Syngap CA1 Pyramidal Neurons Exhibit Upregulated Translation of Long MRNAs Associated with LTP

Area of Science:

• Neuroscience
• Molecular Biology
• Genetics

Background:

• SYNGAP1-related intellectual disability (SRID) is associated with excessive neuronal protein synthesis and impaired synaptic plasticity.
• The Fragile X Syndrome (FXS) model (Fmr1) offers a comparison for understanding monogenic intellectual disabilities.

Purpose of the Study:

• To identify mistranslating mRNAs in Syngap model CA1 pyramidal neurons using Translating Ribosome Affinity Purification and RNA-seq (TRAP-seq).
• To compare the translation environment in the Syngap model with the Fmr1 model and wild-type (WT) responses to synaptic plasticity induction.

Main Methods:

• Utilized Translating Ribosome Affinity Purification and RNA-seq (TRAP-seq) to profile the translatome.
• Investigated changes in mRNA translation associated with long-term potentiation (LTP) and long-term depression (LTD) induction in Syngap and Fmr1 models.

Main Results:

• The Syngap model exhibits altered translation distinct from the Fmr1 model, enriched for DNA repair regulators.
• Upregulation of long (>2kb) coding sequence (CDS) mRNA translation characterizes LTP in the Syngap model.
• Long CDS transcript translation is downregulated during LTD in WT and Fmr1 models, contrasting with LTP.

Conclusions:

• The Syngap and Fmr1 models reflect LTP and LTD translation environments, respectively, correlating with plasticity saturation.
• Translation of long (>2kb) mRNAs is a key feature of LTP and is inversely regulated during LTD, indicating a novel plasticity signature.