title: Modulation of dendritic spines and synaptic function by Rac1: a possible link to Fragile X syndrome pathology.
abstract: Rac1, a protein of the Rho GTPase subfamily, has been implicated in neuronal and spine development as well as the formation of synapses with appropriate partners. Dendrite and spine abnormalities have been implicated in several psychiatric disorders such as Fragile X syndrome, where neurons show a high density of long, thin, and immature dendritic spines. Although abnormalities in dendrites and spines have been correlated with impaired cognitive abilities in mental retardation, the causes of these malformations are not yet well understood. Fragile X syndrome is the most common type of inherited mental retardation caused by the absence of FMRP protein, a RNA-binding protein implicated in the regulation of mRNA translation and transport, leading to protein synthesis. We suggest that FMRP might act as a negative regulator on the synthesis of Rac1. Maintaining an optimal level of Rac1 and facilitating the reorganization of the cytoskeleton likely leads to normal neuronal morphology during activity-dependent plasticity. In our study, we first demonstrated that Rac1 is not only associated but necessary for normal spine development and long-term synaptic plasticity. We further showed that, in Fmr1 knockout mice, lack of FMRP induces an overactivation of Rac1 in the mouse brain and other organs that have been shown to be altered in Fragile X syndrome. In those animals, pharmacological manipulation of Rac1 partially reverses their altered long-term plasticity. Thus, regulation of Rac1 may provide a functional link among deficient neuronal morphology, aberrant synaptic plasticity and cognition impairment in Fragile X syndrome.
authors.affiliation: Department of Pharmacological and Pharmaceutical Sciences, University of Houston, 521 Science and Research Bldg 2, Houston, TX 77204, USA.
authors.forename: Odelia Y N
authors.initials: OY
authors.lastname: Bongmba
authors.forename: Luis A
authors.initials: LA
authors.lastname: Martinez
authors.forename: Mary E
authors.initials: ME
authors.lastname: Elhardt
authors.forename: Karlis
authors.initials: K
authors.lastname: Butler
authors.forename: Maria V
authors.initials: MV
authors.lastname: Tejada-Simon
mesh_terms: D000634:Aminoquinolines / Q000494:pharmacology; D000704:Analysis of Variance; D000818:Animals; D001921:Brain / Q000196:embryology / Q000254:growth & development / Q000473:pathology; D003712:Dendrites / Q000473:pathology / Q000648:ultrastructure*; D049229:Dendritic Spines / Q000187:drug effects / Q000473:pathology*; D004195:Disease Models, Animal; D004558:Electric Stimulation / Q000379:methods; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology; D019706:Excitatory Postsynaptic Potentials / Q000187:drug effects / Q000235:genetics; D051860:Fragile X Messenger Ribonucleoprotein 1 / Q000235:genetics; D005600:Fragile X Syndrome / Q000235:genetics / Q000473:pathology*; D005786:Gene Expression Regulation / Q000235:genetics / Q000502:physiology; D066298:In Vitro Techniques; D008734:Methoxyhydroxyphenylglycol / Q000031:analogs & derivatives / Q000494:pharmacology; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009474:Neurons / Q000187:drug effects / Q000473:pathology / Q000502:physiology; D018408:Patch-Clamp Techniques; D011743:Pyrimidines / Q000494:pharmacology; D015398:Signal Transduction / Q000187:drug effects / Q000235:genetics; D016622:Silver Staining; D013569:Synapses / Q000235:genetics / Q000502:physiology*; D020830:rac1 GTP-Binding Protein / Q000172:deficiency / Q000378:metabolism*
chemical_list: D000634:Aminoquinolines; D018691:Excitatory Amino Acid Antagonists; D051860:Fragile X Messenger Ribonucleoprotein 1; D008734:Methoxyhydroxyphenylglycol; D011743:Pyrimidines; D020830:rac1 GTP-Binding Protein; C497684:Fmr1 protein, mouse; C487513:NSC 23766; C010117:3,4-dihydroxyphenylglycol