080210xf's Blog

L'X fragile sera vaincu | Fragile X will be conquered

SFN: Mark Bear on fulfilling the promise of molecular medicine in autism

Mark Bear à propos de sa théorie des mGluR5 lors de son passage à San Diego dans le cadre de la Society for Neuroscience 2010 et des avancées cliniques encourageantes dans le domaine du X fragile. |

On Saturday, I attended Public Symposium 2 on Autism, Progress & Prospects to hear what Mark Bear had to say about “fullfilling the promise of molecular medicine in Autism” Bear outlined two principle problems with the quest for molecular medicines – the brain is a complicated place, and most neurological disorders are as yet poorly defined (ie. symptomatically rather than biologically). Much of autism is of unknown genetic etiology, but the field has had more success studying syndromic forms of ASDs such as Rett Syndrome and Fragile X Syndrome, the latter of which is studied by the Bear lab.

Bear showed how the successes in fragile X research fit into a general model of the strategy for solving neurological disorders. The syndrome was characterized in 1943, but not identified as a silencing of the gene FMR1 by a CGG repeat until 1991, and a knockout mouse was made in 1994. A hypothesis of the involvement of excess mGluR5 was developed in 2002, and the phenotype of the Fmr1-KO was rescued by reduction in mGluR5 in a 2007 study. Currently mGluR5 NAM inhibitors are in phase 2 clinical trials.

Bear reminded us of the role of precise synaptic connections in sensory processing, and that the basis for this specificity is not genetics alone, but that experience modifies this connectivity during postnatal development, as Hubel and Wiesel showed in their studies of monocular deprivation. Bear has long been interested in the role of Group 1 mGluRs in the weakening of deprived eye synapses. In Huber et al, 2000, LTD was induced by administration of DHPG, an agonist of Group 1 mGluRs. This effect requires synthesis of protein at the synapse, leading to the hypothesis that mGluR5 signaling directly leads to removal of AMPA-Rs from the membrane, but additional protein synthesis is required to stabilize this cache and prevent them from returning back into the membrane. One of these proteins is FMRP.

Bear paused to discuss Fragile X, which is reported to be the most common inherited form of mental retardation, and is a “syndromic” disorder, meaning that there are many phenotypic components, ranging from physical abnormalities to cognitive/behavioral deficits.

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