Autism Risk Gene May Prevent Brain from Calming Down

A major risk gene for autism is also implicated in epilepsy. In fact, around one-third of children with autism spectrum disorder (ASD) have epilepsy. But researchers are still unsure why this mutation causes seizures.

In a new study, scientists at Northwestern Medicine in Chicago may have found some answers. They discovered that the gene mutation, called CNTNAP2 or “catnap2,” acts as an overzealous gardener who cuts away too many branches off the tree.

In the brain, this gene mutation essentially shrinks neurons’ tiny branches and leaves — its dendrite arbors and synapses — that enable brain cells to pass along vital messages and control the brain’s activity. The shrinkage causes a breakdown in message delivery.

The message that gets lost is “Calm down!”

In people with this mutation, inhibitory neurons that normally put the brakes on excitatory neurons don’t grow enough branches and leaves to communicate their “calm down” message, the researchers found. This can lead to seizures.

The researchers also found that catnap2 tends to partner up with another mutated gene, CASK, implicated in mental retardation. Catnap2 is an adhesive molecule that helps cells stick together, in this case causing the synapses to adhere to the dendrites.

This makes it a difficult molecule to target with drugs, Penzes said. But catnap2’s partner, CASK, is referred to as a “social butterfly enzyme” in that it interacts with many other molecules. This allows it to be more easily inhibited or activated with drugs.

As a result of these findings, scientists may have a new drug target to treat the disorder.

“Now we can start testing drugs to treat the seizures as well as other problems in autism,” said lead author Dr. Peter Penzes, the Ruth and Evelyn Dunbar Professor of Psychiatry and Behavioral Sciences at Northwestern University Feinberg School of Medicine. “Patients with the mutation also have language delay and intellectual disability. So a drug targeting the mutation could have multiple benefits.”

Next, the research team will conduct a high-throughput screening (HTS) of molecules with the goal of reversing these abnormalities in patients with autism. HTS is a drug-discovery process commonly used in the pharmaceutical industry to rapidly assess the biochemical activity of drug-like compounds.

The researchers plan to screen drugs that could possibly activate CASK in order to help maintain healthy dendrite branches. When scientists blocked CASK in the study, dendrites didn’t grow.

The new findings are published in the journal Molecular Psychiatry.

Source: Northwestern University