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 occluded long-term potentiation (LTP). We find the translation environment is significantly altered in a manner that is distinct from the Fmr1 model of fragile X syndrome (FXS), another monogenic model of autism and intellectual disability. 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 (>2 kb) 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 in the Fmr1 model that exhibits occluded mGluR-LTD. Together, our results show the Syngap and Fmr1 models mimic the translation environments of LTP and LTD, respectively, consistent with the saturation of plasticity states in each model. Moreover, we show that translation of >2 kb mRNAs is a defining feature of LTP that is oppositely regulated during LTD, revealing a novel mRNA signature of plasticity.