mRNA m⁶A modifications and the RNA-binding protein YTHDF1 affect translational control in both normal and pathological learning.

Abstract

Animals learn and adapt to environmental changes. However, neural plasticity can also become maladaptive, leading to neurological and psychiatric disorders. How do we use known molecular mechanisms to harness the power of neural plasticity to prevent and treat diseases? Consolidating learning is known to require new protein synthesis. We found that mRNA m⁶A modifications and the RNA-binding protein YTHDF1 are required for molecular, cellular, and behavioral adaptations in response to environmental changes. Deletion of <i>Ythdf1</i> in dopamine D1- or D2 receptor-expressing neurons selectively impaired D1- or D2-dependent learning, respectively, including both adaptive and maladaptive learning. This highlights YTHDF1 as a potential therapeutic target for preventing pathological plasticity. YTHDF1 recognizes m⁶A modifications on transcripts and regulates their translation. Elevated cAMP triggered increased protein synthesis in control striatal neurons but not in <i>Ythdf1</i>-deficient neurons. Behaviorally, cell-type-specific <i>Ythdf1</i> deletion resembled learning phenotypes caused by deletion of the m⁶A methyltransferase gene <i>Mettl14</i>, suggesting YTHDF1 as the main mediator of m⁶A-dependent regulation in the striatum.