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Wednesday, October 1, 2008

Fundamental Research & Fragile X Syndrome

On Sep. 23, 2008, National Public Radio's Morning Edition aired a report on progress in research on Fragile X syndrome or FXS for short. You may listen to the podcast here. In FXS, the gene Fmr1 is not expressed in nerve cells. This gene encodes a messenger RNA-binding repressor protein known as fragile X mental retardation protein, or FMRP for short. The protein hinders the translation of the genetic code into protein in protein synthesis. Recent studies in the laboratory of Mark Bear, director of the Picower Institute at M.I.T., suggest that a specific type of receptor for the excitatory neurotransmitter glutamate plays a crucial role in the synthesis of FMRP. Neurotransmitters are molecules that convey information from one nerve cell to another across the synaptic cleft. The synapse constitutes the contact between the nerve cells. Glutamate and its receptors are instrumental in the strengthening of synapses. 

Mark Bear is fundamentally interested in the development of the cerebral cortex. As I summarized in my post dated Aug. 14, 2008, the strengthening of glutamatergic synapses is understood today as the basic mechanism underlying brain plasticity, learning and memory. The stabilization of synapses profoundly affects cortical development. Perturbation of synaptic growth and pruning is suspected to be involved in the development of mental disorders like autism spectrum disorder (ASD), schizophrenia, attention deficit hyperactivity disorder (ADHD), and manic depression.

I met Mark and his family for the first time when I was visiting Wolf Singer's laboratory at the Max-Planck-Institute for Brain Research where Mark was staying as a postdoctoral fellow. The Max-Planck Society funds 80 research establishments covering a broad range of topics from art, law and anthropology to biology, medicine, chemistry, material sciences and physics. The MPI for Brain Research comprised three laboratories at the time. The facilities were located in a cluster of brick-tiled buildings on the opposite bank of the Main in Frankfurt.

Mark proudly drove a very used green BMW 2000Ti and lived with wife and daughter in a small apartment in the western suburb of Schwanheim across the river from a huge chemical plant. Frankfurt's air quality was not as good as today. The river's water was pitch black. A subsidiary of the conglomerate Hoechst AG, Messer Griesheim, was still in full operation. On rainy days the air smelled like in Philadelphia when you pass the refineries.

I remember vividly one occasion on which Mark tried hard with little success to convince his Frankfurter colleagues of the refined taste of the All-American soul food: peanut butter-and-jelly sandwiches. His wife had prepared plates piled high with more than enough for everybody. Not unlike Frankfurt's Aeppelwoi, peanut butter-and-jelly sandwiches are an acquired taste. Only those who have raised children on them will fully appreciate the profound usefulness and true satisfaction they deliver.

By contrast, Mark's work with Wolf Singer and colleagues was a convincing success. The team showed with elegant experiments published in the journals Nature (Bear and Singer, 1986) and Science (Kleinschmidt and others, 1987) and Nature that glutamate and the neuromodulators acetyl choline and norepinephrine play fundamental roles in the plasticity of domains of ocular dominance in visual cortex during postnatal development. The discovery of ocular dominance plasticity had won D.H. Hubel and T.N. Wiesel the Nobel Prize half a dozen years earlier (Hubel and Wiesel, 1998).

After his return to the U.S., Mark continued to investigate the role of glutamate in the organization of nerve cell circuits in cerebral cortex. In a long series of studies, he and his colleagues examined long-term potentiation (LTP) and long-term depression (LTD) as mechanisms for cortical plasticity. The elucidation of the underlying molecular mechanisms led to the G-protein-coupled metabotropic glutamate receptor mGluR5. By contrast to ionotropic receptors that regulate ion fluxes across cellular membranes important to electrical nerve cell signaling, metabotropic receptors regulate cell protein activity and homeostasis. The mGluR5-receptor appears to play a major role in FXS and autism. I have written about this in my post dated April 1, 2008. Designing antagonists against the receptor's actions promises a treatment. Mark points out in his interview with NPR that he was not planning on finding a cure for mental disorders. Things came together serendipitously. It was only with the support and encouragement of the Fragile X Research Foundation (FRAXA) that the work on a potential treatment began.

The National Institutes of Health (NIH) provide most funding for biomedical research in the U.S. Measured in inflation-adjusted dollars, the NIH have seen their budget erode in the past 8 years. By contrast, the number of applications for research grants has doubled. As consequence according to the NIH online report, the success rate of competitive grant applications diminished from 32 percent in fiscal year (FY) 2000 to 21 percent in FY 2007. The NIH were able to award about 41 percent of the total cost to new investigator-initiated applications (R01). These are proposals for projects that scientists submit based on their most recent findings. They advance the most innovative ideas and are most likely to lead to new discoveries. The success rate of R01 applications decreased to 19 percent in FY 2007 from 26 percent in FY 2000. The mounting budgetary constraints inevitably result in increasingly conservative funding decisions. Under these circumstances, it is not surprising that Mark Bear and his colleagues sought funding outside government for their novel ideas.

Addenda

  • First federal funds for research dry up. Now nonprofit private support evaporates. Read here (12/21/08).
  • Brain plasticity and memory share similar underlying molecular mechanisms. Recent studies have provided evidence that the brain-specific protein-phosphorylating enzyme protein kinase Mzeta (PKMzeta) is necessary to sustain LTP (Sacktor, 2008). Such enzymes commonly upregulate the activity of other enzymes. An increase in enzyme activity resulted in the doubling of postsynaptic glutamatergic ionotropic AMPA receptors, augmenting synaptic transmission in rodents. Inhibiting PKMzeta disrupts long-term memory (Serrano and others, 2008). Benedict Carey published an article entitled "Brain Researchers Open Doors to Editing Memory" in The New York Times on this research and its potential implications for future medical treatments today (04/05/08).
  • According to Lauran Neergaard's report for Associated Press with the title "Experiment Takes Aim at Genetic Learning Disorder" published online in The New York Times today, the first clinical trials to treat FXS in adults with mGluR5 antagonists are underway at five medical centers (02/01/10).
  • According to Gardiner Harris' report with the title "Promise Seen in Drug for Retardation Syndrome" for the New York Times dated Apr. 29, 2010, Novartis completed its first double blind study using its mGluR5 drug on adults with FXS with encouraging results. Details of the study were not disclosed (05/01/10).
  • In her report with the title "Special Report: new drugs, fresh hope for autism patients" published online on Reuters today, Julie Steenhuysen informs us how the search for new drugs to treat FXS and ASD has been shaping up. The article's focus is on the use of derivatives of the established psychoactive compound baclofen. Seaside Therapeutics Inc., co-founded by Mark Bear, is testing arbaclofen (STX209) in clinical trials. The compound acts as an agonist of the inhibitory neurotransmitter gamma-aminobutyric acid, or GABA for short. Baclofen binds to G-protein-coupled metabotropic GABAB-receptors and has traditionally been used to relieve skeletal muscle spasms. In contrast to the compounds acting on mGluR5-receptors discussed in the post, this drug modulates the effects of glutamate indirectly (Fejgin and others, 2009). Considering that more than 100 genes have been identified to play a role in autism, Dr. Edwin Cook's claim in Julie Steenhuysen's report that “many of the genes related to autism are right in the same pathway that has been implicated and worked out in Fragile X” does not come as a surprise (05/31/2012).
  • Two studies of note have been published online in Science Translational Medicine yesterday. Henderson and others (2012) showed in a fragile X mouse model, that The GABAB-receptor agonist arbaclofen alleviated known biochemical (basal protein synthesis), molecular (AMPA-receptor internalization), and cellular (dendritic spine density) manifestations of the disorder. In addition, Barry-Kravis and others (2012) report first encouraging results for arbaclofen in phase II clinical trials. The drug seems to improve social function (09/20/2012).
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