mGluR5 Spells Hope For Autism

Mark Bear, director of the Picower Institute and Picower Professor of Neuroscience (right), and Gül Dölen, a graduate student at Brown University,
report the correction of fragile X syndrome in mice. Photo / Donna Coveney

MIT News

Parents of autistic children have been preyed upon by purveyors of unproven treatments for their children's autism. But today there is hope, real hope, for autistic persons and the family members who care about their autistic children. Hope for an effective medical autism treatment is no longer something peddled by charlatans. We can now see it. We can even spell it. Hope for autism is spelled mGluR5.

mGluR5 is the shorthand for a metabotropic glutamate receptor. It was featured in the study led by Mark F. Bear, director of the Picower Institute and Picower Professor of Neuroscience at MIT published in the December 20 2007 edition of Neuron. The study by Professor's Bear's team supports the theory that many of FXS's (Fragile X's) psychiatric and neurological symptoms--learning disabilities, autistic behavior, childhood epilepsy--stem from too much activation of one of the brain's chief network managers, the metabotropic glutamate receptor mGluR5. As reported in MIT News:

Bear and colleagues study how genes and environment interact to refine connections in the brain. Synapses are the brain's connectors and their modifications are the basis for all learning and memory. There's a growing consensus among researchers that developmental brain disorders such as FXS, autism and schizophrenia should be considered "synapsopathies"--diseases of synaptic development and plasticity (the ability to change in response to experience).

Dendritic spines--little nubs on neurons' branchlike projections--receive many of the synaptic inputs from other neurons. Abnormal spines have long been associated with various forms of human mental retardation. In FXS, spines are more numerous, longer and more spindly than they should be. Thin spines tend to form weak connections.

The research team found that a 50 percent reduction in mGluR5 fixed multiple defects in the fragile X mice. In addition to correcting dendritic spines, reduced mGluR5 improved altered brain development and memory, restored normal body growth and reduced seizures--many of the symptoms experienced by humans with FXS.

The researchers used genetic engineering to reduce mGluR5, but a drug could accomplish the same thing. Although not yet approved by the FDA, mGluR5 blockers are entering into human clinical trials. "Insights gained by this study suggest novel therapeutic approaches, not only for fragile X but also for autism and mental retardation of unknown origin," Bear said.

As Christmas approaches families with autistic children may already have received our most wondrous gift of all - the knowledge necessary to provide an effective medical treatment for autism.

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MIT corrects inherited retardation, autism in mice

Wow! This could be the best autism news of all in the year of the Autism Knowledge Revolution.


MIT corrects inherited retardation, autism in mice

Research points to potential drug treatment

CAMBRIDGE, Mass.- Researchers at MIT's Picower Institute for Learning and Memory have corrected key symptoms of mental retardation and autism in mice.

The work, which will be reported in the Dec. 20 issue of Neuron, also indicates that a certain class of drugs could have the same effect. These drugs are not yet approved by the FDA, but will soon be entering into human clinical trials.

Fragile X syndrome (FXS), affecting 100,000 Americans, is the most common inherited cause of mental retardation and autism. The MIT researchers corrected FXS in mice modeling the disease. “These findings have major therapeutic implications for fragile X syndrome and autism,” said study lead author Mark F. Bear, director of the Picower Institute and Picower Professor of Neuroscience at MIT.

The findings support the theory that many of FXS's psychiatric and neurological symptoms-learning disabilities, autistic behavior, childhood epilepsy- stem from too much activation of one of the brain's chief network managers-the metabotropic glutamate receptor mGluR5.

“Fragile X is a disorder of excess-excess synaptic connectivity, protein synthesis, memory extinction, body growth, excitability-and remarkably, all these excesses can be reduced by reducing mGluR5,” said Bear, a Howard Hughes Medical Institute investigator.

Individuals with FXS have mutations in the X chromosome's FMR1 gene, which encodes the fragile X mental retardation protein, FMRP. The MIT study found that FMRP and mGluR5 are at opposite ends of a kind of molecular seesaw. They keep each other in check, and without FMRP, mGluR5 signals run rampant.

Bear and colleagues study how genes and environment interact to refine connections in the brain. Synapses are the brain's connectors and their modifications are the basis for all learning and memory. There's a growing consensus among researchers that developmental brain disorders such as FXS, autism and schizophrenia should be considered “synapsopathies”- diseases of synaptic development and plasticity (the ability to change in response to experience).

Dendritic spines--little nubs on neurons' branchlike projections-receive many of the synaptic inputs from other neurons. Abnormal spines have long been associated with various forms of human mental retardation. In FXS, spines are more numerous, longer and more spindly than they should be. Thin spines tend to form weak connections.

The research team found that a 50 percent reduction in mGluR5 fixed multiple defects in the fragile X mice. In addition to correcting dendritic spines, reduced mGluR5 improved altered brain development and memory, restored normal body growth, and reduced seizures-many of the symptoms experienced by humans with FXS.

The researchers used genetic engineering to reduce mGluR5, but the same thing could be accomplished by a drug. Although not yet approved by the FDA, mGluR5 blockers are entering into human clinical trials. “Insights gained by this study suggest novel therapeutic approaches, not only for fragile X but also for autism and mental retardation of unknown origin,” Bear said.

Earlier this year, MIT Picower Institute researcher Susumu Tonegawa and colleagues reported positive results using a different approach to reversing FXS symptoms. Tonegawa and colleagues identified a key enzyme called p21-activated kinase, or PAK, that affects the number, size and shape of connections between neurons.

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In addition to Bear, authors include Brown University graduate student Gul Dolen; Picower Institute postdoctoral fellow Emily Osterweil, B.S. Shankaranarayana Rao of the National Institute of Mental Health and Neuroscience in India; MIT graduate students Gordon B. Smith and Benjamin D. Auerbach; and Sumantra Chattarji of the National Center for Biological Sciences and Tata Institute of Fundamental Research in India.

This work is supported by the National Institute of Mental Health; the National Institute of Child Health and Human Development; the National Fragile X Foundation; FRAXA, a Fragile X research foundation; and the Simons Foundation.

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Autism and the Missing Protein

The autism buzz in the news today arises from the publication in Neuron of a study led by Li-Huei Tsai, PhD, and Picower Professor of Neuroscience at the Massachusetts Institute of Technology (MIT) which suggests that a missing protein may be the key to autism. The brain protein helps synapses develop, the synapses through which neurons convey information, and which are the basis for memory and learning ability development.

As explained by Debbie Halber, Picower Institute for Learning and Memory at MIT, in Missing protein may be key to autism, the study uncovers an enzyme, called Cdk5, that is a key to the activity of the missing protein. Cdk5 is a "kinase", an enzyme that changes proteins, and interacts with a protein called CASK, which is itself important for developing synapses. The absence of Cdk5 can result in the CASK not being present to perform its role:

""Without Cdk5, CASK was not in the right place at the right time, and failed to interact with essential presynaptic components. This, in turn, led to problems with calcium influx." The flow of calcium in and out of neurons affects processes central to nervous system development and plasticity--its ability to change in response to experience. Gene mutations and/or deletions in synaptic cell surface proteins and molecules called neurexins and neuroligins have been associated with autism. The problem with CASK recruitment investigated by the Tsai laboratory creates the same result as these genetic changes."

In comments reported on Reuters, in Missing protein may underlie autism: U.S. study, Tsai was clear about the significance of Cdk5 failing to facilitate CASK in the development of autism:

""We show that if Cdk5 fails to facilitate CASK, then there is a very profound defect in synapse formation, ....

The most accepted hypothesis for autism is that there is a defect in synapse formation," Tsai said, adding that mutations of genes directly connected to CASK have already been identified as being associated with autism.

Mutations of CASK and Cdk5 are also identified in certain patients with mental retardation.

"I think this study strongly suggests this pathway involving Cdk5 ... is intimately involved (in autism)," she said.

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