Syngap+/- CA1 Pyramidal Neurons Exhibit Upregulated Translation of Long MRNAs Associated with LTP.

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 occluded 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. 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^-/y model that exhibits occluded mGluR-LTD. Together, our results show the Syngap^+/- and Fmr1^-/y 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.