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Logo of neuroscibullNeuroscience Bulletin
Neurosci Bull. 2009 October; 25(5): 296–300.
Published online 2009 October 7. doi:  10.1007/s12264-009-0909-0
PMCID: PMC5552610

Language: English | Chinese

Potential pharmacological treatment of fragile X syndrome during adulthood

成年脆性X 综合症的潜在药物治疗


Fragile X syndrome (FXS) is the most common form of inherited mental retardation, characterized by moderate-tosevere mental retardation, attention deficits, and hyperactivity. This disease results from the expansion of a trinucleotide repeat (CGG) within the X-linked fragile X mental retardation 1 (FMR1) gene, which leads to the lack of the product of the FMR1 gene—fragile X mental retardation protein. Many mental disorders such as FXS and Rett syndrome are thought to originate during early developmental period, but recent findings have suggested the involvement of the processes in the adult nervous system. Here we outline our recent studies and initial clinical trials that may provide an approach to treat FXS in the adulthood.

Keywords: fragile X syndrome, central nervous system, dopamine, clinical trials


脆性X综合症是临床最为常见的遗传性智力发育迟滞综合症, 其特征性表现包括中度至严重的智力发育障碍、 注意力降低、 多动等。 发病原因是X- 基因连锁的脆性基因(FMR1)CGG 序列过度重复表达, 导致FMR1 基因沉默, 其表达产物FMRP缺失。 脆性X综合症与Ratt 综合症等被认为起源于早期的发育障碍, 但最近的研究表明, 成年动物中枢神经系统功能异常也参与疾病的病理发展。 本文对最近的研究结果加以综述, 并对潜在的成年脆性X综合症治疗的相关临床试验进行探讨。

关键词: 脆性X综合症, 中枢神经系统, 多巴胺, 临床试验


[1] Verkerk A.J., Pieretti M., Sutcliffe J.S., Fu Y.H., Kuhl D.P., Pizzuti A., et al. Identification of a gene (FMR-1) containing a CGG repeat coincident with a breakpoint cluster region exhibiting length variation in fragile X syndrome. Cell. 1991;65(5):905–914. doi: 10.1016/0092-8674(91)90397-H. [PubMed] [Cross Ref]
[2] Siomi H., Choi M., Siomi M.C., Nussbaum R.L., Dreyfuss G. Essential role for KH domains in RNA binding: impaired RNA binding by a mutation in the KH domain of FMR1 that causes fragile X syndrome. Cell. 1994;77(1):33–39. doi: 10.1016/0092-8674(94)90232-1. [PubMed] [Cross Ref]
[3] Feng Y., Zhang F., Lokey L.K., Chastain J.L., Lakkis L., Eberhart D., et al. Translational suppression by trinucleotide repeat expansion at FMR1. Science. 1995;268(5211):731–734. doi: 10.1126/science.7732383. [PubMed] [Cross Ref]
[4] Eichler E.E., Holden J.J., Popovich B.W., Reiss A.L., Snow K., Thibodeau S.N., et al. Length of uninterrupted CGG repeats determines instability in the FMR1 gene. Nat Genet. 1994;8(1):88–94. doi: 10.1038/ng0994-88. [PubMed] [Cross Ref]
[5] Oberle I., Rousseau F., Heitz D., Kretz C., Devys D., Hanauer A., et al. Instability of a 550-base pair DNA segment and abnormal methylation in fragile X syndrome. Science. 1991;252(5010):1097–1102. doi: 10.1126/science.252.5009.1097. [PubMed] [Cross Ref]
[6] Kooy R.F. Of mice and the fragile X syndrome. Trends Genet. 2003;19(3):148–154. doi: 10.1016/S0168-9525(03)00017-9. [PubMed] [Cross Ref]
[7] Jin P., Warren S.T. New insights into fragile X syndrome: from molecules to neurobehaviors. Trends Biochem Sci. 2003;28(3):152–158. doi: 10.1016/S0968-0004(03)00033-1. [PubMed] [Cross Ref]
[8] Willemsen R., Oostra B.A., Bassell G.J., Dictenberg J. The fragile X syndrome: from molecular genetics to neurobiology. Ment Retard Dev Disabil Res Rev. 2004;10(1):60–67. doi: 10.1002/mrdd.20010. [PubMed] [Cross Ref]
[9] van Dam D., D’Hooge R., Hauben E., Reyniers E., Gantois I., Bakker C.E., et al. Spatial learning, contextual fear conditioning and conditioned emotional response in Fmr1 knockout mice. Behav Brain Res. 2000;117(1–2):127–136. [PubMed]
[10] Paradee W., Melikian H.E., Rasmussen D.L., Kenneson A., Conn P.J., Warren S.T. Fragile X mouse: strain effects of knockout phenotype and evidence suggesting deficient amygdala function. Neurosci. 1999;94(1):185–192. doi: 10.1016/S0306-4522(99)00285-7. [PubMed] [Cross Ref]
[11] Bagni C., Greenough W.T. From mRNP trafficking to spine dysmorphogenesis: the roots of fragile X syndrome. Nat Rev Neurosci. 2005;6(5):376–387. doi: 10.1038/nrn1667. [PubMed] [Cross Ref]
[12] Bear M.F., Huber K.M., Warren S.T. The mGluR theory of fragile X mental retardation. Trends Neurosci. 2004;27(7):370–377. doi: 10.1016/j.tins.2004.04.009. [PubMed] [Cross Ref]
[13] Grossman A.W., Aldridge G.M., Weiler I.J., Greenough W.T. Local protein synthesis and spine morphogenesis: Fragile X syndrome and beyond. J Neurosci. 2006;26(27):7151–7155. doi: 10.1523/JNEUROSCI.1790-06.2006. [PubMed] [Cross Ref]
[14] Larson J., Jessen R.E., Kim D., Fine A.K., du Hoffmann J. Age-dependent and selective impairment of long-term potentiation in the anterior piriform cortex of mice lacking the fragile X mental retardation protein. J Neurosci. 2005;25(41):9460–9469. doi: 10.1523/JNEUROSCI.2638-05.2005. [PubMed] [Cross Ref]
[15] Lauterborn J.C., Rex C.S., Kramar E., Chen L.Y., Pandyarajan V., Lynch G., et al. Brain-derived neurotrophic factor rescues synaptic plasticity in a mouse model of fragile X syndrome. J Neurosci. 2007;27(40):10685–10694. doi: 10.1523/JNEUROSCI.2624-07.2007. [PubMed] [Cross Ref]
[16] Zhao M.G., Toyoda H., Ko S.W., Ding H.K., Wu L.J., Zhuo M. Deficits in trace fear memory and long-term potentiation in a mouse model for fragile X syndrome. J Neurosci. 2005;25(32):7385–7392. doi: 10.1523/JNEUROSCI.1520-05.2005. [PubMed] [Cross Ref]
[17] Huerta P.T., Sun L.D., Wilson M.A., Tonegawa S. Formation of temporal memory requires NMDA receptors within CA1 pyramidal neurons. Neuron. 2000;25(2):473–480. doi: 10.1016/S0896-6273(00)80909-5. [PubMed] [Cross Ref]
[18] Bliss T.V., Collingridge G.L. A synaptic model of memory: long-term potentiation in the hippocampus. Nature. 1993;361(6407):31–39. doi: 10.1038/361031a0. [PubMed] [Cross Ref]
[19] Malenka R.C., Nicoll R.A. NMDA-receptor-dependent synaptic plasticity: multiple forms and mechanisms. Trends Neurosci. 1993;16(12):521–527. doi: 10.1016/0166-2236(93)90197-T. [PubMed] [Cross Ref]
[20] Ehninger D., Silva A.J. Genetics and neuropsychiatric disorders: treatment during adulthood. Nat Med. 2009;15(8):849–850. doi: 10.1038/nm0809-849. [PubMed] [Cross Ref]
[21] Dolen G., Osterweil E., Rao B.S., Smith G.B., Auerbach B.D., Chattarji S., et al. Correction of fragile X syndrome in mice. Neuron. 2007;56(6):955–962. doi: 10.1016/j.neuron.2007.12.001. [PMC free article] [PubMed] [Cross Ref]
[22] Zeier Z, Kumar A, Bodhinathan K, Feller JA, Foster TC, Bloom DC. Fragile X mental retardation protein replacement restores hippocampal synaptic function in a mouse model of fragile X syndrome. Gene Ther 2009. [PMC free article] [PubMed]
[23] Runyan J.D., Moore A.N., Dash P.K. A role for prefrontal cortex in memory storage for trace fear conditioning. J Neurosci. 2004;24(6):1288–1295. doi: 10.1523/JNEUROSCI.4880-03.2004. [PubMed] [Cross Ref]
[24] Han C.J., O’Tuathaigh C.M., van Trigt L., Quinn J.J., Fanselow M.S., Mongeau R., et al. Trace but not delay fear conditioning requires attention and the anterior cingulate cortex. Proc Natl Acad Sci U S A. 2003;100(22):13087–13092. doi: 10.1073/pnas.2132313100. [PubMed] [Cross Ref]
[25] Blank T., Nijholt I., Kye M.J., Radulovic J., Spiess J. Small-conductance, Ca2+-activated K+ channel SK3 generates age-related memory and LTP deficits. Nat Neurosci. 2003;6(9):911–912. doi: 10.1038/nn1101. [PubMed] [Cross Ref]
[26] Menon V., Leroux J., White C.D., Reiss A.L. Frontostriatal deficits in fragile X syndrome: relation to FMR1 gene expression. Proc Natl Acad Sci U S A. 2004;101(10):3615–3620. doi: 10.1073/pnas.0304544101. [PubMed] [Cross Ref]
[27] Clark R.E., Squire L.R. Classical conditioning and brain systems: the role of awareness. Science. 1998;280(5360):77–81. doi: 10.1126/science.280.5360.77. [PubMed] [Cross Ref]
[28] Baumgardner T.L., Reiss A.L., Freund L.S., Abrams M.T. Specification of the neurobehavioral phenotype in males with fragile X syndrome. Pediatrics. 1995;95(5):744–752. [PubMed]
[29] Fryns J.P., Jacobs J., Kleczkowska A., van den Berghe H. The psychological profile of the fragile X syndrome. Clin Genet. 1984;25(2):131–134. doi: 10.1111/j.1399-0004.1984.tb00474.x. [PubMed] [Cross Ref]
[30] Cornish K., Sudhalter V., Turk J. Attention and language in fragile X. Ment Retard Dev Disabil Res Rev. 2004;10(1):11–16. doi: 10.1002/mrdd.20003. [PubMed] [Cross Ref]
[31] Matsuda Y., Marzo A., Otani S. The presence of background dopamine signal converts long-term synaptic depression to potentiation in rat prefrontal cortex. J Neurosci. 2006;26(18):4803–4810. doi: 10.1523/JNEUROSCI.5312-05.2006. [PubMed] [Cross Ref]
[32] Snyder S.H. Dopamine receptor excess and mouse madness. Neuron. 2006;49(4):484–485. doi: 10.1016/j.neuron.2006.02.002. [PubMed] [Cross Ref]
[33] Surmeier D.J. Dopamine and working memory mechanisms in prefrontal cortex. J Physiol. 2007;581(Pt3):885. doi: 10.1113/jphysiol.2007.134502. [PubMed] [Cross Ref]
[34] Huang Y.Y., Simpson E., Kellendonk C., Kandel E.R. Genetic evidence for the bidirectional modulation of synaptic plasticity in the prefrontal cortex by D1 receptors. Proc Natl Acad Sci U S A. 2004;101(9):3236–3241. doi: 10.1073/pnas.0308280101. [PubMed] [Cross Ref]
[35] Carlsson A. A half-century of neurotransmitter research: impact on neurology and psychiatry. Nobel lecture. Biosci Rep. 2001;21(6):691–710.. doi: 10.1023/A:1015556204669. [PubMed] [Cross Ref]
[36] West A.R., Grace A.A. Opposite influences of endogenous dopamine D1 and D2 receptor activation on activity states and electrophysiological properties of striatal neurons: studies combining in vivo intracellular recordings and reverse microdialysis. J Neurosci. 2002;22(1):294–304. [PubMed]
[37] Williams G.V., Goldman-Rakic P.S. Modulation of memory fields by dopamine D1 receptors in prefrontal cortex. Nature. 1995;376(6541):572–575. doi: 10.1038/376572a0. [PubMed] [Cross Ref]
[38] Sun X., Zhao Y., Wolf M.E. Dopamine receptor stimulation modulates AMPA receptor synaptic insertion in prefrontal cortex neurons. J Neurosci. 2005;25(32):7342–7351. doi: 10.1523/JNEUROSCI.4603-04.2005. [PubMed] [Cross Ref]
[39] Tseng K.Y., O’Donnell P. Dopamine-glutamate interactions controlling prefrontal cortical pyramidal cell excitability involve multiple signaling mechanisms. J Neurosci. 2004;24(22):5131–5139. doi: 10.1523/JNEUROSCI.1021-04.2004. [PubMed] [Cross Ref]
[40] Chen G., Greengard P., Yan Z. Potentiation of NMDA receptor currents by dopamine D1 receptors in prefrontal cortex. Proc Natl Acad Sci U S A. 2004;101(8):2596–2600. doi: 10.1073/pnas.0308618100. [PubMed] [Cross Ref]
[41] Li N., Gao Z., Luo D., Tang X., Chen D., Hu Y. Selenium level in the environment and the population of Zhoukoudian area, Beijing, China. Sci Total Environ. 2007;381(1–3):105–111. [PubMed]
[42] Trantham-Davidson H, Neely LC, Lavin A, Seamans JK. Mechanisms underlying differential D1 versus D2 dopamine receptor regulation of inhibition in prefrontal cortex. J Neurosci. 2004;24(47):10652–10659. [PMC free article] [PubMed]
[43] Wang H., Wu L.J., Kim S.S., Lee F.J., Gong B., Toyoda H., et al. FMRP acts as a key messenger for dopamine modulation in the forebrain. Neuron. 2008;59(4):634–647. doi: 10.1016/j.neuron.2008.06.027. [PubMed] [Cross Ref]
[44] Weinshenker D., Warren S.T. Neuroscience: fragile dopamine. Nature. 2008;455(7213):607–608. doi: 10.1038/455607a. [PubMed] [Cross Ref]
[45] de Vrij F.M., Levenga J., van der Linde H.C., Koekkoek S.K., De Zeeuw C.I., Nelson D.L., et al. Rescue of behavioral phenotype and neuronal protrusion morphology in Fmr1 KO mice. Neurobiol Dis. 2008;31(1):127–132. doi: 10.1016/j.nbd.2008.04.002. [PMC free article] [PubMed] [Cross Ref]
[46] Berry-Kravis E., Sumis A., Hervey C., Nelson M., Porges S.W., Weng N., et al. Open-label treatment trial of lithium to target the underlying defect in fragile X syndrome. J Dev Behav Pediatr. 2008;29(4):293–302. doi: 10.1097/DBP.0b013e31817dc447. [PubMed] [Cross Ref]
[47] Berry-Kravis E., Hessl D., Coffey S., Hervey C., Schneider A., Yuhas J., et al. A pilot open label, single dose trial of fenobam in adults with fragile X syndrome. J Med Genet. 2009;46(4):266–271. doi: 10.1136/jmg.2008.063701. [PMC free article] [PubMed] [Cross Ref]
[48] Jope R.S. Lithium and GSK-3: one inhibitor, two inhibitory actions, multiple outcomes. Trends Pharmacol Sci. 2003;24(9):441–443. doi: 10.1016/S0165-6147(03)00206-2. [PubMed] [Cross Ref]
[49] Phiel C.J., Klein P.S. Molecular targets of lithium action. Annu Rev Pharmacol Toxicol. 2001;41:789–813. doi: 10.1146/annurev.pharmtox.41.1.789. [PubMed] [Cross Ref]
[50] De Sarno P., Li X., Jope R.S. Regulation of Akt and glycogen synthase kinase-3 beta phosphorylation by sodium valproate and lithium. Neuropharmacology. 2002;43(7):1158–1164. doi: 10.1016/S0028-3908(02)00215-0. [PubMed] [Cross Ref]
[51] Doble B.W., Woodgett J.R. GSK-3: tricks of the trade for a multitasking kinase. J Cell Sci. 2003;116(Pt7):1175–1186. doi: 10.1242/jcs.00384. [PMC free article] [PubMed] [Cross Ref]
[52] Kozikowski A.P., Gaisina I.N., Petukhov P.A., Sridhar J., King L.T., Blond S.Y., et al. Highly potent and specific GSK-3beta inhibitors that block tau phosphorylation and decrease alpha-synuclein protein expression in a cellular model of Parkinson’s disease. ChemMedChem. 2006;1(2):256–266. doi: 10.1002/cmdc.200500039. [PubMed] [Cross Ref]
[53] Martinez A., Alonso M., Castro A., Perez C., Moreno F.J. First non- ATP competitive glycogen synthase kinase 3 beta (GSK-3beta) inhibitors: thiadiazolidinones (TDZD) as potential drugs for the treatment of Alzheimer’s disease. J Med Chem. 2002;45(6):1292–1299. doi: 10.1021/jm011020u. [PubMed] [Cross Ref]
[54] Berry-Kravis E., Krause S.E., Block S.S., Guter S., Wuu J., Leurgans S., et al. Effect of CX516, an AMPA-modulating compound, on cognition and behavior in fragile X syndrome: a controlled trial. J Child Adolesc Psychopharmacol. 2006;16(5):525–540. doi: 10.1089/cap.2006.16.525. [PubMed] [Cross Ref]

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