 |
|
|
MIT corrects inherited retardation, autism in mice
December 19, 2007
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, indicates that
a certain class of drugs could have the same effect in humans. These drugs are
not yet approved by the FDA, but will soon be entering into 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.
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
|
"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 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.
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.
In addition to Bear, authors include Brown University graduate student Gül Dölen;
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.
| |
