Cell-Type-Specific Translation Profiling Reveals a Novel Strategy for Treating Fragile X Syndrome

Abstract

SummaryExcessive mRNA translation downstream of group I metabotropic glutamate receptors (mGlu1/5) is a core pathophysiology of fragile X syndrome (FX); however, the differentially translating mRNAs that contribute to altered neural function are not known. We used translating ribosome affinity purification (TRAP) and RNA-seq to identify mistranslating mRNAs in CA1 pyramidal neurons of the FX mouse model (Fmr1−/y) hippocampus, which exhibit exaggerated mGlu1/5-induced long-term synaptic depression (LTD). In these neurons, we find that the Chrm4 transcript encoding muscarinic acetylcholine receptor 4 (M4) is excessively translated, and synthesis of M4 downstream of mGlu5 activation is mimicked and occluded. Surprisingly, enhancement rather than inhibition of M4 activity normalizes core phenotypes in the Fmr1−/y, including excessive protein synthesis, exaggerated mGluR-LTD, and audiogenic seizures. These results suggest that not all excessively translated mRNAs in the Fmr1−/y brain are detrimental, and some may be candidates for enhancement to correct pathological changes in the FX brain.

Spatial mapping of cell types by integration of transcriptomics data

“…When assessing our results for the mouse brain, Rarres2 is taken as a marker gene for Ependymal cells (cluster 47), Prox1 for Dentate Granule Neurons (cluster 59) and Wfs1 for Pyramidal Neurons (cluster 27); only broad classes like "Neurons" are provided in the single cell data annotations, but observing their spatial arrangement enables us to assign more granular types of these classes to the clusters. [13][14][15] It's evident how the estimated proportions agree with the signals observed in the ISH experiments, confirming the proposed locations of these cell types. There is a high degree of consistency of the mapping between the different sections that are analyzed, speaking in favor of the method's robustness.…”

Lovastatin suppresses hyperexcitability and seizure in Angelman syndrome model

“…The long burst activity induced by BMI in CA3 of Ube3a m − /p + mice was very similar to that observed in FXS mouse model (Chuang et al 2005). Because epilepsy and seizures are also frequent features in the FXS (Contractor et al 2015; Heard et al 2014; Musumeci et al 1999; Thomson et al 2017), our observations suggest a shared mechanism underlying the susceptibility to seizures in both models. The same response to the lovastatin treatment in both models supports this conclusion.…”

Transcriptome analysis of hippocampal subfields identifies gene expression profiles associated with long-term active place avoidance memory

“…Many of the genes that are mutated in autism spectrum disorder are crucial components of the activity-dependent signaling networks that regulate synapse development and plasticity (Ebert and Greenberg, 2013). Deletion of Fmr1 can lead to dysregulated mRNA translation, altered synaptic function, loss of protein synthesis-dependent synaptic plasticity (Bassell and Warren, 2008; Thomson et al, 2017;Talbot et al, 2018). Some memory molecules have been characterized because they were found to be relevant in cancer, thus, it's possible that studies of memory can lead to discoveries that are important for cancer or development.…”