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 GABA_B-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 GABA_B-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).

References

• Bear MF, Singer W (1986) Modulation of visual cortical plasticity by acetylcholine and noradrenaline. Nature 320: 172-176.
• Berry-Kravis EM, Hessl D, Rathmell B, Zarevics P, Cherubini M, Walton-Bowen K, Mu Y, Nguyen DV, Gonzalez-Heydrich J, Wang PP, Carpenter RL, Bear MF, Hagerman RF (2012) Effects of STX209 (Arbaclofen) on Neurobehavioral Function in Children and Adults with Fragile X Syndrome: A Randomized, Controlled, Phase 2 Trial. Sci. Transl. Med. 4, 152ra127.
• Fejgin K, Erik Pålsson E, Wass C, Finnerty N, Lowry J, Klame D (2009) Prefrontal GABA_B Receptor Activation Attenuates Phencyclidine-Induced Impairments of Prepulse Inhibition: Involvement of Nitric Oxide. Neuropsychopharmacol 34: 1673–1684.
• Henderson C, Wijetunge L, Kinoshita MN, Shumway M, Hammond RS, Postma FR, Brynczka C, Rush R, Thomas A, Paylor R, Warren ST, Vanderklish PW, Kind PC, Carpenter RL, Bear MF, Healy AM (2012) Reversal of Disease-Related Pathologies in the Fragile X Mouse Model by Selective Activation of GABA_B Receptors with Arbaclofen. Sci. Transl. Med. 4, 152ra128.
• Hubel DH, Wiesel TN (1998) Early Exploration of the Visual Cortex. Neuron 20: 401-412.
• Kleinschmidt A, Bear MF, Singer W (1987) Blockade of "NMDA" receptors disrupts experience-dependent plasticity of kitten striate cortex. Science 238: 355-358.
• Sacktor TC (2008) PKMzeta, LTP maintenance, and the dynamic molecular biology of memory storage. Prog Brain Res 169: 27-40.
• Serrano P, Friedman EL, Kenney J, Taubenfeld SM, Zimmerman JM, Hanna J, Alberini C, Kelley AE, Maren S, Rudy JW, Yin JC, Sacktor TC, Fenton AA (2008) PKMzeta maintains spatial, instrumental, and classically conditioned long-term memories. PLoS Biol 6:2698-2706.
  

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The Brain: A Giant Self-Medicating Gland

The use of psychoactive drugs is older than humanity. Primates have been observed to deliberately feast on fermenting fruit rich with alcohol. The debate over the benefits and perils of treating mental disorders with psychoactive drugs has been unrelenting and passionate among patients, physicians and scientists. Alternative treatments promising improvement are hotly disputed. Two recent articles in The New York Times highlight the substantial public attention paid to these issues.

The first one, published online Apr. 15, 2008, was written by Richard Friedman M.D., a concerned physician who worries about the presently unknown health effects of life-long medication beginning at an age when our brain still develops. The prescription of anti-depressants to youngsters diagnosed with adolescent depression is used as an example. Brain and mind may develop differently with the constant exposure to these drugs. The body will be burdened with a foreign compound for a life time. The author argues convincingly that more research is needed to examine the long-term effects of the chronic exposure to psychoactive drugs. This concise, informed, and sensitive contribution initiated comments from 360 readers.

The second article, published online Jun. 16, 2008, is a post by Tara Parker-Pope describing therapies for Attention Deficit Hyperactivity Disorder alternative to conventional drug treatments. The article has attracted 160 comments to date. Prudence is advised when examining the options discussed in this post. The assessment of recently developed treatments is wrought with difficulty. The time for gathering experience with a novel therapy is commonly too short to allow a valid comparison with the risk/benefit analyses of established therapies supported by large bodies of data.

It is important to emphasize that any type of intervention will influence the biochemical make-up of the brain. The nerve cells in the brain produce psychoactive substances and modify their production at all times. The nerve cells excrete chemical substances known as neurotransmitters to communicate with each other. Neurotransmitters affect the behavior of nerve cells immediately. The predominant excitatory neurotransmitter is glutamate. Glutamate bound to specific receptors on the cell body surface stimulates the production of electrical signals known as action potentials. Action potentials travel along the nerve cell's outgoing arbor, i.e. its axon, and exact the release of neurotransmitters at its contacts with other nerve cells known as synapses. Gamma-aminobutyric acid, by contrast, inhibits the production of action potentials. Acetylcholine, norepinephrine, dopamine, and serotonin may influence neural behavior more persistently and are also known as neuromodulators, playing crucial roles in psychiatric disorders. Opiates constitute the purest type of neuromodulator, because they do not act as neurotransmitters. Eventually, it is important to understand that some neurotransmitters can excite or inhibit nerve cells, depending on the type of receptor they bind to.

Compared to neurotransmitters and neuromodulators, however, hormones exert the longest lasting effects on the brain. When I was a student I participated in research on the Siberian hamster Phodopus sungorus of Siberia in the laboratory of Professor Gerhard Heldmaier (Rafael and others, 1985). These amazing creatures are only the size of a mouse. Yet, they cope with the frigid temperatures of Siberian winters. They grow a thick white coat for the winter and can rely on paws padded with dense fur even on the palms. But, the key to the hamsters' survival is the brown body fat, known as brown adipose tissue or BAT for short, that they build up before snow fall sets in. The hamsters are crepuscular, that is they are most active during the twilight hours of the day. As the light grows more orange and the days grow shorter, the hamsters forage more intensely for food, almost double their body weight, and their physiology changes. Come Winter, the hamsters can resist deep freezer temperatures as low as -70 °C for many hours without any harm, using their brown body fat to maintain body temperature. When the brown fat is depleted, they begin to shiver and die in short time. By contrast, animals unconditioned during the autumn would perish already at -30 °C.

The hormone melatonin is thought to play a crucial role in the hamsters' seasonal behavioral and physiological changes. Nerve cells in the brain's pineal gland secrete this hormone into the blood stream. The cells are light sensitive and increase hormone production, when the animals are more exposed to long wavelength-rich autumn light and extended nights. Heldmaier and others (1981) observed that hamsters that were artificially maintained at long daylight hours in the autumn, developed only mild cold resistance. However, their sensitivity to melatonin was enhanced. Chronic administration of melatonin increased cold resistance in these animals. By contrast, short daylight-adapted hamsters showed the anticipated increase in cold resistance and no sensitivity to melatonin treatment. Summer- and winter-adapted hamsters are shown in the video below.

Melatonin does not only govern the Siberian hamster's life. It plays a crucial role in the bouts of depression that people living above the polar circle confront during the long and dark winters. The control of nerve cell function through a substance that nerve cells produce in response to environmental changes constitutes a powerful demonstration of experience-dependent brain self-administration.

Normally, the nerve cells in our brain are well poised to maintain control over the diverse processes that keep our brain's biochemistry in balance. However, genetic predisposition, developmental mishaps, and traumatic experience may sway that balance toward extremes beyond control. We may be able to bounce back by just taking time out, re-balancing our brain and calming our mind. If our own coping mechanisms do not suffice, we need professional help.

Psychotherapies have proven effective for some. Yet, success seems subtle. Time is needed to produce measurable results. By contrast, drugs targeting specific neurotransmitters are known to restore functionality quickly and robustly. An overwhelming number of comments from affected people sent to The New York Times supports this contention. But, there is no reason to believe that substances purified from natural products should be a priori more beneficial than pharmaceuticals synthesized in laboratories, solely because the former originate in nature. Only thorough research and experience will tell which drugs produce positive results regardless of provenance.

Drug therapies entail one drawback. The substances are administered systemically. That is, they are injected or ingested and absorbed by the whole body, although their intended targets may only consist of small regions of the brain. Other organs may be susceptible to the drugs. notably, the walls of the intestines contain more nerve cells than the brain. The intestinal nerve cells possess receptors similar to those found on brain nerve cells and may respond to the drugs with adverse effects on digestive function.

Moreover, drugs accumulate in the liver. Foreign chemical compounds are made water-soluble by oxidative liver enzymes. The increased concentration of the drugs may induce detrimental hyperactivity of these enzymes. The load that the metabolites add to the kidneys, where they are excreted with the urine, may damage kidney tissue. The risks mount, when medication begins early in life. But as Dr. Friedman so validly pointed out in his article, we simply do not know at present what the precise consequences of the life-long exposure to psychotherapeutics will be.

Therapies that are targeted only to the brain regions involved in the disorder would reduce the risk of adverse effects. Psychotherapeutic drugs are designed to target specific receptors on nerve cells and modify the molecular pathways that are particularly involved in a specific disorder. However, their action could be directed to specific brain regions only, if they were infused directly into the tissue, requiring a craniotomy.

By contrast, biofeedback-based therapies may improve nerve cell function locally without invasive intervention. Cognitive therapies can be considered as providing biofeedback, if they concentrate on the behavioral manifestations of the disorder and address specific symptoms. Conscientious modification of behavior may re-adjust the biochemical balance of the involved brain regions and this re-adjustment may conversely improve the behavior. Other therapies involving biofeedback consist of learning to play a musical instrument or a sport. These methods challenge sensory and motor skills. They demand focus and render immediate sensory feedback. With practice, brain function and skill improve concomitantly.

Neurofeedback, e.g. BrainMaster, is a technologically more sophisticated extension of the behavioral interventions described above. Electrical brain waves are recorded from the scalp with button electrodes. The power of these brain waves is used to inform the participants whether they are making progress in the desired direction. The measurements can be displayed in dynamic graphs on computer screens or integrated into computer games. I have written about such electroencephalographic techniques and the experience I had with equipment manufactured by J&J Engineering in my post published on this site on May 24, 2008. The brain waves of interest are known as alpha waves. Their profound role in mental focus can be explored with Mind ball popular in science museums.

Neurofeedback is an emerging technology and several comments to Parker-Pope's article lament its shortcomings with frustration. The applications using this technology must be sufficiently flexible to accommodate the very specific needs of the participants. Costly, time-consuming experimentation may be needed to find effective parameters in each instance. Moreover, the recordings of the minuscule surface potentials from the scalp are sensitive and easily compromised. Thick hair diminishes conductance and attenuates the strength of the recordings. Firm contact between the electrodes and the scalp needs to be established with sufficient amounts of conductance paste that must not dry out during the session. The impedance of the electrodes needs to be held stable to produce accurate and reproducible measurements of brain wave power. Thus, participants need to be fully cooperative and must be careful not to pull on the recording wires. Failing at any step may render the whole session useless.

References

• Heldmaier G, Steinlechner S, Rafael J, Vsiansky P (1981) Photoperiodic control and effects of melatonin on nonshivering thermogenesis and brown adipose tissue. Science 22:917-919.
• Rafael J, Vsiansky P, Heldmaier G (1985) Increased contribution of brown adipose tissue to nonshivering thermogenesis in the Djungarian hamster during cold-adaptation. J Comp Physiol B 155:717-722.

Revised: 01/30/2012