for striatal development and function.
• MSK1 deficiency leads to inhibitory circuit imbalances and behavioral abnormalities.
• MSK1 represents a potential therapeutic target for neurodevelopmental and psychiatric disorders, including those linked to MeCP2 dysfunction.