Convergence of Hippocampal Pathophysiology in Syngap+/- and Fmr1-/y Mice.
Journal of Neuroscience. 2015-11-11; 35(45): 15073-15081
DOI: 10.1523/JNEUROSCI.1087-15.2015
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1. J Neurosci. 2015 Nov 11;35(45):15073-81. doi: 10.1523/JNEUROSCI.1087-15.2015.
Convergence of Hippocampal Pathophysiology in Syngap+/- and Fmr1-/y Mice.
Barnes SA(1), Wijetunge LS(2), Jackson AD(3), Katsanevaki D(1), Osterweil EK(4),
Komiyama NH(5), Grant SG(5), Bear MF(6), Nägerl UV(7), Kind PC(8), Wyllie DJ(8).
Author information:
(1)Centre for Integrative Physiology and Patrick Wild Centre, University of
Edinburgh, Edinburgh EH8 9XD, United Kingdom.
(2)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.
(3)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.
(4)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.
(5)Centre for Clinical Brain Sciences, University of Edinburgh, Edinburgh EH16
4SB, United Kingdom.
(6)Picower Institute for Learning and Memory, Massachusetts Institute of
Technology, Cambridge, Massachusetts 02139, and.
(7)Interdisciplinary Institute for Neuroscience, Centre National de la Recherche
Scientifique, Unité Mixte de Recherche 5297, University of Bordeaux, Bordeaux
33077, France,
.
(8)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,
.
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.SIGNIFICANCE STATEMENT: 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.
Copyright © 2015 Barnes et al.
DOI: 10.1523/JNEUROSCI.1087-15.2015
PMCID: PMC4642239
PMID: 26558778 [Indexed for MEDLINE]