Sorry folks - getting a little behind on these, but I hope they're still interesting and helpful! 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.
But how is this related to the mechanism of LTD? Excessive mGluR activity may affect protein synthesis at many points in the brain, which could produce the syndromic nature of the disorder. Further, downregulation of mGluR5 seems to correct aspects of Fragile X syndrome. FMRP does seem to be important for regulating protein synthesis, as 25% increase in protein synthesis was observed in hippocampus of the FMRP-KO animal. But, Bear asked, are psychiatric symptoms a consequence of excessive mGluR5 activity? His group crossed the FMRP-KO with animals heterozygous for mGluR5, and found that decreased mGluR5 rescued excessive protein synthesis in HC as well as many phenotypes of excess (such as increased spine density) through the brain. Bear hoped that this could be a valid therapeutic target - MGluR5 antagonist MPEP has worked in mouse and even fruitfly models of fragile X disorder.
Bear presented a model in which mGluR5 signaling produces increased translation, while FMRP acts as a brake on protein synthesis, such that when FMRP is impaired, excess synthesis results in response to normal mGluR5 signaling, which can be corrected by decreasing mGluR5 activity. This avenue has recently led to exciting results in phase 2 clinical trials of mGluR antagonists, although there are still many important considerations, however, including determining appropriate treatment age, dose, duration of treatment, and domains and instruments to measure improvement in the syndrome.
Bear proposes that the findings on single-gene disorders may suggest a final common pathway to all autism spectrum disorders. Many of the syndromes involve proteins in the synaptic protein synthesis cascade: NF1, PTEN, TSC1/2, FMRP etc. are all repressors of synthesis at the synapse. Could Autism Spectrum Disorders involve a common dysregulation of synaptic protein synthesis?
Bear outlines once more his proposed roadmap to treatment of neurological disorders and ASDs: Study genetically engineered animal models of rare highly penetrant causes of ASDs to understand pathophysiology and discover therapeutic targets. Test shared pathophysiology hypothesis in animals. Connect the dots to discern relevant genes. Focus on variants. Conduct clinical trials.