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PMID: 19487570 Published · ppublish English Journal Article Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't Research Support, U.S. Gov't, Non-P.H.S.

The Rho-linked mental retardation protein oligophrenin-1 controls synapse maturation and plasticity by stabilizing AMPA receptors.

Genes & development ·Vol. 23 ·No. 11 ·2009-06-01 ·Pages 1289-302

Nadif Kasri N, Nakano-Kobayashi A, Malinow R, Li B, Van Aelst L

Abstract

Oligophrenin-1 (OPHN1) encodes a Rho-GTPase-activating protein (Rho-GAP) whose loss of function has been associated with X-linked mental retardation (MR). The pathophysiological role of OPHN1, however, remains poorly understood. Here we show that OPHN1 through its Rho-GAP activity plays a critical role in the activity-dependent maturation and plasticity of excitatory synapses by controlling their structural and functional stability. Synaptic activity through NMDA receptor activation drives OPHN1 into dendritic spines, where it forms a complex with AMPA receptors, and selectively enhances AMPA-receptor-mediated synaptic transmission and spine size by stabilizing synaptic AMPA receptors. Consequently, decreased or defective OPHN1 signaling prevents glutamatergic synapse maturation and causes loss of synaptic structure, function, and plasticity. These results imply that normal activity-driven glutamatergic synapse development is impaired by perturbation of OPHN1 function. Thus, our findings link genetic deficits in OPHN1 to glutamatergic dysfunction and suggest that defects in early circuitry development are an important contributory factor to this form of MR.

MeSH Terms
Animals Cytoskeletal Proteins/metabolism Endocytosis/drug effects Excitatory Amino Acid Agonists/pharmacology GTPase-Activating Proteins/metabolism Gene Expression Regulation, Developmental/drug effects Hippocampus/cytology,growth & development,metabolism Intellectual Disability/physiopathology N-Methylaspartate/pharmacology Neurons/cytology,drug effects,metabolism,physiology Nuclear Proteins/metabolism Protein Transport/physiology Rats Receptors, AMPA/metabolism Synapses/physiology
Chemicals
Cytoskeletal Proteins Excitatory Amino Acid Agonists GTPase-Activating Proteins Nuclear Proteins OPHN1 protein, rat Receptors, AMPA N-Methylaspartate glutamate receptor ionotropic, AMPA 2
Authors & Affiliations
5 authors, click to expand affiliations / ORCID
Nadif Kasri Nael
Cold Spring Harbor Laboratory, Cold Spring Harbor, New York 11724, USA.
Nakano-Kobayashi Akiko
Malinow Roberto
Li Bo
Van Aelst Linda
References (51)
51 references, click to expand
  1. A role of actin filament in synaptic transmission and long-term potentiation.
    J Neurosci. 1999 Jun 1;19(11):4314-24 PMID: 10341235
  2. The novel Rho-GTPase activating gene MEGAP/ srGAP3 has a putative role in severe mental retardation.
    Proc Natl Acad Sci U S A. 2002 Sep 3;99(18):11754-9 PMID: 12195014
  3. Genes, plasticity and mental retardation.
    Behav Brain Res. 2008 Sep 1;192(1):88-105 PMID: 18329113
  4. Structural basis of long-term potentiation in single dendritic spines.
    Nature. 2004 Jun 17;429(6993):761-6 PMID: 15190253
  5. AMPA receptor and GEF-H1/Lfc complex regulates dendritic spine development through RhoA signaling cascade.
    Proc Natl Acad Sci U S A. 2009 Mar 3;106(9):3549-54 PMID: 19208802
  6. Small GTPases Rac and Rho in the maintenance of dendritic spines and branches in hippocampal pyramidal neurons.
    J Neurosci. 2000 Jul 15;20(14):5329-38 PMID: 10884317
  7. Regulation of dendritic spine morphology by the rho family of small GTPases: antagonistic roles of Rac and Rho.
    Cereb Cortex. 2000 Oct;10(10):927-38 PMID: 11007543
  8. Tyrosine phosphorylation of the GluR2 subunit is required for long-term depression of synaptic efficacy in young animals in vivo.
    Hippocampus. 2007;17(8):600-5 PMID: 17534972
  9. The X-linked mental retardation protein oligophrenin-1 is required for dendritic spine morphogenesis.
    Nat Neurosci. 2004 Apr;7(4):364-72 PMID: 15034583
  10. Dynamic actin filaments are required for stable long-term potentiation (LTP) in area CA1 of the hippocampus.
    Proc Natl Acad Sci U S A. 2000 Jun 6;97(12):6856-61 PMID: 10823894
  11. Mapping of the X-breakpoint involved in a balanced X;12 translocation in a female with mild mental retardation.
    Eur J Hum Genet. 1997 Mar-Apr;5(2):105-9 PMID: 9195162
  12. From mRNP trafficking to spine dysmorphogenesis: the roots of fragile X syndrome.
    Nat Rev Neurosci. 2005 May;6(5):376-87 PMID: 15861180
  13. Some assembly required: the development of neuronal synapses.
    Nat Rev Mol Cell Biol. 2003 Nov;4(11):833-41 PMID: 14625534
  14. Inhibition of Rho via Arg and p190RhoGAP in the postnatal mouse hippocampus regulates dendritic spine maturation, synapse and dendrite stability, and behavior.
    J Neurosci. 2007 Oct 10;27(41):10982-92 PMID: 17928439
  15. Dynamic aspects of CNS synapse formation.
    Annu Rev Neurosci. 2007;30:425-50 PMID: 17417940
  16. Differential roles for NSF and GRIP/ABP in AMPA receptor cycling.
    Proc Natl Acad Sci U S A. 2002 May 14;99(10):7096-101 PMID: 12011465
  17. Dendritic spine changes associated with hippocampal long-term synaptic plasticity.
    Nature. 1999 May 6;399(6731):66-70 PMID: 10331391
  18. Structure and function of the Lowe syndrome protein OCRL1.
    Traffic. 2005 Sep;6(9):711-9 PMID: 16101675
  19. Rho-linked genes and neurological disorders.
    Pflugers Arch. 2008 Feb;455(5):787-97 PMID: 18004590
  20. Genetics and pathophysiology of mental retardation.
    Eur J Hum Genet. 2006 Jun;14(6):701-13 PMID: 16721406
  21. Specific clinical and brain MRI features in mentally retarded patients with mutations in the Oligophrenin-1 gene.
    Am J Med Genet A. 2004 Feb 1;124A(4):364-71 PMID: 14735583
  22. Hippocampal LTP is accompanied by enhanced F-actin content within the dendritic spine that is essential for late LTP maintenance in vivo.
    Neuron. 2003 May 8;38(3):447-60 PMID: 12741991
  23. Quantitation of AMPA receptor surface expression in cultured hippocampal neurons.
    Neuroscience. 1997 May;78(2):361-71 PMID: 9145793
  24. Oligophrenin-1 encodes a rhoGAP protein involved in X-linked mental retardation.
    Nature. 1998 Apr 30;392(6679):923-6 PMID: 9582072
  25. Oligophrenin 1 (OPHN1) gene mutation causes syndromic X-linked mental retardation with epilepsy, rostral ventricular enlargement and cerebellar hypoplasia.
    Brain. 2003 Jul;126(Pt 7):1537-44 PMID: 12805098
  26. Nucleus accumbens long-term depression and the expression of behavioral sensitization.
    Science. 2005 Nov 25;310(5752):1340-3 PMID: 16311338
  27. Synaptic plasticity: multiple forms, functions, and mechanisms.
    Neuropsychopharmacology. 2008 Jan;33(1):18-41 PMID: 17728696
  28. The story of Rett syndrome: from clinic to neurobiology.
    Neuron. 2007 Nov 8;56(3):422-37 PMID: 17988628
  29. Deletion including the oligophrenin-1 gene associated with enlarged cerebral ventricles, cerebellar hypoplasia, seizures and ataxia.
    Eur J Hum Genet. 1999 Jul;7(5):541-8 PMID: 10439959
  30. Tyrosine phosphorylation of GluR2 is required for insulin-stimulated AMPA receptor endocytosis and LTD.
    EMBO J. 2004 Mar 10;23(5):1040-50 PMID: 14976558
  31. The cell biology of synaptic plasticity: AMPA receptor trafficking.
    Annu Rev Cell Dev Biol. 2007;23:613-43 PMID: 17506699
  32. Ras and Rap control AMPA receptor trafficking during synaptic plasticity.
    Cell. 2002 Aug 23;110(4):443-55 PMID: 12202034
  33. Actin in action: the interplay between the actin cytoskeleton and synaptic efficacy.
    Nat Rev Neurosci. 2008 May;9(5):344-56 PMID: 18425089
  34. Loss of X-linked mental retardation gene oligophrenin1 in mice impairs spatial memory and leads to ventricular enlargement and dendritic spine immaturity.
    J Neurosci. 2007 Aug 29;27(35):9439-50 PMID: 17728457
  35. Rho GTPases and activity-dependent dendrite development.
    Curr Opin Neurobiol. 2004 Jun;14(3):297-304 PMID: 15194109
  36. Molecular and comparative genetics of mental retardation.
    Genetics. 2004 Feb;166(2):835-81 PMID: 15020472
  37. NMDA receptor subunit composition controls synaptic plasticity by regulating binding to CaMKII.
    Neuron. 2005 Oct 20;48(2):289-301 PMID: 16242409
  38. Rho proteins, mental retardation and the neurobiological basis of intelligence.
    Prog Brain Res. 2005;147:295-317 PMID: 15581714
  39. GluR1 links structural and functional plasticity at excitatory synapses.
    J Neurosci. 2007 Dec 12;27(50):13706-18 PMID: 18077682
  40. The Rho-specific GEF Lfc interacts with neurabin and spinophilin to regulate dendritic spine morphology.
    Neuron. 2005 Jul 7;47(1):85-100 PMID: 15996550
  41. Mutations in the oligophrenin-1 gene (OPHN1) cause X linked congenital cerebellar hypoplasia.
    J Med Genet. 2003 Jun;40(6):441-6 PMID: 12807966
  42. The role of the Rho GTPases in neuronal development.
    Genes Dev. 2005 Jan 1;19(1):1-49 PMID: 15630019
  43. Sequential implication of the mental retardation proteins ARHGEF6 and PAK3 in spine morphogenesis.
    J Cell Sci. 2006 Dec 1;119(Pt 23):4986-93 PMID: 17105769
  44. Glutamate receptor exocytosis and spine enlargement during chemically induced long-term potentiation.
    J Neurosci. 2006 Feb 15;26(7):2000-9 PMID: 16481433
  45. Three-dimensional structure of dendritic spines and synapses in rat hippocampus (CA1) at postnatal day 15 and adult ages: implications for the maturation of synaptic physiology and long-term potentiation.
    J Neurosci. 1992 Jul;12(7):2685-705 PMID: 1613552
  46. Oligophrenin 1 mutations frequently cause X-linked mental retardation with cerebellar hypoplasia.
    Neurology. 2005 Nov 8;65(9):1364-9 PMID: 16221952
  47. The mental retardation protein PAK3 contributes to synapse formation and plasticity in hippocampus.
    J Neurosci. 2004 Dec 1;24(48):10816-25 PMID: 15574732
  48. The neuregulin-1 receptor erbB4 controls glutamatergic synapse maturation and plasticity.
    Neuron. 2007 May 24;54(4):583-97 PMID: 17521571
  49. Abnormal long-lasting synaptic plasticity and cognition in mice lacking the mental retardation gene Pak3.
    J Neurosci. 2005 Jul 13;25(28):6641-50 PMID: 16014725
  50. Hippocampal long-term depression mediates acute stress-induced spatial memory retrieval impairment.
    Proc Natl Acad Sci U S A. 2007 Jul 3;104(27):11471-6 PMID: 17592137
  51. AMPAR removal underlies Abeta-induced synaptic depression and dendritic spine loss.
    Neuron. 2006 Dec 7;52(5):831-43 PMID: 17145504
Article Info
Journal
Genes & development
Abbr.
Genes Dev
ISSN
1549-5477
DOI
10.1101/gad.1783809
Published
2009-06-01
Pages
1289-302
Language
English
Region
United States
NLM ID
8711660
PMCID
PMC2701582
Subset
IM
Grants
NIMH NIH HHS · R01 MH049159 · United States
NIMH NIH HHS · R01 MH082808 · United States
External Links
PubMed source DOI: 10.1101/gad.1783809 PMC Full Text View journal details
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