Regulation of mGluR signaling by lipid domains in Fragile X Syndrome
Albert Einstein College of Medicine of Yeshiva University
Autism is a complex heritable neurodevelopmental disorder, likely involving interaction between the environment and genetic factors, some of which have been identified. In contrast, Fragile X Syndrome (FXS), the most common form of inherited mental retardation, is due to mutations that turn off a single genetic factor, the Fmr1 gene. Approximately 30% of children affected by FXS are diagnosed with autism, indicating that autism and FXS share common molecular and cellular disturbances. Understanding the molecular and cellular disturbances that give rise to behavioral dysfunctions in FXS can greatly advance our understanding of the molecular pathophysiology of autism and lead to the development of novel treatments for both disorders. Molecular and cellular studies in FXS are greatly facilitated by the availability of animal models, such as mice in which the Fmr1 gene is absent. The use of these animal models has been instrumental to the great progress made in recent years in understanding the cellular basis for some of the brain dysfunctions that occur in FXS. An important discovery was that brain neuroreceptors called metabotropic glutamate receptors (mGluRs) show excessive, unchecked activity when the protein made by the Fmr1 gene is no longer present. More importantly still, was the discovery that drugs that can decrease mGluR activity can rescue many of the pathologies associated with FXS in animal models. The research team has focused on understanding why the activity of mGluRs and other neuroreceptors is abnormal in FXS, with the objective of being able in the future to design novel pharmacological therapies that can correct the receptor abnormal function. They have discovered that the activity of mGluRs is dependent on the composition of specialized regions of the cell membrane where the receptors are present: these membrane regions, called ‘lipid domains', are characterized by enrichment in certain lipids, in particular cholesterol. This study tests the possibility that the composition of lipid domains is abnormal in FXS, by examining their properties in brain cells of Fmr1 mice. A further important objective of this study is examination of whether changing the composition of the membrane lipid environment by reducing cholesterol can rescue the abnormal activity of mGluRs in Fmr1 mice. The finding that pharmacological interventions that alter lipid domains composition modify aberrant neuroreceptor activity could lead to new therapies to treat FXS and autism.