P3.27. A NEW MOLECULAR MECHANISM OF NEUROPLASTICITY
Batuhan Uygar1, Hang Zeng1, Rajitha Indukuri1, Luis Enrique Arroyo Garcia2
1 Karolinska Institutet, Department of Medical Biochemistry and Biophysics, Division of Molecular Neurobiology, Biomedicum, Solnavägen 9, Stockholm, Sweden
2 Karolinska Institutet, Department of Neurobiology, Health Sciences and Society, Division of Neurogeriatrics, BioClinicum, Visionsgatan 4, Stockholm, Sweden
INTRODUCTION: Neuronal activity-dependent transcription is essential for synaptic plasticity and cognitive function. Its disruption contributes to disorders such as autism, schizophrenia, and Alzheimer’s disease, and can be exacerbated by environmental stress. RNA-binding proteins are increasingly recognized as key regulators of activity-dependent gene expression. Among them, YTHDC1, a nuclear reader of m6A-modified RNA, has emerged as a candidate, though its role in the brain remains poorly understood. Investigating YTHDC1 may uncover new mechanisms linking RNA processing to experience-driven transcription and learning.
AIM(S): This study aims to investigate the role of the RNA-binding protein YTHDC1 in regulating activity-dependent transcription and synaptic plasticity in the hippocampus.
METHOD(S): We used a conditional knockout approach to selectively delete Ythdc1 in the CA1 region of the adult mouse hippocampus. Cognitive function was assessed using behavioral paradigms including novel object recognition and contextual fear conditioning. To examine synaptic physiology, we performed ex vivo electrophysiology on acute hippocampal slices using whole-cell patch-clamp recordings. Network-level activity was evaluated through local field potential recordings, with a focus on gamma oscillations in the CA3 region.
RESULTS: YTHDC1-deficient mice exhibited impaired memory formation and retention, as indicated by reduced object discrimination and freezing behavior. While intrinsic neuronal properties remained unchanged, local field potential recordings revealed decreased gamma oscillation power and peak frequency in the CA3 region, suggesting disrupted hippocampal network activity.
CONCLUSIONS: YTHDC1 is essential for hippocampal-dependent learning and synaptic function. These findings highlight a novel link between RNA processing and activity-dependent transcription, offering new insights into the molecular mechanisms underlying cognitive function and dysfunction.
FINANCIAL SUPPORT: This work was supported by a Starting Grant from the European Research Council.