Autism Vox

Autism’s Cause at the Synapse?

by Kristina Chew, PhD on July 14th, 2007

An article in the July 13th Science magazine notes that Autism’s Cause May Reside in Abnormalities at the Synapse:

New genetic evidence is leading researchers to home in on the cleft separating neurons as the site where the disorder may originate.

(The full text is available via subscription.)

Huda Zoghbi, a pediatric neurologist at Baylor College of Medicine in Houston, TX, first proposed that the origins of autism are at the synapse in 2003. Synapses are “junctions across which neurons communicate” and are essential for “virtually all brain function”—memory, sensory perception, motor coordination, learning. Zoghbi’s hypothesis rested on research done by a group led by Thomas Bougeron of the Pasteur Institute in Paris that found mutations in proteins called neuroligins in two pairs of Swedish brothers who have autism. Neurologins ensure that signal transitions between nerve cells function and are “expressed on the surface of the postsynaptic neuron” and bind to neurexins, which are proteins on the presynaptic neuron. It is thought that neuroligins and neurexins together “play key roles in the forming and functioning of synapses.” Bougeron has postulated that there is a “neuroligin autism pathway” in which “abnormalities in any of these dozen or more proteins could predispose their possessors” to autism spectrum disorder.

New evidence, Science notes, is lending support to Bougeron’s “neurologin autism pathway” and also to Zoghbi’s hypothesis. The “new genetic evidence” is the data from the 5-year-study on the genetics of autism led by the Autism Genome Project Consortium, which involves scientists from 50 institutions in 19 countries. Two new genetic links that may predispose a child for autism were found:

The study incriminated a gene called neurexin 1 involved with glutamate, a brain chemical previously implicated in autism that plays a role in early brain development, as a possible susceptibility gene for autism. A previously unidentified region of chromosome 11 also was implicated.

Neurexins are “a large family of proteins that act as neuronal cell-surface receptors” (Nature Neuroscience 6, 708 - 716 (2003) ); they and neuroligins have been implicated as having a role in autism.

Notes the Science magazine article:

Now the race is on to figure out how neuroligins and their binding proteins are contributing to autism…….

…..One theory is that an abnormal neuroligin pathway upsets the balance of excitatory and inhibitory synapses in neurons, thereby affecting learning and memory, and thus language and social communication. Broadly speaking, synapses can be either excitatory, when the neurotransmitter glutamate is released, or inhibitory, with release of the neurotransmitter gamma-aminobutyric acid (GABA). The ratio of excitatory and inhibitory synapses on a neuron determines whether it will fire in any given situation. In the June 21 issue of Neuron, [Thomas] Südhof [a neuroscientist at the University of Texas Southwestern in Dallas; his lab discovered neurexins in 1992 and neuroligins in 1995] reported that in experiments in cells, overexpressing neuroligin-1 leads to excitatory transmission at synapses, whereas neuroligin-2 overexpression leads to inhibition. Südhof speculates that an alteration in either neuroligin could change the excitatory-inhibitory balance, subtly changing the number of neurons that are firing during brain development. Such disruptions could eventually produce the lasting symptoms of autism, he explains, because synapses change with use, becoming more or less sensitive to stimuli depending on experience. This “synaptic plasticity” is the basis of learning and memory.

That’s just one possibility. The synapse is extraordinarily complex, both chemically and structurally, and a lot could go wrong there as the brain develops. Studies in animals to understand the different components of the synapse and to determine mutation effects are just beginning.

Many research groups are now focusing on finding links between synapse genes and autism………

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POSTED IN: Genetics, Neuroscience, Science