title: Convergence of Hippocampal Pathophysiology in Syngap+/- and Fmr1-/y Mice.
abstract: Previous studies have hypothesized that diverse genetic causes of intellectual disability (ID) and autism spectrum disorders (ASDs) converge on common cellular pathways. Testing this hypothesis requires detailed phenotypic analyses of animal models with genetic mutations that accurately reflect those seen in the human condition (i.e., have structural validity) and which produce phenotypes that mirror ID/ASDs (i.e., have face validity). We show that SynGAP haploinsufficiency, which causes ID with co-occurring ASD in humans, mimics and occludes the synaptic pathophysiology associated with deletion of the Fmr1 gene. Syngap(+/-) and Fmr1(-/y) mice show increases in basal protein synthesis and metabotropic glutamate receptor (mGluR)-dependent long-term depression that, unlike in their wild-type controls, is independent of new protein synthesis. Basal levels of phosphorylated ERK1/2 are also elevated in Syngap(+/-) hippocampal slices. Super-resolution microscopy reveals that Syngap(+/-) and Fmr1(-/y) mice show nanoscale alterations in dendritic spine morphology that predict an increase in biochemical compartmentalization. Finally, increased basal protein synthesis is rescued by negative regulators of the mGlu subtype 5 receptor and the Ras-ERK1/2 pathway, indicating that therapeutic interventions for fragile X syndrome may benefit patients with SYNGAP1 haploinsufficiency.
  
  
  CONCLUSIONS
  As the genetics of intellectual disability (ID) and autism spectrum disorders (ASDs) are unraveled, a key issue is whether genetically divergent forms of these disorders converge on common biochemical/cellular pathways and hence may be amenable to common therapeutic interventions. This study compares the pathophysiology associated with the loss of fragile X mental retardation protein (FMRP) and haploinsufficiency of synaptic GTPase-activating protein (SynGAP), two prevalent monogenic forms of ID. We show that Syngap(+/-) mice phenocopy Fmr1(-/y) mice in the alterations in mGluR-dependent long-term depression, basal protein synthesis, and dendritic spine morphology. Deficits in basal protein synthesis can be rescued by pharmacological interventions that reduce the mGlu5 receptor-ERK1/2 signaling pathway, which also rescues the same deficit in Fmr1(-/y) mice. Our findings support the hypothesis that phenotypes associated with genetically diverse forms of ID/ASDs result from alterations in common cellular/biochemical pathways.
authors.affiliation: Centre for Integrative Physiology and Patrick Wild Centre, University of Edinburgh, Edinburgh EH8 9XD, United Kingdom.
authors.forename: Stephanie A
authors.identifier: http://orcid.org/0000-0002-8764-5666
authors.initials: SA
authors.lastname: Barnes
authors.affiliation: Centre for Integrative Physiology and Patrick Wild Centre, University of Edinburgh, Edinburgh EH8 9XD, United Kingdom, Interdisciplinary Institute for Neuroscience, Centre National de la Recherche Scientifique, Unité Mixte de Recherche 5297, University of Bordeaux, Bordeaux 33077, France.
authors.forename: Lasani S
authors.initials: LS
authors.lastname: Wijetunge
authors.affiliation: Centre for Integrative Physiology and Patrick Wild Centre, University of Edinburgh, Edinburgh EH8 9XD, United Kingdom, Centre for Brain Development and Repair, inStem, Bangalore 560065, India.
authors.forename: Adam D
authors.identifier: http://orcid.org/0000-0002-1247-6618
authors.initials: AD
authors.lastname: Jackson
authors.affiliation: Centre for Integrative Physiology and Patrick Wild Centre, University of Edinburgh, Edinburgh EH8 9XD, United Kingdom.
authors.forename: Danai
authors.initials: D
authors.lastname: Katsanevaki
authors.affiliation: Centre for Integrative Physiology and Patrick Wild Centre, University of Edinburgh, Edinburgh EH8 9XD, United Kingdom, Picower Institute for Learning and Memory, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, and.
authors.forename: Emily K
authors.initials: EK
authors.lastname: Osterweil
authors.affiliation: Centre for Clinical Brain Sciences, University of Edinburgh, Edinburgh EH16 4SB, United Kingdom.
authors.forename: Noboru H
authors.initials: NH
authors.lastname: Komiyama
authors.affiliation: Centre for Clinical Brain Sciences, University of Edinburgh, Edinburgh EH16 4SB, United Kingdom.
authors.forename: Seth G N
authors.identifier: http://orcid.org/0000-0001-8732-8735
authors.initials: SG
authors.lastname: Grant
authors.affiliation: Picower Institute for Learning and Memory, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, and.
authors.forename: Mark F
authors.identifier: http://orcid.org/0000-0002-9903-2541
authors.initials: MF
authors.lastname: Bear
authors.affiliation: Interdisciplinary Institute for Neuroscience, Centre National de la Recherche Scientifique, Unité Mixte de Recherche 5297, University of Bordeaux, Bordeaux 33077, France, valentin.nagerl@u-bordeaux2.fr p.kind@ed.ac.uk david.j.a.wyllie@ed.ac.uk.
authors.forename: U Valentin
authors.initials: UV
authors.lastname: Nägerl
authors.affiliation: Centre for Integrative Physiology and Patrick Wild Centre, University of Edinburgh, Edinburgh EH8 9XD, United Kingdom, Centre for Brain Development and Repair, inStem, Bangalore 560065, India, valentin.nagerl@u-bordeaux2.fr p.kind@ed.ac.uk david.j.a.wyllie@ed.ac.uk.
authors.forename: Peter C
authors.initials: PC
authors.lastname: Kind
authors.affiliation: Centre for Integrative Physiology and Patrick Wild Centre, University of Edinburgh, Edinburgh EH8 9XD, United Kingdom, Centre for Brain Development and Repair, inStem, Bangalore 560065, India, valentin.nagerl@u-bordeaux2.fr p.kind@ed.ac.uk david.j.a.wyllie@ed.ac.uk.
authors.forename: David J A
authors.identifier: http://orcid.org/0000-0002-4957-6049
authors.initials: DJ
authors.lastname: Wyllie
mesh_terms: D000818:Animals; D049229:Dendritic Spines / Q000378:metabolism / Q000473:pathology; D019706:Excitatory Postsynaptic Potentials / Q000502:physiology; D051860:Fragile X Messenger Ribonucleoprotein 1 / Q000096:biosynthesis* / Q000235:genetics; D006624:Hippocampus / Q000378:metabolism* / Q000503:physiopathology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D009924:Organ Culture Techniques; D020703:ras GTPase-Activating Proteins / Q000096:biosynthesis* / Q000235:genetics
chemical_list: D051860:Fragile X Messenger Ribonucleoprotein 1; D020703:ras GTPase-Activating Proteins; C497684:Fmr1 protein, mouse; C484512:Syngap1 protein, mouse
keywords: STED; SynGAP; fragile X syndrome; long-term depression; mGluR; neurodevelopmental disorder