Singh Aditi, Rizzi Manuela, Seo Sang S, Osterweil Emily K
Rosamund Stone Zander Translational Neuroscience Center, F. M. Kirby Center, Department of Neurology, Harvard Medical School, Boston Children's Hospital, Boston, Massachusetts 02115.
Simons Initiative for the Developing Brain, University of Edinburgh, Edinburgh EH8 9XD, United Kingdom.
eNeuro. 2025 May 19;12(5). doi: 10.1523/ENEURO.0086-25.2025. Print 2025 May.
In the 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 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 model of fragile X syndrome (FXS), another monogenic model of autism and intellectual disability. The 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 model that exhibits occluded mGluR-LTD. Together, our results show the and 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.
在与SYNGAP1相关的智力障碍（SRID）模型中，过量的神经元蛋白质合成与突触可塑性缺陷有关。在这里，我们使用翻译核糖体亲和纯化和RNA测序（TRAP-seq）来鉴定CA1锥体神经元中表现出阻塞性长时程增强（LTP）的错误翻译的mRNA。我们发现翻译环境发生了显著改变，其方式不同于脆性X综合征（FXS）模型，FXS是另一种自闭症和智力障碍的单基因模型。翻译组富含DNA修复调节因子，并模拟野生型中化学LTP（cLTP）诱导的变化。这包括编码序列（CDS）长度较长（>2 kb）的mRNA翻译显著上调。相比之下，在野生型以及表现出阻塞性代谢型谷氨酸受体诱导的长时程抑制（mGluR-LTD）的模型中，长CDS转录本在mGluR-LTD诱导时下调。总之，我们的结果表明，该模型和FXS模型分别模拟了LTP和LTD的翻译环境，这与每个模型中可塑性状态的饱和一致。此外，我们表明>2 kb mRNA的翻译是LTP的一个决定性特征，在LTD期间受到相反的调节，揭示了一种新的可塑性mRNA特征。
