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PROTEINS ASSOCIATED WITH AUTISM SHOWN TO SUPPRESS PROPER SYNAPSE FORMATION: Genetic mutation leads to imbalance of inhibitory and excitatory synapses
Version of Record online: 22 APR 2013
Copyright © 2013 Wiley Periodicals, Inc.
American Journal of Medical Genetics Part A
Volume 161, Issue 5, pages vii–viii, May 2013
How to Cite
(2013), PROTEINS ASSOCIATED WITH AUTISM SHOWN TO SUPPRESS PROPER SYNAPSE FORMATION: Genetic mutation leads to imbalance of inhibitory and excitatory synapses. Am. J. Med. Genet., 161: vii–viii. doi: 10.1002/ajmg.a.35976
- Issue online: 22 APR 2013
- Version of Record online: 22 APR 2013
Mutations in genes that express MAM domain-containing glycosyl-phosphatidylinositol anchors (MGDAs) cause faulty synapse development, resulting in an imbalance of inhibitory and excitatory neurons that may be involved in autism, according to researchers at the University of British Columbia (UBC) in Vancouver, Canada.
Synapses—small gaps at the end of neurons that allow information to pass from one neuron to the next—are located where nerve cells connect and are the basic units of communication in the brain. While synapses develop, many types of cell adhesion molecules connect neurons and organize proteins. Some mutations in genes that express these proteins have been associated with autism and schizophrenia. These include genes for neuroligin and neurexin [Betancur et al., 2009; Bourgeron et al., 2009].
In a recent paper published in the Journal of Cell Biology, the UBC research team led by Katherine L. Pettem, PhD, suggests that excess MDGA1 binds to neuroligin-2, which helps organize inhibitory neuron connections [Pettem et al., 2013]. That excess MDGA1 prevents neuroligin-2 from binding with neurexin, which normally helps glue together neurons in synapses. The result is an imbalance marked by too many excitatory synapses and too few inhibitory synapses, the researchers write. They note that MDGA1 is one of the very few identified negative regulators of synapse development.
Moreover, the team focused on MDGAs because particular portions of the proteins, called domains, are similar to other cell adhesion and synapse-organizing proteins also implicated in autism and other neurodevelopmental disorders.
Their findings show that MDGAs are in the same pathway as neurexin and neuroligin, and provide further evidence that the synapse-organizing proteins, and the genes that express them, have a role in autism [Pettem et al., 2013].
The research also “presents a very plausible model of how an imbalance in inhibitory and excitatory synapses could lead to autism,” says biochemical genetics researcher Gerard Berry, MD, Director of the Metabolism Program at Boston Children's Hospital in Massachusetts.
Impetus for Study
The findings by the UBC team build on earlier research that identified multiple protein-truncating variants in MDGA2 in DNA from 912 unrelated patients with autism in the Autism Genetics Resource Exchange. But, these variants were not found in 1,488 healthy controls [Bucan et al., 2009].
UBC researcher and senior author Ann Marie Craig, PhD, Professor of Psychiatry at UBC in Vancouver, Canada and the university's Canada Research Chair in Neurobiology, said for the current study, the team focused on MGDA1, which has less evidence linking it to autism. Using an assay that promotes artificial synapse formation between nerve cells and non-neuronal cells, Dr. Craig and her colleagues found that MDGA1 didn't drive synapse formation. Instead, MDGA1 prevented neuroligin-2 from promoting synapse development. Some of MDGA1's domains bound to neuroligin-2, blocking its interaction with neurexin.
These observations suggest that, by inhibiting neuroligin-2, MDGA1 might specifically suppress the development of inhibitory synapses. Dr. Craig and her colleagues then investigated MDGA1 function in cultured hippocampal neurons. Overexpressed MDGA1 in these neurons reduced the density of inhibitory synapses without affecting excitatory synapses. “Knocking down MDGA1, on the other hand, increased inhibitory synapse development but had no effect on excitatory synapses,” Dr. Craig notes.
Possibly, A new Model
“If in fact a disturbance in synaptic connections and imbalance in excitatory and inhibitory synapses is necessary and sufficient to cause autism, this paper gives us a new way to view how it develops,” says Dr. Berry.
Noting that many processes “must go right” to make a properly functioning nerve terminal, Dr. Berry says the model presented in the paper may explain the continuum of severity of neurodevelopmental disorders geneticists see in the clinic. While some patients have behavioral problems of varying degrees, but show little or no cognitive impairment, others patients' cognitive impairment is so serious that expression of behavioral problems is limited. “Maybe if synapse formation fails altogether, the clinical picture may simply be that of a severe encephalopathy,” he says, adding that a patient has to have sufficient cognitive ability to show symptoms of autism or psychiatric disease like schizophrenia.
There may be a very large number of genes that, if mutated, could perturb the system of synapse development, says Dr. Berry, adding that, “Even deficits in local energy metabolism may impair synaptic development.”
Others are less enthusiastic about the model presented in the paper. “It's potentially important,” says William B. Dobyns, MD, Professor of Pediatrics and Neurology, University of Washington in Seattle, and Principal Investigator at the Center for Integrative Brain Research at Seattle Children's Research Institute in Washington. “It's likely there are underlying pathways common in different causes of autism. Possibly, inhibitory regulation in brain is important.”
Dr. Dobyns emphasizes the disorder's heterogeneity and plethora of genetic causes. “Only a very small percentage of patients with autism will have these [MDGA1] mutations,” he notes, adding that other research has found MDGA2 mutations in people with autism.
Dr. Craig says autism's heterogeneity is an important factor in developing therapies. “Better understanding of the heterogeneous nature of autism spectrum disorders, particularly in relation to genetic alteration” is needed, she says. With that understanding, she hopes to explore the therapeutic potential of MDGA1 inhibitors for autism and schizophrenia, as well as epilepsy, which also involves an imbalance of excitatory and inhibitory synapses.
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