The relevance of the synapse is becoming more clear from Huda Zoghbi's findings in Rett syndrome and Thomas Südhof's mouse model of autism.

An estimated 5 to15 percent of cases stem from chromosomal abnormalities causing rare diseases with autistic features, such as Rett syndrome and fragile X syndrome. As for the remainder, no single gene has been linked to a large portion of cases. A likely scenario is that mutations or slight variants in a handful of genes, or maybe in hundreds of different genes, acting in combination account for most autism.

		In his classic 1943 paper, child psychiatrist Leo Kanner described the peculiar behaviors of 11 children he had observed in the late 1930s and early 1940s. He was most dismayed—and intrigued—by what he called their “profound aloneness.” These self-absorbed children didn't respond to their names or make eye contact, and their isolation was evident from their earliest days. In general, Kanner noted, they showed no more interest in people than in “the desk, the bookshelf, or the filing cabinet.” The disease, it was thought at the time, was rare, the cause unknown. Today, the label “autism” is applied to a spectrum of what are called “pervasive developmental disorders” (PDD), and it is still based on symptoms and behaviors. Disorders on the spectrum—including autistic disorder, PDD-NOS (not otherwise specified), childhood disintegration disorder, and Asperger's syndrome—range in severity from devastatingly disabling to so-called “high-functioning autism.” Rett syndrome is sometimes included on the more severe end of the spectrum. Autistic disorders, once considered rare, are now diagnosed in about 1 in 150 children. The Simons Foundation's Gerald Fischbach believes that the broadening definition of autism accounts for most of the increase. In addition, he says, the expansion of services for children with autism could be promoting more-frequent diagnoses. Delays in normal development, causing cognitive and social deficit, usually appear in the first two or three years. Autistic children may walk on their toes, flap their hands, or become fascinated with spinning things. They may be absorbed in obsessive rituals, such as lining up toys in peculiar ways, flipping light switches on and off, or unraveling their socks thread by thread. Boys are diagnosed with autism four times more often than girls. —R.S.

In the absence of any known biological abnormality or “biomarker” in autism, scientists' best bet is to hunt for altered genes in patients and families. Just such a discovery, in a rare syndrome caused by a single damaged gene, opened a new window on autism less than a decade ago.

In 1999, HHMI investigator Huda Zoghbi identified gene mutations that cause Rett syndrome—a rare, devastating “autism spectrum” disease that affects girls. After normal development for the first 6 to 18 months, affected girls' speech, motor control, and social development plateau and then deteriorate, accompanied by the onset of tremors, seizures, and stereotypic hand-wringing movements. Zoghbi, a pediatric neurologist and geneticist at Baylor College of Medicine, found that 95 percent of Rett cases involve mutations in a gene on the X chromosome called MECP2. “This was the first identification of a gene [mutation] in any developmental cognitive disorder,” observes Fischbach.

Zoghbi created a mouse model in which she has been studying the effects of the mutant gene. “MeCP2 is present in every mature neuron—thus, it is not surprising that it is important for social behavior and communication,” says Zoghbi. The MeCP2 protein regulates the activity of other genes in its pathway and also controls variable splicing of the genes' RNA blueprints to make different forms of the protein.

Zoghbi's group later described MECP2 mutations in a handful of girls and boys with autistic features who did not have Rett syndrome. Although MECP2 mutations don't appear to be very common in “pure” autism, findings by Zoghbi and others have shown that they can occur. These discoveries point a suspicious finger at synapses.

In 2007, Zoghbi and colleagues reported in Neuron that MeCP2 regulates the formation of synapses connecting neurons that secrete glutamate—an “excitatory” chemical messenger that causes neurons to fire. Glutamate is like a green light that encourages nerve signals to jump across the synapse; its opposite “red light” neurotransmitter is GABA, an inhibitor that quickly halts nerve firing when appropriate.

A proper balance of excitatory and inhibitory events is key for learning, memory, and other information-processing tasks. If there's a generalized excitatory-inhibitory imbalance, it might well explain why the autistic brain falters in trying to build networks for learning, language, and social awareness. In 2003, Zoghbi proposed that changes in the function of synapses may be a fundamental cause of neurological disorders—including autism.

Photos: Huda Zoghbi: Jack Thompson; Thomas Südhof: Misty Keasler

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