Abstract
Abnormalities in dendritic spine morphologies are often associated with mental retardation. Since dendritic spines are thought to represent a morphological correlate of neuronal plasticity, altered spine morphologies may underlie or contribute to cognitive deficits seen in mental retardation. Signaling cascades that are important for cytoskeletal regulation may have an impact upon spine morphologies. The Rho GTPase signaling pathway has been shown to be involved in the regulation of the cytoskeleton and to play fundamental roles in the structural plasticity of dendritic spines. Moreover, alterations in the Rho GTPase signaling pathway have been shown to contribute to mental retardation. Recently, different mental retardation-associated genes have been identified that encode modulators of the Rho GTPases. Disturbances in these genes can lead to mental retardation and—on the morphological level—to alterations in dendritic spines. Thus, getting more insight into the Rho GTPase signaling pathways, and the molecules involved, would not only help in understanding the basic mechanisms by which the morphologies of dendritic spines are modulated but may also allow the development of therapeutic strategies to counteract some aspects of mental retardation.
Similar content being viewed by others
References
Allen KM, Gleeson JG, Bagrodia S, Partington MW, MacMillan JC, Cerione RA, Mulley JC, Walsh CA (1998) PAK3 mutation in nonsyndromic X-linked mental retardation. Nat Genet 20:25–30
Antonarakis SE, van Aelst L (1998) Mind the GAP, Rho, Rab and GDI. Nat Genet 19:106–108
Bastrikova N, Gardner GA, Reece JM, Jeromin A, Dudek SM (2008) Synapse elimination accompanies functional plasticity in hippocampal neurons. Proc Natl Acad Sci USA 105:3123–3127
Bergmann C, Zerres K, Senderek J, Rudnik-Schoneborn S, Eggermann T, Hausler M, Mull M, Ramaekers VT (2003) Oligophrenin 1 (OPHN1) gene mutation causes syndromic X-linked mental retardation with epilepsy, rostral ventricular enlargement and cerebellar hypoplasia. Brain 126:1537–1544
Bienvenu T, des Portes V, McDonell N, Carrie A, Zemni R, Couvert P, Ropers HH, Moraine C, van Bokhoven H, Fryns JP, Allen K, Walsh CA, Boue J, Kahn A, Chelly J, Beldjord C (2000) Missense mutation in PAK3, R67C, causes X-linked nonspecific mental retardation. Am J Med Genet 93:294–298
Billuart P, Bienvenu T, Ronce N, des Portes V, Vinet MC, Zemni R, Roest CH, Carrie A, Fauchereau F, Cherry M, Briault S, Hamel B, Fryns JP, Beldjord C, Kahn A, Moraine C, Chelly J (1998) Oligophrenin-1 encodes a rhoGAP protein involved in X-linked mental retardation. Nature 392:923–926
Boda B, Alberi S, Nikonenko I, Node-Langlois R, Jourdain P, Moosmayer M, Parisi-Jourdain L, Muller D (2004) The mental retardation protein PAK3 contributes to synapse formation and plasticity in hippocampus. J Neurosci 24:10816–10825
Boda B, Jourdain L, Muller D (2008) Distinct, but compensatory roles of PAK1 and PAK3 in spine morphogenesis. Hippocampus 18:857–861
Chechlacz M, Gleeson JG (2003) Is mental retardation a defect of synapse structure and function? Pediatr Neurol 29:11–17
Chelly J, Khelfaoui M, Francis F, Cherif B, Bienvenu T (2006) Genetics and pathophysiology of mental retardation. Eur J Hum Genet 14:701–713
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 USA 94:5401–5404
D'Hulst C, Kooy RF (2009) Fragile X syndrome: from molecular genetics to therapy. J Med Genet 46:577–584
Endris V, Wogatzky B, Leimer U, Bartsch D, Zatyka M, Latif F, Maher ER, Tariverdian G, Kirsch S, Karch D, Rappold GA (2002) The novel Rho-GTPase activating gene MEGAP/ srGAP3 has a putative role in severe mental retardation. Proc Natl Acad Sci USA 99:11754–11759
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
Fiala JC, Spacek J, Harris KM (2002) Dendritic spine pathology: cause or consequence of neurological disorders? Brain Res Brain Res Rev 39:29–54
Garber KB, Visootsak J, Warren ST (2008) Fragile X syndrome. Eur J Hum Genet 16:666–672
Geinisman Y (2000) Structural synaptic modifications associated with hippocampal LTP and behavioral learning. Cereb Cortex 10:952–962
Godfraind JM, Reyniers E, De BK, D'Hooge R, De Deyn PP, Bakker CE, Oostra BA, Kooy RF, Willems PJ (1996) Long-term potentiation in the hippocampus of fragile X knockout mice. Am J Med Genet 64:246–251
Govek EE, Newey SE, Akerman CJ, Cross JR, van der Veken L, van Aelst L (2004) The X-linked mental retardation protein oligophrenin-1 is required for dendritic spine morphogenesis. Nat Neurosci 7:364–372
Greenough WT, Klintsova AY, Irwin SA, Galvez R, Bates KE, Weiler IJ (2001) Synaptic regulation of protein synthesis and the fragile X protein. Proc Natl Acad Sci USA 98:7101–7106
Grossman AW, Elisseou NM, McKinney BC, Greenough WT (2006) Hippocampal pyramidal cells in adult Fmr1 knockout mice exhibit an immature-appearing profile of dendritic spines. Brain Res 1084:158–164
Huttenlocher PR (1970) Dendritic development and mental defect. Neurology 20:381
Huttenlocher PR (1974) Dendritic development in neocortex of children with mental defect and infantile spasms. Neurology 24:203–210
Irwin SA, Galvez R, Greenough WT (2000) Dendritic spine structural anomalies in fragile-X mental retardation syndrome. Cereb Cortex 10:1038–1044
Kasri NN, Nakano-Kobayashi A, Malinow R, Li B, van Aelst L (2009) The Rho-linked mental retardation protein oligophrenin-1 controls synapse maturation and plasticity by stabilizing AMPA receptors. Genes Dev 23:1289–1302
Kasri NN, van Aelst L (2008) Rho-linked genes and neurological disorders. Pflügers Arch 455:787–797
Kaufmann WE, Moser HW (2000) Dendritic anomalies in disorders associated with mental retardation. Cereb Cortex 10:981–991
Khelfaoui M, Denis C, van Galen E, de Bock F, Schmitt A, Houbron C, Morice E, Giros B, Ramakers G, Fagni L, Chelly J, Nosten-Bertrand M, Billuart P (2007) Loss of X-linked mental retardation gene oligophrenin1 in mice impairs spatial memory and leads to ventricular enlargement and dendritic spine immaturity. J Neurosci 27:9439–9450
Kreis P, Thevenot E, Rousseau V, Boda B, Muller D, Barnier JV (2007) The p21-activated kinase 3 implicated in mental retardation regulates spine morphogenesis through a Cdc42-dependent pathway. J Biol Chem 282:21497–21506
Kutsche K, Yntema H, Brandt A, Jantke I, Nothwang HG, Orth U, Boavida MG, David D, Chelly J, Fryns JP, Moraine C, Ropers HH, Hamel BC, van Bokhoven H, Gal A (2000) Mutations in ARHGEF6, encoding a guanine nucleotide exchange factor for Rho GTPases, in patients with X-linked mental retardation. Nat Genet 26:247–250
Leuner B, Falduto J, Shors TJ (2003) Associative memory formation increases the observation of dendritic spines in the hippocampus. J Neurosci 23:659–665
Lu R, Wang H, Liang Z, Ku L, O'donnell WT, Li W, Warren ST, Feng Y (2004) The fragile X protein controls microtubule-associated protein 1B translation and microtubule stability in brain neuron development. Proc Natl Acad Sci USA 101:15201–15206
Matsuzaki M, Ellis-Davies GC, 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
Matus A, Brinkhaus H, Wagner U (2000) Actin dynamics in dendritic spines: a form of regulated plasticity at excitatory synapses. Hippocampus 10:555–560
Maul B, von Bohlen und Halbach O, Becker A, Sterner-Kock A, Voigt JP, Siems WE, Grecksch G, Walther T (2008) Impaired spatial memory and altered dendritic spine morphology in angiotensin II type 2 receptor-deficient mice. J Mol Med 86:563–571
McKinney BC, Grossman AW, Elisseou NM, Greenough WT (2005) Dendritic spine abnormalities in the occipital cortex of C57BL/6 Fmr1 knockout mice. Am J Med Genet B Neuropsychiatr Genet 136B:98–102
Meng J, Meng Y, Hanna A, Janus C, Jia Z (2005) Abnormal long-lasting synaptic plasticity and cognition in mice lacking the mental retardation gene Pak3. J Neurosci 25:6641–6650
Meng Y, Zhang Y, Tregoubov V, Janus C, Cruz L, Jackson M, Lu WY, MacDonald JF, Wang JY, Falls DL, Jia Z (2002) Abnormal spine morphology and enhanced LTP in LIMK-1 knockout mice. Neuron 35:121–133
Monfils MH, Teskey GC (2004) Induction of long-term depression is associated with decreased dendritic length and spine density in layers III and V of sensorimotor neocortex. Synapse 53:114–121
Moon SY, Zheng Y (2003) Rho GTPase-activating proteins in cell regulation. Trends Cell Biol 13:13–22
Moser MB, Trommald M, Andersen P (1994) An increase in dendritic spine density on hippocampal CA1 pyramidal cells following spatial learning in adult rats suggests the formation of new synapses. Proc Natl Acad Sci USA 91:12673–12675
Muller D, Toni N, Buchs PA (2000) Spine changes associated with long-term potentiation. Hippocampus 10:596–604
Nasu-Nishimura Y, Hayashi T, Ohishi T, Okabe T, Ohwada S, Hasegawa Y, Senda T, Toyoshima C, Nakamura T, Akiyama T (2006) Role of the Rho GTPase-activating protein RICS in neurite outgrowth. Genes Cells 11:607–614
Newey SE, Velamoor V, Govek EE, Van AL (2005) Rho GTPases, dendritic structure, and mental retardation. J Neurobiol 64:58–74
Nimchinsky EA, Oberlander AM, Svoboda K (2001) Abnormal development of dendritic spines in FMR1 knock-out mice. J Neurosci 21:5139–5146
Nimchinsky EA, Sabatini BL, Svoboda K (2002) Structure and function of dendritic spines. Annu Rev Physiol 64:313–353
Node-Langlois R, Muller D, Boda B (2006) Sequential implication of the mental retardation proteins ARHGEF6 and PAK3 in spine morphogenesis. J Cell Sci 119:4986–4993
Parnass Z, Tashiro A, Yuste R (2000) Analysis of spine morphological plasticity in developing hippocampal pyramidal neurons. Hippocampus 10:561–568
Purpura DP (1974) Dendritic spine "dysgenesis" and mental retardation. Science 186:1126–1128
Riederer BM (2007) Microtubule-associated protein 1B, a growth-associated and phosphorylated scaffold protein. Brain Res Bull 71:541–558
Rosenberger G, Jantke I, Gal A, Kutsche K (2003) Interaction of alphaPIX (ARHGEF6) with beta-parvin (PARVB) suggests an involvement of alphaPIX in integrin-mediated signaling. Hum Mol Genet 12:155–167
Stanyon CA, Bernard O (1999) LIM-kinase1. Int J Biochem Cell Biol 31:389–394
Tassabehji M, Metcalfe K, Fergusson WD, Carette MJ, Dore JK, Donnai D, Read AP, Proschel C, Gutowski NJ, Mao X, Sheer D (1996) LIM-kinase deleted in Williams syndrome. Nat Genet 13:272–273
Tentler D, Gustavsson P, Leisti J, Schueler M, Chelly J, Timonen E, Anneren G, Willard HF, Dahl N (1999) Deletion including the oligophrenin-1 gene associated with enlarged cerebral ventricles, cerebellar hypoplasia, seizures and ataxia. Eur J Hum Genet 7:541–548
Threadgill R, Bobb K, Ghosh A (1997) Regulation of dendritic growth and remodeling by Rho, Rac, and Cdc42. Neuron 19:625–634
Toni N, Buchs PA, Nikonenko I, Bron CR, Muller D (1999) LTP promotes formation of multiple spine synapses between a single axon terminal and a dendrite. Nature 402:421–425
Vaillend C, Poirier R, Laroche S (2008) Genes, plasticity and mental retardation. Behav Brain Res 192:88–105
Vanderklish PW, Edelman GM (2002) Dendritic spines elongate after stimulation of group 1 metabotropic glutamate receptors in cultured hippocampal neurons. Proc Natl Acad Sci USA 99:1639–1644
von Bohlen und Halbach O (2009) Structure and function of dendritic spines within the hippocampus. Ann Anat 191:518–531
von Bohlen und Halbach O, Zacher C, Gass P, Unsicker K (2006) Age-related alterations in hippocampal spines and deficiencies in spatial memory in mice. J Neurosci Res 83:525–531
Waltereit R, Kautt S, Bartsch D (2008) Expression of MEGAP mRNA during embryonic development. Gene Expr Patterns 8:307–310
Yuste R, Bonhoeffer T (2001) Morphological changes in dendritic spines associated with long-term synaptic plasticity. Annu Rev Neurosci 24:1071–1089
Zhang H, Webb DJ, Asmussen H, Niu S, Horwitz AF (2005) A GIT1/PIX/Rac/PAK signaling module regulates spine morphogenesis and synapse formation through MLC. J Neurosci 25:3379–3388
Zhao MG, Toyoda H, Ko SW, Ding HK, Wu LJ, Zhuo M (2005) Deficits in trace fear memory and long-term potentiation in a mouse model for fragile X syndrome. J Neurosci 25:7385–7392
Zhou Q, Homma KJ, Poo MM (2004) Shrinkage of dendritic spines associated with long-term depression of hippocampal synapses. Neuron 44:749–757
Zito K, Knott G, Shepherd GM, Shenolikar S, Svoboda K (2004) Induction of spine growth and synapse formation by regulation of the spine actin cytoskeleton. Neuron 44:321–334
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
von Bohlen und Halbach, O. Dendritic spine abnormalities in mental retardation. Cell Tissue Res 342, 317–323 (2010). https://doi.org/10.1007/s00441-010-1070-9
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s00441-010-1070-9