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Targeting hyperactive Rho GTPase regulatory proteins in autism (845.7)
Author(s) -
Martinez Luis,
TejadaSimon Maria
Publication year - 2014
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.28.1_supplement.845.7
Subject(s) - dendritic spine , neuroscience , hippocampus , autism , morris water navigation task , fragile x syndrome , gtpase , cofilin , synaptic plasticity , fear conditioning , rac1 , small gtpase , neuroplasticity , psychology , biology , actin cytoskeleton , microbiology and biotechnology , amygdala , cytoskeleton , psychiatry , genetics , signal transduction , receptor , hippocampal formation , cell
Cognitive impairment in neurological disorders like Fragile X syndrome (FX), a leading cause of autism, is thought to be due to abnormal neuroplasticity. These learning‐induced modifications require reorganization of the actin cytoskeleton within dendritic spines, a dynamic process that is known to be regulated by the Rho family of small GTPases. In a mouse model of FX we found increased levels of the Rho GTPase Rac1 in the hippocampus, a brain structure involved in learning. The FX mouse hippocampus also exhibits impaired synaptic plasticity and malformed dendritic spines. In an effort to define whether there is a critical role for the small GTPases in FX‐associated learning deficiencies, Rac1 was pharmacologically targeted using novel agents that inhibit its activation and therefore, its function. Mice treated chronically with Rac1 inhibitors were subjected to behavioral tasks that examine contextual and cued memory (associated fear conditioning) as well as spatial memory (Morris Water maze). Performance on these tasks is dependent on the neuronal integrity of the hippocampus. Our results showed that FX mice treated with the inhibitors improved their cognitive capabilities. These findings suggest that Rac1 hyperactivity may play an important, yet reversible role in FX and autism‐related molecular pathology contributing to cognitive difficulties. Grant Funding Source : Supported by the Jérôme LeJeune Foundation (France), FRAXA Research Foundation (USA) and the Grants