New Autism Insights

Two studies investigating facets of autism have honed in on underlying mechanisms of the disease.

In one, David Sulzer, PhD, professor of neurobiology in psychiatry, neurology, and pharmacology, focused his attention on a neurological process akin to that of orchardists pruning the lush spring growth produced by their apple trees. During infancy, synapses—the structures responsible for neural communications—form at a brisk pace. Over the next two decades, biological processes “prune” them by half to optimize cognitive function. “While people usually think of learning as requiring formation of new synapses,” says Dr. Sulzer, “the removal of inappropriate synapses may be just as important.”

Dr. Sulzer and co-author Guomei Tang, PhD, assistant professor of neurology, have a theory of the role of slowed synaptic pruning in autism. They demonstrate evidence of slowed pruning in the brains of children with autism who died of other causes and identify evidence of the underlying mechanism. In children with autism, they found that autophagy—the cell’s recycling and waste management process—seemed impaired. Using a mouse model of autism, the team identified the protein—mTOR—that impedes pruning and tested a drug that ameliorates its effect.

Because large amounts of overactive mTOR were found in almost all of the brains of the autism patients, the scientists hypothesize that the same processes may occur in children with autism. “Hundreds of genes have been linked to autism,” says Dr. Sulzer, “but almost all of our human subjects had overactive mTOR and decreased autophagy, and all appear to have a lack of normal synaptic pruning. Overactive mTOR and reduced autophagy, by blocking normal synaptic pruning that may underlie learning appropriate behavior, may be a unifying feature of autism.”

Dennis Vitkup, PhD, associate professor of systems biology and of biomedical informatics, has conducted a large-scale genomic analysis of hundreds of people with autism spectrum disorder—ASD—to discover how diversity among disease traits can be traced to differences in patients’ genetic mutations.

More damaging genetic mutations usually lead to worse disease outcomes, Dr. Vitkup found. Patients with low verbal or nonverbal IQs usually have New Autism Insights mutations in genes that are more active in the brain. Individuals with high IQs are less likely to have mutations that completely shut down genes. In fact, mutations that only partially damage normal gene function in the brain appear to be predominantly associated with high-functioning autism cases.

Behavioral variability in autism patients may stem from the types of brain cells affected, and the Columbia researchers have taken the first steps in determining which cell types in the brain are most affected by autism mutations. Dr. Vitkup and colleagues identified these cells by looking at the normal activity of autism-related genes in dozens of similar cell types in mouse brains. The analysis showed that many different types of neurons throughout the brain are affected by mutations in autism genes.

“The idea that eventually all autism mutations would converge onto a single type of neuron or single brain area isn’t what we see in the data,” Dr. Vitkup says. “Instead, an autism mutation usually affects multiple brain areas simultaneously.” Certain neurons, however, appear to be more affected than others. The Columbia researchers found strong effects in cortical and striatal neurons that form a circuit that controls repetitive motions and behaviors, such as rocking, an insistence on sameness, and restricted interests, which are common in people with ASD.

This is a summary of research by Dr. Sulzer published in Neuron, Sept. 3, 2014, and by Dr. Vitkup in Nature Neuroscience, Dec. 22, 2014.