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Deciphering A Mystery: New Research Provides Clues To The Genetic, Neurological, And Molecular Basis Of Autism

November 3, 2004
Society For Neuroscience
In new research, scientists have found that a specific gene contributes to autism and that autistic people have fewer receptors for the brain messenger acetylcholine, as well as more tightly packed columns of neurons in the cerebral cortex. Another study found that autistic children were less able to discriminate similar sounds than were other children.


In new research, scientists have found that a specific gene contributes to autism and that autistic people have fewer receptors for the brain messenger acetylcholine, as well as more tightly packed columns of neurons in the cerebral cortex. Another study found that autistic children were less able to discriminate similar sounds than were other children.

The research is providing new clues to the genetic, neurological, and molecular basis of this still mysterious disease.

Autism is a devastating disorder that affects two to six of every 1000 children—mostly boys. Autism actually encompasses a wide array of symptoms—called autism spectrum disorder (ASD)—including various degrees of behavioral, developmental, and sensory deficits. Many people first became aware of autism with the 1988 movie Rain Man, starring Dustin Hoffman as a middle-aged autistic man. Hoffman portrayed an autistic savant with tremendous mental capabilities. In reality, only about 10 percent of autistic people display signs of genius—typically in mathematics, music, and art.

Although autism has long been identified as a genetic disease, the genes that contribute to autism have been difficult to track down. Unlike Huntington's disease or Down syndrome, in which a single gene or an entire chromosome is inherited, many gene mutations are probably involved in autism. Now the laboratories of James Millonig, PhD, and Linda Brzustowicz, MD, at the University of Medicine and Dentistry of New Jersey and Rutgers University have isolated a specific gene that contributes to ASD.

In searching for the gene, the researchers focused on previous research showing that autistic people often have a smaller cerebellum, a separate structure at the back of the brain. “The cerebellum is thought to control many of the functions that are impaired in autistic children, such as language and attention span,” Millonig says.

Their next clue came from studies of mutant mice. Mice with a mutation in the ENGRAILED 2 (EN2) gene also have a smaller cerebellum. And while scientists had not yet pinpointed a gene that causes autism, they had identified a particular region of a chromosome that is inherited by autistic children more often than their nonautistic siblings—a clue that the region contributes to the disease. Millonig and Brzustowicz realized that this identified region contains the EN2 gene.

In earlier work, Millonig and his colleagues found two heritable variations in the DNA sequence of the EN2 gene. “These specific variations were twice as likely to be inherited by autistic siblings,” says Millonig. In the original study, published in the May 2004 issue of Molecular Psychiatry , the group tested the DNA of 167 families with autism. They have now repeated those tests in an additional 381 families. The evidence from the total of 548 families strengthens the case for EN2 as an autism gene.


The EN2 gene encodes a protein called a transcription factor that binds to cells' DNA to control the expression of dozens or even hundreds of other genes. Therefore, a variation in EN2 could have far-reaching effects on brain development and behavior.

The next step in this line of research will be to show that the variations in EN2 have an effect on the transcription factor's function. “We hope that by identifying this and other genes involved in autism, we will be able to detect individuals at high risk for autism and use early interventions to lessen the symptoms as they develop,” Millonig says.

In other research, Gene Blatt, PhD, and his colleagues at the Boston University School of Medicine found that a specific type of receptor for the neurotransmitter acetylcholine was expressed at lower levels in a specific brain area of autistic people compared with controls.

Neurotransmitters are small molecules that bind at specific receptors on neurons to send either inhibitory or excitatory signals. Communication throughout the brain depends on complex circuits between cells sending these messages to one another. Blatt hypothesizes that in autism the delicate balance of excitatory and inhibitory input to specific brain areas may be disrupted.

“By determining what neurochemicals are affected in the autistic brain, we can begin to understand the underlying mechanisms that give rise to the behaviors we see with autism,” Blatt says.

In previous work, Blatt identified changes in the inhibitory neurotransmitter GABA. Those changes occurred specifically in the hippocampus—a brain structure crucial to learning and memory—and in the cerebellum. They also found a decrease in the type 2A receptors for serotonin, another neurotransmitter, in an area of the cortex.


Work from another group then identified changes in the receptors for an excitatory neurotransmitter, acetylcholine. In autism, fewer receptors appeared in specific areas of the cerebral cortex, which is used for complex thought processing. All this prior research suggests that multiple neurotransmitter systems are affected in autism.

In the present study, Blatt and his colleagues examined tissue samples from the brains of four autistic patients and four nonautistic people, aged 19 to 30. They found a decrease in type-2 muscarinic receptors, one of the receptor types for acetylcholine. To see these changes, they used a radioactive labeling chemical that binds specifically to the muscarinic receptors.

The inferior olive (IO) is a brainstem structure that forms a direct line of communication to the cerebellum. Blatt had theorized that the IO might be a site where receptor levels were different, because the size of the individual IO neurons is affected by autism. The decreased receptor expression appeared only in one specific area of the IO, called the medial accessory olive. In four other subregions of the IO, the labeling revealed no difference between autistic and control brains.

“These studies not only reveal important changes in the neurotransmitter systems of autistic brains, but also the specific regions of the brain in which they occur,” says Blatt. “Together, this information may ultimately help guide pharmaceutical companies to develop drugs that specifically target the underlying causes of autism and not just the behavioral symptoms.”

Daniel Buxhoeveden, PhD, of the University of South Carolina looked for differences in the organization of neurons within the autistic brain. He and his colleagues, Eric Courshesne, PhD, and Katerina Semendeferi, PhD, of the University of California, San Diego, saw changes in specific regions of the cortex that provide clues to the neural makeup of autistic behaviors.

Cells of the cerebral cortex are arranged into functional units called mini-columns. Each of these tiny vertical structures is made up of about a hundred neurons that act as a cohesive unit. The axons and dendrites, which neurons use to send and receive information, form fiber bundles that connect the columns to one another. “These connections for incoming and outgoing information are analogous to wires in a computer,” says Buxhoeveden.

In tissue samples from two autistic brains—one a 41-year-old adult and the other a three-and-one-half-year-old child—the mini-columns of neurons appeared narrower and closer together, and therefore more numerous than in the brains of three normal adults. The tightly packed columns turned up only in particular areas of the cortex, however. The researchers saw the greatest difference in a region of the brain thought to be the site of the most complex processing—the frontal cortex. The part of the cortex that processes visual information contained normal-looking columns.

The autistic child had the same size columns as the adult autistic patient,” says Buxhoeveden, “suggesting an unusually rapid early development like that seen in Down syndrome.”

Because the column units are smaller and more densely packed in these autistic brains, yet the brain size remains the same, the autistic brain appears to contain more of the processing units, says Buxhoeveden. Returning to the computer analogy, he considers the implications: “Computer modeling has shown that having smaller processing units allows for greater fine-tuning of information,” he says. “Incoming signals can be distributed over more units, thereby allowing each unit to handle a more specific part of the overall signal.”

Such improved processing might manifest as the potential for the great mental capabilities seen in autistic savants, although this is strictly speculative, says Buxhoeveden. “Alternatively,” suggests Courshesne, “the smaller mini-columns may have reduced functional capacity, which may explain why autistic children have reduced ability to process complex social and emotional information.”

Another group of researchers used neuroimaging coupled with measurements of human behavior to investigate the autistic brain. Nicole Gage, PhD, at the University of California , Irvine , used magnetoencephalography ( MEG ) to explore the neural correlates of sound sensitivity and language deficits in autistic children. Many children with autism are delayed in the development of language, either not speaking at all or with very limited language capability.

Autistic children often also have a peculiar sensitivity to sound. “Autistic people can become quite anxious and upset when they hear certain types of sounds,” Gage says. Her goal is to define the brain systems that are responsible for these impairments.

First, she tested both autistic and typical children, ages 8 to 11 , on their ability to discriminate similar sounds from one another. Although neither group of children performed as well as adults, autistic children showed poorer performance than nonautistic children their age. This test presented a simplified version of the ability to discern the complex features of human speech.

Next, the children performed the same task while the scientists used MEG to measure brain activity from the auditory cortex, which processes the sensation of sound. MEG is a noninvasive technique that is highly sensitive to the brain's response to sounds. This work is among very few MEG studies carried out with autistic children.

The researchers measured a brain response called the M100, a neuromagnetic signal that reflects the cortex's activity after a sound is presented. The studies revealed a “flattened” brain response to sound in autistic children. “The children with autism had a much smaller dynamic range for the same sounds than did their peers,” says Gage. “That smaller range may indicate a reduced ability to understand a complex, fast-moving human speech stream. For example, to accurately decode speech, we need to be able to tell the difference between sounds such as the 'b' in beach and the 'p' in peach. We do this without conscious effort, even though the distinction occurs within only 20 to 40 thousandths of a second.”

For those unable to quickly and easily make this distinction, understanding everyday speech may become difficult or even impossible. “These neuroimaging findings may present the neural 'answer' to why autistic children show poor speech sound perception,” says Gage.

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Society For Neuroscience. "Deciphering A Mystery: New Research Provides Clues To The Genetic, Neurological, And Molecular Basis Of Autism." ScienceDaily. ScienceDaily, 3 November 2004. <>.
Society For Neuroscience. (2004, November 3). Deciphering A Mystery: New Research Provides Clues To The Genetic, Neurological, And Molecular Basis Of Autism. ScienceDaily. Retrieved October 2, 2023 from
Society For Neuroscience. "Deciphering A Mystery: New Research Provides Clues To The Genetic, Neurological, And Molecular Basis Of Autism." ScienceDaily. (accessed October 2, 2023).

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