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

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.