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Establishing a link between small GTPases and mental health
Author(s) -
TejadaSimon Maria Victoria,
Gutala Ramana
Publication year - 2009
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.23.1_supplement.938.13
Subject(s) - dendritic spine , fragile x syndrome , fmr1 , knockout mouse , neuroscience , cdc42 , biology , gtpase , regulator , microbiology and biotechnology , fragile x , genetics , receptor , hippocampal formation , gene
In Fragile X syndrome (the most common type of inherited mental retardation) cognitive impairment is not associated with brain malformations or neuro‐degeneration, but with deficiency in neuronal connectivity due to aberrant spine morphology. Although abnormalities in spines have been associated with impaired cognition in mental retardation, how they generated is not yet well understood. Evidence is pointing to the Rho family of small GTPases (Rac, Rho, Cdc42), which mediate actin reorganization and neuronal morphogenesis. Neuronal plasticity requires actin remodeling and local protein translation. Rac plays a key role in actin remodeling, formation, maturation and maintenance of dendritic spines. By combining biochemistry, electrophysiology and behavioral studies coupled with the use of a Fmr1 knockout mouse as animal model of Fragile X, our investigations suggest that under normal conditions, FMRP (protein missing in Fragile X syndrome) acts as a regulator on the synthesis of Rac. In contrast, in Fmr1 knockout mice, lack of FMRP induces an increase of Rac in brain, leading to abnormal actin remodeling, generating the anomalies reported in the structure of dendritic spines, and resulting in cognitive deficiencies. Additionally, pharmacological manipulations of Rac improve abnormalities observed in Fmr1 knockout mice.