Role of intracellular mGluR5 in fragile X syndrome and autism
Karen O’Malley, Ph.D.
Washington University in St. Louis
The most common inherited form of autism is fragile X syndrome, which is caused by genetic inactivation of the fragile X mental retardation protein (FMRP). In addition to intellectual disability, children with this disorder exhibit extreme social anxiety, poor eye contact, repetitive behaviors, hand flapping and tactile avoidance — hallmark characteristics of people with autism.
Many studies suggest that FMRP inactivation and other mutations associated with autism disrupt signaling between neurons, leading to widespread impairment of brain functions that require complex signaling. In the last few years, it has been shown that FMRP activity is normally kept in check by the G-protein coupled receptor mGluR5.
Karen O’Malley and her colleagues have shown that 80 to 90 percent of mGluR5 stays inside the neuron, where it can regulate various signaling systems. Using special drugs that are able to activate receptors within the cell only, the researchers found that intracellular mGluR5, more than receptors on the cell surface, activates many of the features associated with fragile X syndrome and autism. Some of these features are the weakening of connections between neurons, dysregulated protein synthesis, and inappropriate positioning of proteins that either strengthen or weaken a given neuronal connection. Some of these studies are published1.
Certain drugs that block mGluR5 actions are in clinical trials as therapeutics. Therefore, information about the cellular distribution and functional effects of mGluR5 is important for understanding how and where these new drugs act.
1. Kumar V. et al. J. Biol. Chem. 287, 5412-5425 (2012) PubMed