Genetic removal of matrix metalloproteinase 9 rescues the symptoms of fragile X syndrome in a mouse model

Journal of Neuroscience

Volumn 34, Issue 30, 2014, Pages 9867-9879

  Sidhu, Harpreet ^a   Dansie, Lorraine E ^a   Hickmott, Peter W ^b   Ethell, Douglas W ^c   Ethell, Iryna M ^a  

^a Keck School of Medicine   (United States)

^b UNIVERSITY OF CALIFORNIA   (United States)

^c WESTERN UNIVERSITY OF HEALTH SCIENCES   (United States)

Author keywords

Dendritic spines; Extracellular matrix; Fragile X syndrome; Hippocampus; Matrix metalloproteinase; MTOR signaling

Indexed keywords

BETA3 INTEGRIN; FOCAL ADHESION KINASE; FRAGILE X MENTAL RETARDATION PROTEIN; GELATINASE A; GELATINASE B; GLUTAMATE DECARBOXYLASE 65; INITIATION FACTOR 4E; MAMMALIAN TARGET OF RAPAMYCIN; MESSENGER RNA; MITOGEN ACTIVATED PROTEIN KINASE; POSTSYNAPTIC DENSITY PROTEIN 95; PROTEIN KINASE B; SYNAPSIN I; VESICULAR GLUTAMATE TRANSPORTER 1;

ADULT; ANIMAL CELL; ANIMAL EXPERIMENT; ANIMAL MODEL; ANIMAL TISSUE; ANXIETY; ARTICLE; BRAIN ELECTROPHYSIOLOGY; CONTROLLED STUDY; DENDRITIC SPINE; ENZYME LINKED IMMUNOSORBENT ASSAY; EXPERIMENTAL BEHAVIORAL TEST; FRAGILE X SYNDROME; GENE DELETION; GENETIC REGULATION; HUMAN; IMMUNOCYTOCHEMISTRY; IMMUNOHISTOCHEMISTRY; IMMUNOPRECIPITATION; MACROORCHIDISM; MALE; MOUSE; NONHUMAN; OPEN FIELD TEST; PHOSPHORYLATION; PRIORITY JOURNAL; REVERSE TRANSCRIPTION POLYMERASE CHAIN REACTION; SOCIAL NOVELTY TEST; SPINE ABNORMALITY; SPINE DISEASE; WESTERN BLOTTING; ZYMOGRAPHY;

DENDRITIC SPINES; EXTRACELLULAR MATRIX; FRAGILE X SYNDROME; HIPPOCAMPUS; MATRIX METALLOPROTEINASE; MTOR SIGNALING;

ANIMALS; ANIMALS, NEWBORN; CELLS, CULTURED; DISEASE MODELS, ANIMAL; FRAGILE X SYNDROME; MALE; MATRIX METALLOPROTEINASE 9; MICE; MICE, 129 STRAIN; MICE, KNOCKOUT; PHENOTYPE;

EID: 84904554983     PISSN: 02706474     EISSN: 15292401     Source Type: Journal    
DOI: 10.1523/JNEUROSCI.1162-14.2014     Document Type: Article

References (90)

1. Bagni C, Tassone F, Neri G, Hagerman R (2012) Fragile X syndrome: causes, diagnosis, mechanisms, and therapeutics. J Clin Invest 122:4314-4322. CrossRef Medline
2. Bassell GJ, Gross C (2008) Reducing glutamate signaling pays off in fragile X. Nat Med 14:249-250. CrossRef Medline
3. Bear MF, Huber KM, Warren ST (2004) The mGluR theory of fragile X mental retardation. Trends Neurosci 27:370-377. CrossRef Medline
4. Bhattacharya A, Kaphzan H, Alvarez-Dieppa AC, Murphy JP, Pierre P, Klann E (2012) Genetic removal of p70 S6 kinase 1 corrects molecular, synaptic, and behavioral phenotypes in fragile X syndrome mice. Neuron 76: 325-337. CrossRef Medline
5. Bilousova T. Rusakov D, Ethell DW, Ethell IM (2006) Matrix metalloproteinase-7 disrupts dendritic spines in hippocampal neurons through NMDA receptor activation. J Neurochem 97:44-56. CrossRef Medline
6. Bilousova TV, Dansie L, Ngo M, Aye J, Charles JR, Ethell DW, Ethell IM (2009) Minocycline promotes dendritic spine maturation and improves behavioral performance in the fragile X mouse model. J Med Genet 46: 94-102. CrossRef Medline
7. Blackwell E, Zhang X, Ceman S (2010) Arginines of the RGG box regulate FMRP association with polyribosomes and mRNA. Hum Mol Genet 19: 1314-1323. CrossRef Medline
8. Bozdagi O, Nagy V, Kwei KT, Huntley GW (2007) In vivo roles for matrix metalloproteinase-9 in mature hippocampal synaptic physiology and plasticity. J Neurophysiol 98:334-344. CrossRef Medline
9. Braun K, Segal M (2000) FMRP involvement in formation of synapses among cultured hippocampal neurons. Cereb Cortex 10:1045-1052. CrossRef Medline
10. Brown RE, Corey SC, Moore AK (1999) Differences in measures of exploration and fear in MHC-congenic C57BL/6J and B6-H-2K mice. Behav Genet 29:263-271. CrossRef
11. Brückner G, Grosche J, Schmidt S, Härtig W, Margolis RU, Delpech B, Seidenbecher CI, Czaniera R, Schachner M (2000) Postnatal development of perineuronal nets in wild-type mice and in a mutant deficient in tenascin-R. J Comp Neurol 428:616-629. CrossRef Medline
12. Bureau I, Shepherd GM, Svoboda K (2008) Circuit and plasticity defects in the developing somatosensory cortex of FMR1 knock-out mice. J Neurosci 28:5178-5188. CrossRef Medline
13. Chen ZL, Haegeli V, Yu H, Strickland S (2009) Cortical deficiency of laminin gamma1 impairs the AKT/GSK-3beta signaling pathway and leads to defects in neurite outgrowth and neuronal migration. Dev Biol 327:158-168. CrossRef Medline
14. Comery TA, Harris JB, Willems PJ, Oostra BA, Irwin SA, Weiler IJ, Greenough WT (1997) Abnormal dendritic spines in fragile X knockout mice: maturation and pruning deficits. Proc Natl Acad Sci U S A 94:5401-5404. CrossRef Medline
15. Cruz-Martín A, Crespo M, Portera-Cailliau C (2010) Delayed stabilization of dendritic spines in fragile X mice. J Neurosci 30:7793-7803. CrossRef Medline
16. Dansie LE, Ethell IM (2011) Casting a net on dendritic spines: the extracellular matrix and its receptors. Dev Neurobiol 7:956-981. CrossRef Medline
17. Dansie LE, Phommahaxay K, Okusanya AG, Uwadia J, Huang M, Rotschafer SE, Razak KA, Ethell DW, Ethell IM (2013) Long-lasting effects of minocycline on behavior in young but not adult fragile X mice. Neuroscience 246:186-198. CrossRef Medline
18. Darnell JC, Van Driesche SJ, Zhang C, Hung KY, Mele A, Fraser CE, Stone EF, Chen C, Fak JJ, Chi SW, Licatalosi DD, Richter JD, Darnell RB (2011) FMRP stalls ribosomal translocation on mRNAs linked to synaptic function and autism. Cell 146:247-261. CrossRef Medline
19. De Rubeis S, Pasciuto E, Li K, Fernández E, Di Marino D, Buzzi A, Ostroff LE, Klann E, Zwartkruis FJ, Komiyama NH, Grant SG, Poujol C, Choquet D, Achsel T, Posthuma D, Smit AB, Bagni C (2013) CYFIP1 coordinates mRNA translation and cytoskeleton remodeling to ensure proper dendritic spine formation. Neuron 79:1169-1182. CrossRef Medline
20. D'Hulst C, Heulens I, Brouwer JR, Willemsen R, De Geest N, Reeve SP, De Deyn PP, Hassan BA, Kooy RF (2009) Expression of the GABAergic system in animal models for fragile X syndrome and fragile X associated tremor/ataxia syndrome (FXTAS). Brain Res 1253:176-183. CrossRef Medline
21. Dictenberg JB, Swanger SA, Antar LN, Singer RH, Bassell GJ (2008) A direct role for FMRP in activity-dependent dendritic mRNA transport links filopodial-spine morphogenesis to fragile X syndrome. Dev Cell 14:926-939. CrossRef Medline
22. Dziembowska M, Wlodarczyk J (2012) MMP-9: a novel function in synaptic plasticity. Int J Biochem Cell Biol 44:709-713. CrossRef Medline
23. Dziembowska M, Pretto DI, Janusz A, Kaczmarek L, Leigh MJ, Gabriel N, Durbin-Johnson B, Hagerman RJ, Tassone F (2013) High MMP-9 activity levels in fragile X syndrome are lowered by minocycline. Am J Med Genet A 161A:1897-1903. CrossRef Medline
24. Ethell IM, Ethell DW (2007) Matrix metalloproteinases in brain development and remodeling: synaptic functions and targets. J Neurosci Res 85:2813-2823. CrossRef Medline
25. Feng Y, Gutekunst CA, Eberhart DE, Yi H, Warren ST, Hersch SM (1997) Fragile X mental retardation protein: nucleocytoplasmic shuttling and association with somatodendritic ribosomes. J Neurosci 17:1539-1547. Medline
26. Fiala JC, Feinberg M, Popov V, Harris KM (1998) Synaptogenesis via dendritic filopodia in developing hippocampal area CA1. J Neurosci 18: 8900-8911. Medline
27. Fritz IB, Tung PS, Ailenberg M (1993) Proteases and anti-proteases in the seminiferous tubule. In: The Sertoli cell (Russell LD, Griswold MD, eds), pp 217-235. Clearwater, FL: Cache River.
28. Furic L, Rong L, Larsson O, Koumakpayi IH, Yoshida K, Brueschke A, Petroulakis E, Robichaud N, Pollak M, Gaboury LA, Pandolfi PP, Saad F, Sonenberg N (2010) eIF4E phosphorylation promotes tumorigenesis and is associated with prostate cancer progression. Proc Natl Acad Sci U S A 107:14134-14139. CrossRef Medline
29. Garber KB, Visootsak J, Warren ST (2008) Fragile X syndrome. Eur J Hum Genet 16:666-672. CrossRef Medline
30. Gross C, Nakamoto M, Yao X, Chan CB, Yim SY, Ye K, Warren ST, Bassell GJ (2010) Excess phosphoinositide 3-kinase subunit synthesis and activity as a novel therapeutic target in fragile X syndrome. J Neurosci 30:10624-10638. CrossRef Medline
31. Hagerman R, Hagerman P (2013) Advances in clinical and molecular understanding of the FMR1 premutation and fragile X-associated tremor/ ataxia syndrome. Lancet Neurol 12:786-798. CrossRef Medline
32. Hagerman RJ, Berry-Kravis E, Kaufmann WE, Ono MY, Tartaglia N, Lachiewicz A, Kronk R, Delahunty C, Hessl D, Visootsak J, Picker J, Gane L, Tranfaglia M (2009) Advances in the treatment of fragile X syndrome. Pediatrics 123:378-390. CrossRef Medline
33. Hanson JE, Madison DV (2007) Presynaptic FMR1 genotype influences the degree of synaptic connectivity in a mosaic mouse model of fragile X syndrome. J Neurosci 27:4014-4018. CrossRef Medline
34. Hinton VJ, Brown WT, Wisniewski K, Rudelli RD (1991) Analysis of neocortex in three males with the fragile X syndrome. Am J Med Genet 41:289-294. CrossRef Medline
35. Hoeffer CA, Sanchez E, Hagerman RJ, Mu Y, Nguyen DV, Wong H, Whelan AM, Zukin RS, Klann E, Tassone F (2012) Altered mTOR signaling and enhanced CYFIP2 expression levels in subjects with fragile X syndrome. Genes Brain Behav 11:332-341. CrossRef Medline
36. Hou L, Klann E (2004) Activation of the phosphoinositide 3-kinase-Aktmammalian target of rapamycin signaling pathway is required for metabotropic glutamate receptor-dependent long-term depression. J Neurosci 24:6352-6361. CrossRef Medline
37. Hou L, Antion MD, Hu D, Spencer CM, Paylor R, Klann E (2006) Dynamic translational and proteasomal regulation of fragile X mental retardation protein controls mGluR-dependent long-term depression. Neuron 51: 441-454. CrossRef Medline
38. Huber KM, Gallagher SM, Warren ST, Bear MF (2002) Altered synaptic plasticity in a mouse model of fragile X mental retardation. Proc Natl Acad Sci U S A 99:7746-7750. CrossRef Medline
39. Huntley GW (2012) Synaptic circuit remodelling by matrix metalloproteinases in health and disease. Nat Rev Neurosci 13:743-757. CrossRef Medline
40. Hwang JJ, Park MH, Choi SY, Koh JY (2005) Activation of the Trk signaling pathway by extracellular zinc. Role of metalloproteinases. J Biol Chem 280:11995-12001. CrossRef Medline
41. Irwin SA, Galvez R, Greenough WT (2000) Dendritic spine structural anomalies in fragile-X mental retardation syndrome. Cereb Cortex 10: 1038-1044. CrossRef Medline
42. Janusz A, Milek J, Perycz M, Pacini L, Bagni C, Kaczmarek L, Dziembowska M (2013) The fragile x mental retardation protein regulates matrix metalloproteinase 9 mRNA at synapses. J Neurosci 33:18234-18241. CrossRef Medline
43. Kaidanovich-Beilin O, Lipina T, Vukobradovic I, Roder J, Woodgett JR (2011) Assessment of social interaction behaviors. J Vis Exp e2473. CrossRef Medline
44. Khandjian EW, Tournier B, Séguin S, Tremblay S, De Koninck P, Davidovich L (2009) RNA granules: functions within presynaptic terminals and postsynaptic spines. In: Encyclopedia of neuroscience, Vol 8 (Squire L, Albright T, Bloom F, Gage F, Spitzer N, eds), pp 389-395. New York: Elsevier.
45. Lauterborn JC, Jafari M, Babayan AH, Gall CM (2013) Environmental enrichment reveals effects of genotype on hippocampal spine morphologies in the mouse model of fragile X syndrome. Cereb Cortex. Advance online publication. Retrieved June 12, 2014. doi:10. 1093/cercor/bht249. CrossRef Medline
46. Lauterborn J, Rex CS, Kramár E, Chen LY, Pandyarajan V, Lynch G, Gall CM (2007) Brain-derived neurotrophic factor rescues synaptic plasticity in a mouse model of fragile X syndrome. J Neurosci 27:10685-10694. CrossRef Medline
47. Legate KR, Wickström SA, Fässler R (2009) Genetic and cell biological analysis of integrin outside-in signaling. Genes Dev 23:397-418. CrossRef Medline
48. Leigh MJ, Nguyen DV, Mu Y, Winarni TI, Schneider A, Chechi T, Polussa J, Doucet P, Tassone F, Rivera SM, Hessl D, Hagerman RJ (2013) A randomized double-blind, placebo-controlled trial of minocycline in children and adolescents with fragile X syndrome. J Dev Behav Pediatr 34: 147-155. CrossRef Medline
49. Levenga J, de Vrij FM, Buijsen RA, Li T, Nieuwenhuizen IM, Pop A, Oostra BA, Willemsen R (2011) Subregion-specific dendritic spine abnormalities in the hippocampus of Fmr1 KO mice. Neurobiol Learn Mem 95:467-472. CrossRef Medline
50. Louhivuori V, Vicario A, Uutela M, Rantamäki T, Louhivuori LM, CastrénE, Tongiorgi E, Akerman KE, Castrén ML (2011) BDNF and TrkB in neuronal differentiation of Fmr1-knockout mouse. Neurobiol Dis 41:469-480. CrossRef Medline
51. Maddigan A, Truitt L, Arsenault R, Freywald T, Allonby O, Dean J, Narendran A, Xiang J, Weng A, Napper S, Freywald A (2011) EphB receptors trigger Akt activation and suppress Fas receptor-induced apoptosis in malignant T lymphocytes. J Immunol 187:5983-5994. CrossRef Medline
52. Manabe S, Gu Z, Lipton SA (2005) Activation ofmatrix metalloproteinase-9 via neuronal nitric oxide synthase contributes to NMDA-induced retinal ganglion cell death. Invest Ophthalmol Vis Sci 46:4747-4753. CrossRef Medline
53. Matsuzaki M, Ellis-Davies G, Nemoto T, Miyashita Y, Iino M, Kasai H (2001) Dendritic spine geometry is critical for AMPA receptor expression in hippocampal CA1 pyramidal neurons. Nat Neurosci 4:1086-1092. CrossRef Medline
54. Meighan SE, Meighan PC, Choudhury P, Davis CJ, Olson ML, Zornes PA, Wright JW, Harding JW (2006) Effects of extracellular matrix degrading proteases matrix metalloproteinases 3 and 9 on spatial learning and synaptic plasticity. J Neurochem 96:1227-1241. CrossRef Medline
55. Michalon A, Sidorov M, Ballard TM, Ozmen L, Spooren W, Wettstein JG, Jaeschke G, Bear MF, Lindemann L (2012) Chronic pharmacological mGlu5 inhibition corrects fragile X in adult mice. Neuron 74:49-56. CrossRef Medline
56. Moeller ML, Shi Y, Reichardt LF, Ethell IM (2006) EphB receptors regulate dendritic spine morphogenesis through the recruitment/phosphorylation of focal adhesion kinase and RhoA activation. J Biol Chem 281:1587-1598. CrossRef Medline
57. Nagy V, Bozdagi O, Matynia A, Balcerzyk M, Okulski P, Dzwonek J, Costa RM, Silva AJ, Kaczmarek L, Huntley GW (2006) Matrix metalloproteinase-9 is required for hippocampal late-phase long-term potentiation and memory. J Neurosci 26:1923-1934. CrossRef Medline
58. Napoli I, Mercaldo V, Boyl PP, Eleuteri B, Zalfa F, De Rubeis S, Di Marino D, Mohr E, Massimi M, Falconi M, Witke W, Costa-Mattioli M, Sonenberg N, Achsel T, Bagni C (2008) The fragile X syndrome protein represses activity-dependent translation through CYFIP1, a new 4E-BP. Cell 134: 1042-1054. CrossRef Medline
59. Nho RS, Kahm J (2010) Beta1-integrin-collagen interaction suppresses FoxO3a by the coordination of Akt and PP2A. J Biol Chem 285:14195-14209. CrossRef Medline
60. Nosyreva ED, Huber KM (2006) Metabotropic receptor-dependent long-term depression persists in the absence of protein synthesis in the mouse model of fragile X syndrome. J Neurophysiol 95:3291-3295. CrossRef Medline
61. Oostra BA, Willemsen R (2009) Fmr1: a gene with three faces. Biochim Biophys Acta 1790:467-477. CrossRef Medline
62. Pacey LK, Heximer SP, Hampson DR (2009) Increased GABAB receptormediated signaling reduces the susceptibility of fragile X knockout mice to audiogenic seizures. Mol Pharmacol 76:18-24. CrossRef Medline
63. Paribello C, Tao L, Folino A, Berry-Kravis E, Tranfaglia M, Ethell IM, Ethell DW (2010) Open label add-on treatment trial of minocycline in fragile X syndrome. BMC Neurol 10:91-99. CrossRef Medline
64. Robinson L, Sznajder NA, Riley SC, Anderson RA (2001) Matrix metalloproteinases and tissue inhibitors of metalloproteinases in human fetal testis and ovary. Mol Hum Reprod 7:641-648. CrossRef Medline
65. Ronesi JA, Huber KM (2008) Homer interactions are necessary for metabotropic glutamate receptor-induced long-term depression and translational activation. J Neurosci 28:543-547. CrossRef Medline
66. Ronesi JA, Collins KA, Hays SA, Tsai N-P, Guo W, Birnbaum SG, Hu JH, Worley PF, Gibson JR, Huber KM (2012) Disrupted Homer scaffolds mediate abnormal mGluR5 function in a mouse model of fragile X syndrome. Nat Neurosci 15:431-440. CrossRef Medline
67. Rotschafer SE, Trujillo MS, Dansie LE, Ethell IM, Razak KA (2012) Minocycline treatment reverses ultrasonic vocalization production deficit in a mouse model of fragile X syndrome. Brain Res 1439:7-14. CrossRef Medline
68. Rudelli RD, Brown WT, Wisniewski K, Jenkins EC, Laure-Kamionowska M, Connell F, Wisniewski HM (1985) Adult fragile X syndrome. Acta Neuropathol 67:289-295. CrossRef Medline
69. Schneider A, Leigh MJ, Adams P, Nanakul R, Chechi T, Olichney J, Hagerman R, Hessl D (2013) Electrocortical changes associated with minocycline treatment in fragile X syndrome. J Psychopharmacol 27:956-963. CrossRef Medline
70. Sharma A, Hoeffer CA, Takayasu Y, Miyawaki T, McBride SM, Klann E, Zukin RS (2010) Dysregulation of mTOR signaling in fragile X syndrome. J Neurosci 30:694-702. CrossRef Medline
71. Shi Y, Ethell IM (2006) Integrins control dendritic spine plasticity in hippocampal neurons through NMDA receptor and Ca2_/calmodulindependent protein kinase II-mediated actin reorganization. J Neurosci 26:1813-1822. CrossRef Medline
72. Siller SS, Broadie K (2011) Neural circuit architecture defects in a Drosophila model of fragile X syndrome are alleviated by minocycline treatment and genetic removal of matrix metalloproteinase. Dis Model Mech 4:673-685. CrossRef Medline
73. Siu MK, Lee WM, Cheng CY (2003) The interplay of collagen IV, tumor necrosis factor-a, gelatinase B (matrix metalloprotease-9) and tissue inhibitor of metalloproteases-1 in the basal lamina regulates Sertoli cell tight junction dynamics in the rat testis. Endocrinology 144:371-387. CrossRef Medline
74. Slegtenhorst-Eegdeman KE, de Rooij DG, Verhoef-Post M, van de Kant HJ, Bakker CE, Oostra BA, Grootegoed JA, Themmen AP (1998) Macroorchidism in FMR1 knockout mice is caused by increased Sertoli cell proliferation during testicular development. Endocrinology 139:156-162. Medline
75. Stefani G, Fraser CE, Darnell JC, Darnell RB (2004) Fragile X mental retardation protein is associated with translating polyribosomes in neuronal cells. J Neurosci 24:7272-7276. CrossRef Medline
76. Szepesi Z, Bijata M, Ruszczycki B, Kaczmarek L, Wlodarczyk J (2013) Matrix metalloproteinases regulate the formation of dendritic spine head protrusions during chemically induced long-term potentiation. PLoS One 8:e63314. CrossRef Medline
77. Tashiro A, Yuste R (2003) Structure and molecular organization of dendritic spines. Histol Histopathol 18:617-634. Medline
78. Udagawa T, Farny NG, Jakovcevski M, Kaphzan H, Alarcon JM, Anilkumar S, Ivshina M, Hurt JA, Nagaoka K, Nalavadi VC, Lorenz LJ, Bassell GJ, Akbarian S, Chattarji S, Klann E, Richter JD (2013) Genetic and acute CPEB1 depletion ameliorate fragile X pathophysiology. Nat Med 19: 1473-1477. CrossRef Medline
79. Uutela M, Lindholm J, Louhivuori V, Wei H, Louhivuori LM, Pertovaara A, Akerman K, Castrén E, Castrén ML (2012) Reduction of BDNF expression in Fmr1 knockout mice worsens cognitive deficits but improves hyperactivity and sensorimotor deficits. Genes Brain Behav 11:513-523. CrossRef Medline
80. Verkerk AJ, Pieretti M, Sutcliffe JS, Fu YH, Kuhl DP, Pizzuti A, Reiner O, Richards S, Victoria MF, Zhang FP (1991) Identification of a gene (FMR-1) containing a CGG repeat coincident with a breakpoint cluster region exhibiting length variation in fragile X syndrome. Cell 65:905-914. CrossRef Medline
81. Wang XB, Bozdagi O, Nikitczuk JS, Zhai ZW, Zhou Q, Huntley GW (2008) Extracellular proteolysis by matrix metalloproteinase-9 drives dendritic spine enlargement and long-term potentiation coordinately. Proc Natl Acad Sci U S A 105:19520-19525. CrossRef Medline
82. Weiler IJ, Greenough WT (1999) Synaptic synthesis of the fragile X protein: possible involvement in synapse maturation and elimination. Am J Med Genet 83:248-252. CrossRef Medline
83. Wlodarczyk J, Mukhina I, Kaczmarek L, Dityatev A (2011) Extracellular matrix molecules, their receptors, and secreted proteases in synaptic plasticity. Dev Neurobiol 71:1040-1053. CrossRef Medline
84. Yan QJ, Asafo-Adjei PK, Arnold HM, Brown RE, Bauchwitz RP (2004) A phenotypic and molecular characterization of the fmr1-tm1Cgr fragile X mouse. Genes Brain Behav 3:337-359. CrossRef Medline
85. Yan QJ, Rammal M, Tranfaglia M, Bauchwitz RP (2005) Suppression of two major fragile X syndrome mouse model phenotypes by the mGluR5 antagonist MPEP. Neuropharmacology 49:1053-1066. CrossRef Medline
86. Yang F, Je HS, Ji Y, Nagappan G, Hempstead B, Lu B (2009) Pro-BDNFinduced synaptic depression and retraction at developing neuromuscular synapses. J Cell Biol 185:727-741. CrossRef Medline
87. Yu LN, Zhou XL, Yu J, Huang H, Jiang LS, Zhang FJ, Cao JL, Yan M (2012) PI3K contributed to modulation of spinal nociceptive information related to ephrinBs/EphBs. PLoS One 7:e40930. CrossRef Medline
88. Zalfa F, Eleuteri B, Dickson KS, Mercaldo V, De Rubeis S, di Penta A, Tabolacci E, Chiurazzi P, Neri G, Grant SG, Bagni C (2007) A new function for the fragile X mental retardation protein in regulation of PSD-95 mRNA stability. Nat Neurosci 10:578-587. CrossRef Medline
89. Zhang JW, Gottschall PE (1997) Zymographic measurement of gelatinase activity in brain tissue after detergent extraction and affinity-support purification. J Neurosci Methods 76:15-20. CrossRef Medline
90. Zhang YQ, Bailey AM, Matthies HJ, Renden RB, Smith MA, Speese SD, Rubin GM, Broadie K (2001) Drosophilafragile X-related gene regulates the MAP1B homolog Futsch to control synaptic structure and function. Cell 107:591-603. CrossRef Medline