Nat Commun. 2025 Mar 15;16(1):2560. doi: 10.1038/s41467-025-57651-7

Axonal RNA localization is essential for long-term memory

Bruna R de Queiroz¹, Hiba Laghrissi^#1, Seetha Rajeev^#1, Lauren Blot^#1, Fabienne De Graeve¹, Marine Dehecq¹, Martina Hallegger^2,3,4, Ugur Dag⁵, Marion Dunoyer de Segonzac¹, Mirana Ramialison^6,7,8, Chantal Cazevieille⁹, Krystyna Keleman⁵, Jernej Ule^2,3,10, Arnaud Hubstenberger¹, Florence Besse¹¹

Affiliations
¹Institut de Biologie Valrose, Université Côte d’Azur, CNRS, Inserm, Nice, France.
²The Francis Crick Institute, London, UK.
³UK Dementia Research Institute at King’s College London, London, UK.
⁴Oxford-GSK Institute of Molecular and Computational Medicine (IMCM), Centre for Human Genetics, Nuffield Department of Medicine, University of Oxford, Oxford, UK.
⁵Howard Hughes Medical Institute, Janelia Research Campus, Ashburn, VA, USA.
⁶Murdoch Children’s Research Institute, Department of Paediatrics, Royal Children’s Hospital, University of Melbourne, Parkville, VIC, Australia.
⁷Australian Regenerative Medicine Institute, Clayton, VIC, Australia.
⁸Novo Nordisk Foundation Center for Stem Cell Medicine (reNEW), Murdoch Children’s Research Institute, University of Melbourne, Parkville, VIC, Australia.
⁹INM, Université de Montpellier, Inserm, Montpellier, France.
¹⁰Department of Basic and Clinical Neuroscience, Institute of Psychiatry, Psychology and Neuroscience, King’s College London, London, UK.
¹¹Institut de Biologie Valrose, Université Côte d’Azur, CNRS, Inserm, Nice, France.
^#Contributed equally.

Abstract

Localization of mRNAs to neuronal terminals, coupled to local translation, has emerged as a prevalent mechanism controlling the synaptic proteome. However, the physiological regulation and function of this process in the context of mature in vivo memory circuits has remained unclear. Here, we combined synaptosome RNA profiling with whole brain high-resolution imaging to uncover mRNAs with different localization patterns in the axons of Drosophila Mushroom Body memory neurons, some exhibiting regionalized, input-dependent, recruitment along axons. By integrating transcriptome-wide binding approaches and functional assays, we show that the conserved Imp RNA binding protein controls the transport of mRNAs to Mushroom Body axons and characterize a mutant in which this transport is selectively impaired. Using this unique mutant, we demonstrate that axonal mRNA localization is required for long-term, but not short-term, behavioral memory. This work uncovers circuit-dependent mRNA targeting in vivo and demonstrates the importance of local RNA regulation in memory consolidation.

DOI: 10.1038/s41467-025-57651-7