title: Negative Allosteric Modulation of mGluR5 Partially Corrects Pathophysiology in a Mouse Model of Rett Syndrome.
abstract: Rett syndrome (RTT) is caused by mutations in the gene encoding methyl-CpG binding protein 2 (MECP2), an epigenetic regulator of mRNA transcription. Here, we report a test of the hypothesis of shared pathophysiology of RTT and fragile X, another monogenic cause of autism and intellectual disability. In fragile X, the loss of the mRNA translational repressor FMRP leads to exaggerated protein synthesis downstream of metabotropic glutamate receptor 5 (mGluR5). We found that mGluR5- and protein-synthesis-dependent synaptic plasticity were similarly altered in area CA1 of Mecp2 KO mice. CA1 pyramidal cell-type-specific, genome-wide profiling of ribosome-bound mRNAs was performed in wild-type and Mecp2 KO hippocampal CA1 neurons to reveal the MeCP2-regulated "translatome." We found significant overlap between ribosome-bound transcripts overexpressed in the Mecp2 KO and FMRP mRNA targets. These tended to encode long genes that were functionally related to either cytoskeleton organization or the development of neuronal connectivity. In the Fmr1 KO mouse, chronic treatment with mGluR5-negative allosteric modulators (NAMs) has been shown to ameliorate many mutant phenotypes by correcting excessive protein synthesis. In Mecp2 KO mice, we found that mGluR5 NAM treatment significantly reduced the level of overexpressed ribosome-associated transcripts, particularly those that were also FMRP targets. Some Rett phenotypes were also ameliorated by treatment, most notably hippocampal cell size and lifespan. Together, these results suggest a potential mechanistic link between MeCP2-mediated transcription regulation and mGluR5/FMRP-mediated protein translation regulation through coregulation of a subset of genes relevant to synaptic functions.
  
  
  
  Altered regulation of synaptic protein synthesis has been hypothesized to contribute to the pathophysiology that underlies multiple forms of intellectual disability and autism spectrum disorder. Here, we show in a mouse model of Rett syndrome (Mecp2 KO) that metabotropic glutamate receptor 5 (mGluR5)- and protein-synthesis-dependent synaptic plasticity are abnormal in the hippocampus. We found that a subset of ribosome-bound mRNAs was aberrantly upregulated in hippocampal CA1 neurons of Mecp2 KO mice, that these significantly overlapped with FMRP direct targets and/or SFARI human autism genes, and that chronic treatment of Mecp2 KO mice with an mGluR5-negative allosteric modulator tunes down upregulated ribosome-bound mRNAs and partially improves mutant mice phenotypes.
authors.affiliation: Picower Institute for Learning and Memory and.|Department of Brain and Cognitive Sciences, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139.
authors.forename: Jifang
authors.identifier: 0000-0003-0383-9226
authors.initials: J
authors.lastname: Tao
authors.affiliation: Howard Hughes Medical Institute, Boston, Massachusetts 02115.|Program in Cellular and Molecular Medicine, Boston Children's Hospital, Boston, Massachusetts 02115.|Department of Genetics, Harvard Medical School, Boston, Massachusetts 02115, and.
authors.forename: Hao
authors.initials: H
authors.lastname: Wu
authors.affiliation: Picower Institute for Learning and Memory and.|Department of Brain and Cognitive Sciences, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139.
authors.forename: Amanda A
authors.initials: AA
authors.lastname: Coronado
authors.affiliation: Picower Institute for Learning and Memory and.|Department of Brain and Cognitive Sciences, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139.
authors.forename: Elizabeth
authors.initials: E
authors.lastname: de Laittre
authors.affiliation: Centre for Integrative Physiology, University of Edinburgh, Edinburgh EH8 9XD, United Kingdom.
authors.forename: Emily K
authors.identifier: 0000-0003-0582-2284
authors.initials: EK
authors.lastname: Osterweil
authors.affiliation: Howard Hughes Medical Institute, Boston, Massachusetts 02115.|Program in Cellular and Molecular Medicine, Boston Children's Hospital, Boston, Massachusetts 02115.|Department of Genetics, Harvard Medical School, Boston, Massachusetts 02115, and.
authors.forename: Yi
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: Picower Institute for Learning and Memory and mbear@mit.edu.|Department of Brain and Cognitive Sciences, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139.
authors.forename: Mark F
authors.identifier: 0000-0002-9903-2541
authors.initials: MF
authors.lastname: Bear
mesh_terms: D000494:Allosteric Regulation / Q000187:drug effects; D000818:Animals; D015536:Down-Regulation / Q000187:drug effects; D005260:Female; D005786:Gene Expression Regulation / Q000187:drug effects; D006624:Hippocampus / Q000187:drug effects / Q000473:pathology / Q000503:physiopathology*; D007093:Imidazoles / Q000008:administration & dosage*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D009097:Multienzyme Complexes / Q000378:metabolism*; D011725:Pyridines / Q000008:administration & dosage*; D064529:Receptor, Metabotropic Glutamate 5 / Q000037:antagonists & inhibitors / Q000378:metabolism*; D015518:Rett Syndrome / Q000188:drug therapy* / Q000473:pathology / Q000503:physiopathology*
chemical_list: C569289:2-chloro-4-((2,5-dimethyl-1-(4-(trifluoromethoxy)phenyl)-1H-imidazol-4-yl)ethynyl)pyridine; C578936:Grm5 protein, mouse; D007093:Imidazoles; D009097:Multienzyme Complexes; D011725:Pyridines; D064529:Receptor, Metabotropic Glutamate 5
keywords: Rett syndrome; autism; fragile X; intellectual disability; metabotropic glutamate receptor; synaptic protein synthesis