Neuroscientists Have Discovered A Clue To What Is Hidden Behind The Smiling Face Of A Child With Angelman Syndrome
    By Kathy Murphy | June 4th 2009 07:10 PM | 6 comments | Print | E-mail | Track Comments
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    Children with Angelman Syndrome develop normally until about 1 year of age and then their intellectual development stops.  They fail to develop language and other cognitive skills, are severely mentally handicapped,  but have a happy disposition, laughing, smiling and enjoying social interaction.  What could be behind this syndrome?

    A new study of Angelman Syndrome shows that an interaction between the genetic defect and sensory activity robs cortical synapses of their normal plasticity. Simply using the synapses depletes them of plasticity.  This leaves neural connections in the cortex rigid, unable to be fine tuned and to develop normal function.

    Angelman Syndrome is a form of mental retardation that results from a mutation in the UBE3A gene.  This mutation affects the production of the enzyme ubiquitin protein ligase 3A, a key player in the degradation of protein to remove damaged proteins and maintain the healthy functioning of cells.   In the brain, only the maternal copy of the UBE3A gene is active, so a random mutation of the maternal chromosome 15 between positions 11 and 13 can lead to Angelman Syndrome.

    Ubiquitin protein ligase 3A is not expressed in the brain of a mouse model for Angelman Syndrome with a mutation of the maternal copy of the UBE3A gene.  This mutation leads to a number of changes in the plasticity of hippocampal and cortical neurons.    A recent study of mice with the Ube3A deletion, led by Neuroscientists Dr. Ben Philpot at the University of North Carolina,  has made an important link between the deletion of Ube3A, the loss of synaptic plasticity, and sensory experience in Angelman Syndrome.

    During development the Ube3A mice had less spontaneous excitatory activity, fewer dendritic spines, no long term synaptic depression and needed much stronger stimulation to cause long term strengthening of the synapses (longterm potentiation - LTP).   The excitatory synapses seemed to be rigid and only changed when a very strong train of stimulation was applied.
    During normal development synapses are easily manipulated and fine tuned by the patterns of neural activity that are driven by experience.  But in the Angelman mice the synapses had shutdown this fundamental process of experience-dependent development.  They were defective in the experience-dependent development of excitatory neural connections.  The Ube4A mutation had effectively turned off the process that shapes the development neural circuits and supports the maturation of normal cognitive, perceptual, social, and emotional development.  

    But why was this happening?

    To figure out why the synapses were so rigid the neuroscientists used visual deprivation to eliminate sensory driven activity in visual cortex.  Just 2 weeks of dark rearing during the critical period was enough to restore synaptic plasticity.  This showed that the Ube3a mice are born with the mechanisms for long term potentiation and depression.  But the combination of no Ube3a protein and normal vision strips synapses their capacity to adapt to experience.

    The researchers asked:  What if deprivation occurs later in development?  They wanted to know if it is possible to restore synaptic plasticity when the Angelman mice are adolescents.  Surprisingly, just 10 days of dark rearing restored synaptic plasticity (long term depression) in adolescent Ube3a mice.

    The final experiment asked about function.  They used closure of one eye to challenge the neural circuits on Ube3a mice to change.  In normal animals, closing one eye causes a loss of connections to the deprived eye.  But nothing happened with the Ube3a mice.  Closing one eye in young Ube3a mice did not change the visual cortex, the circuits were unable to rearrange the connections in response to the abnormal experience.  This provides another piece of evidence that synapses of Angelman mice become fixed and don't respond to changes in experience that are crucial for normal development of the cortex.

    But all is not lost in the search for a treatment for Angelman Syndrome.  The researchers say that since the mechanisms for synaptic plasticity remain in Angelman mice it may be possible to develop a behavioral or pharmacological treatment that can help improve brain function in individuals with Angelman Syndrome.

    "By showing that brain plasticity can be restored in Angelman syndrome model mice, our findings suggest that brain cells in Angelman syndrome patients maintain a latent ability to express plasticity. We are now collaborating to find a way to tap into this latent plasticity, as this could offer a treatment, or even a cure, for Angelman syndrome," said Philpot.

    For more information about Dr. Philpot's research you can look at his website.

    For more information about the research paper on Angelman Syndrome you can read the abstract for the paper published in the journal Nature Neuroscience.  Nature Neuroscience 12, 777 - 783 (2009)  Ube3a is required for experience-dependent maturation of the neocortex, Koji Yashiro1,8, Thorfinn T Riday1,2, Kathryn H Condon3, Adam C Roberts1,4,5, Danilo R Bernardo1, Rohit Prakash1, Richard J Weinberg4,6, Michael D Ehlers3,7&Benjamin D Philpot1,2,4,5


    Thanks for the good reporting.  I admit I find the actual syndrome very chilling.  A mutation that makes you mentally retarded, but happy, sounds like a science fiction concept.  But as usual, reality is stranger than we can imagine.
    Great article, Kathy.

    I would like to know the effect of rearing these mice in specific light spectra/polarities, rather than dark alone.  Although few animals see in infra red, for example, most can sense it.  I'm also reminded of synaesthesia - the brain is such a complex device.  It's perverse, as well.  Bright light improves my depression, but the light reflected off water on a sunny day gives me a migraine.  I continually wonder why that should be so.  I think that genes are not so much selfish as sadistic.
    What timing! I just attended a talk by Aaron Ciechanover (of Nobel ubiquitin fame) earlier today where he spoke shortly on this very topic.

    A very excellent and important article.  The syndrome is very saddening for parents, especially.  Research progress is encouraging. The challenge, in my mind, is to investigate how to stimulate the brain to begin to cure itself.  Not being dreamy here.  I have seen real magic from the brain in cases of autism, traumatic head injuries and cerebral palsy.
    I hope you will track this area of research and give us follow ups.
    Thanks everyone for the very positive comments. 

    I too think this is an important area of research and I echo Waddell's comment about the need for more research on  "stimulating the brain to cure itself".   I'll keep an eye out for more research in that area to write about.  Perhaps I'll even write something about some of my research projects that are studying training induce recovery after early deprivation.
    Thank you Kathy, and I look forward to your future reports.