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bioRxiv · 10.1101/2025.02.19.639128

Syngap+/- CA1 pyramidal neurons exhibit upregulated translation of long mRNAs associated with LTP

Osterweil, E. K.·Singh, A.·Rizzi, M.·Seo, S. S.
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Abstract

In the Syngap+/- model of SYNGAP1-related intellectual disability (SRID), excessive neuronal protein synthesis is linked to deficits in synaptic plasticity. Here, we use Translating Ribosome Affinity Purification and RNA-seq (TRAP-seq) to identify mistranslating mRNAs in Syngap+/- CA1 pyramidal neurons that exhibit enhanced synaptic stability and impaired long-term potentiation (LTP). We find the translation environment is significantly altered in a manner that is distinct from the Fmr1-/y model of Fragile X Syndrome (FXS), another monogenic model of autism and intellectual disability (ID). The Syngap+/- translatome is enriched for regulators of DNA repair, and mimics changes induced with chemical LTP (cLTP) in WT. This includes a striking upregulation in the translation of mRNAs with a longer length (>2kb) coding sequence (CDS). In contrast, long CDS transcripts are downregulated with induction of Gp1 metabotropic glutamate receptor induced long-term depression (mGluR-LTD) in WT, and this profile is mimicked in the Fmr1-/y model. Together, our results show the Syngap+/- and Fmr1-/y models mimic the translation environments of LTP and LTD, respectively, consistent with the dysregulation of these plasticity states in each model. Moreover, we show that translation of >2kb mRNAs is a defining feature of LTP that is oppositely regulated during LTD, revealing a novel mRNA signature of plasticity.

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Osterweil, E. K., Singh, A., Rizzi, M., Seo, S. S.. 2025-02-20. Syngap+/- CA1 pyramidal neurons exhibit upregulated translation of long mRNAs associated with LTP. https://doi.org/10.1101/2025.02.19.639128

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