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UPF2 leads to degradation of dendritically targeted mRNAs to regulate synaptic plasticity and cognitive function

Abstract

Synaptic plasticity requires a tight control of mRNA levels in dendrites. RNA translation and degradation pathways have been recently linked to neurodevelopmental and neuropsychiatric diseases, suggesting a role for RNA regulation in synaptic plasticity and cognition. While the local translation of specific mRNAs has been implicated in synaptic plasticity, the tightly controlled mechanisms that regulate local quantity of specific mRNAs remain poorly understood. Despite being the only RNA regulatory pathway that is associated with multiple mental illnesses, the nonsense-mediated mRNA decay (NMD) pathway presents an unexplored regulatory mechanism for synaptic function and plasticity. Here, we show that neuron-specific disruption of UPF2, an NMD component, in adulthood attenuates learning, memory, spine density, synaptic plasticity (L-LTP), and potentiates perseverative/repetitive behavior in mice. We report that the NMD pathway operates within dendrites to regulate Glutamate Receptor 1 (GLUR1) surface levels. Specifically, UPF2 modulates the internalization of GLUR1 and promotes its local synthesis in dendrites. We identified neuronal Prkag3 mRNA as a mechanistic substrate for NMD that contributes to the UPF2-mediated regulation of GLUR1 by limiting total GLUR1 levels. These data establish that UPF2 regulates synaptic plasticity, cognition, and local protein synthesis in dendrites, providing fundamental insight into the neuron-specific function of NMD within the brain.

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Acknowledgements

We thank J. Lykke-Andersen for generously providing the anti-UPF1 and anti-UPF2 antibodies, M.E. Ross for helpful comments and suggestions and M. Toth for helpful suggestions regarding behavioral assays. This work was supported by a NHMRC CJ Martin Biomedical Fellowship awarded to MN, KoreaNRF-2015R1A2A1A09005662 to NLJ, NIH grants NS034007 and NS047384 to EK, and NIH R01 MH114888 and Leon Levy Foundation Grants to DC.

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MN designed, performed, and/or analyzed most of the experiments including in vivo assays, as well as manuscript preparation/writing. MA prepared all neuronal cultures. FL performed electrophysiology experiments. NV provided technical assistance. MT provided infrastructure support. NLJ designed and manufactured microfluidic devices. EK supervised electrophysiology experiments. DC initiated and conceived the project; designed, analyzed, and supervised experiments; and wrote the manuscript. All authors contributed to the experimental design and interpretation and commented on the manuscript.

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Correspondence to Dilek Colak.

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Notaras, M., Allen, M., Longo, F. et al. UPF2 leads to degradation of dendritically targeted mRNAs to regulate synaptic plasticity and cognitive function. Mol Psychiatry 25, 3360–3379 (2020). https://doi.org/10.1038/s41380-019-0547-5

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