AAAS Fellow William Catterall wants to unravel the mysteries of autism. To do this, he's examining a debilitating form of the disorder that causes seizures and sometimes death in young children. His key suspects: a genetic mutation and tiny bioelectrical circuits called ion channels.
Ion channels are a series of minute electrical-signaling pathways that use electrons from ions to aid numerous biological processes—from triggering the release of neurotransmitters to helping the body absorb nutrients. They are now recognized as so fundamental to essential biological processes that they're often called "gatekeepers".
Unlocking the secrets of ion channels—how they work and how they're structured—has instigated a tsunami of research. Surfing one crest is Catterall.
A gray-haired professor in his late sixties, Catterall chairs the pharmacology department at the University of Washington, where he runs a lab that focuses on sodium and calcium ion channels, so named because they use ions of sodium and calcium to transmit electricity.
For nearly three decades, Catterall's work has focused on the basic research of how ion channels work. More recently his lab has led the way in mapping the microscopic structure of both the sodium and calcium ion channels. But what really excites Catterall is how his earlier efforts are now informing his detective work on autism.
Catterall is currently investigating a specific genetic mutation tied to autism, a mutation known for turning off the sodium ion channel's electrical switch. Counterintuitively, this turning off, actually leads to excessive turning on in the brain.
"What does it mean to have a circuit that is too excitatory?" asks Catterall. "You might say, 'It's a good a thing, it will make you run faster,' but, as in all things, balance is important, especially in the brain."
The issue of balance is particularly key in autism: Healthy brains are balanced between excitation and inhabitation but autistic brains often lack this balance, resulting in autistic behaviors.
"One of the characteristics of autistic children and adults is they engage in repetitive activities," says Catterall. "They do things too much. Or they get too focused on one thing."
Autistics, says Catterall, can't turn off when they need to.
What's commonly called "autism" is in fact a spectrum of disorders. This includes Asperger syndrome and its savant-like traits—first popularized in the film "Rain Man." Catterall's own interest is in Dravet syndrome, a rare form of autism that's also a form of epilepsy.
Beginning in infancy, Dravet syndrome affects babies at around six months. Intractable, Dravet syndrome inflicts on its little victims seizures, cognitive and behaviors problems, injuries, and even death. The latter is due in part to the syndrome's seizures and in part because children afflicted with the disease often lack the ability to learn how to avoid dangers.
The mutation causing Dravet syndrome turns off the sodium ion switch in neurons that release the brain's main inhibitory neurotransmitter, Gamma-Aminobutyric acid (GABA). Flipping off the sodium ion GABA switch pushes the brain into over excitation. In other words, not enough firing in one part of the brain leads to too much in another.
To understand what this means for learning and behavior, Catterall and his team measured the electrical activity in the brains of mice both with and without Dravet syndrome. Not surprisingly, mice with the syndrome showed an imbalance of electrical activity. Then the team did something no one had tried before. They administered the sedative clonazepam to the Dravet syndrome mice.
Clonazepam, Catterall knew, increases GABA receptor activity. What happened next was surprising. Instead of dulling the mutated mice, the sedative actually improved their learning and social behavior. Catterall says dosage was key.
Clonazepam and other drugs in the benzodiazepine family—which includes Valium—are typically prescribed to combat anxiety. But Catterall and his team didn't want sedated mice. So they administered a low dose, well below that used to treat anxiety. At the low dose, the Dravet syndrome mice not only showed improvements throughout the experiment, they also did not develop a tolerance to the drug, something that's common at higher doses.
Catterall has repeated the Clonazepam experiments in another mouse breed displaying a different form of autism. Again, the sedative improved learning and social behavior in the affected mice.
Catterall says it's still too soon to tell what these findings mean for children with Dravet syndrome and other forms of autism. (No similar experiments have been tried in humans.) Yet he's hopeful his research will lead to better treatments. This, he says, will no doubt come after still more years of plodding research devoted to ion channels. But for now the researcher is happy to have uncloaked something of the mystery of autism.
"We can [now] really understand Dravet syndrome and maybe even something about autism," says Catterall.