Mettl14 Is Essential for Epitranscriptomic Regulation of Striatal Function and Learning

Area of Science:

• Neuroscience
• Molecular Biology
• Epigenetics

Background:

• N-methyladenosine (m6A) is a crucial RNA modification regulating gene expression post-transcriptionally.
• The role of m6A in the adult brain, particularly in striatal neuronal function, remains largely unexplored.

Purpose of the Study:

• To investigate the functional consequences of m6A deficiency in adult mouse striatal neurons.
• To elucidate the impact of Mettl14 deletion on neuronal excitability, gene expression, and behavior.

Main Methods:

• Conditional deletion of Mettl14 in striatonigral and striatopallidal neurons in mice.
• Transcriptome-wide profiling of m6A-modified mRNAs.
• Electrophysiological recordings to assess neuronal excitability.
• Behavioral tests to evaluate striatal-mediated functions.

Main Results:

• Mettl14 deletion significantly reduced striatal m6A levels without affecting neuronal morphology or numbers.
• Downregulation of neuron- and synapse-specific mRNAs, with unique effects on striatal subtype identity genes.
• Increased neuronal excitability and impaired spike frequency adaptation.
• Profound deficits in striatal-mediated behaviors.

Conclusions:

• m6A, regulated by Mettl14, is essential for maintaining normal striatal function in adult mice.
• m6A deficiency leads to altered gene expression, increased neuronal excitability, and behavioral impairments.
• These findings highlight the critical role of m6A epitranscriptomics in adult brain function and behavior.