John Huguenard, PhD, started his academic career studying the electrical excitability of brain cells. Now, at his namesake lab in Stanford’s Department of Neurology & Neurological Sciences, he and his team are learning what role that excitability plays in epilepsy — and how we might someday control it.
“The premise of our lab is that the brain is complex, and its complexity has required that it evolve mechanisms to keep things well controlled,” Huguenard said. “Our lab is searching for those mechanisms.”
An ongoing project aims to understand how brain cells regulate their outgoing signals. The lab’s research specifically focuses on a brain structure called the thalamus and its connections — via nerve cells — to the cortex.
Pulses of electricity race down a neuron’s primary output cable, known as its axon, and send messages out to neighboring cells. In the past, these signals have been thought to be as reliable as mailmen or women — able to deliver information from one cell to the next rain or shine. But Huguenard’s lab has found that, as with snail mail, not every message reaches its destination.
“Some of the axons work well, and others stop working,” said Huguenard. “That failure can have catastrophic results, because this seems to be a critical control point in some epileptic networks.”
Epilepsy develops when neuron's signaling becomes dysregulated, according to past research. Neurons direct many parallel processes in the brain at the same time, all the time. Despite constantly shooting off signals, neurons normally don’t fire in synchrony. Built-in safety mechanisms keep this from happening, but when these measures fail, many neurons fire together and seizures can occur. A recent study from Huguenard’s lab, led by Christopher Makinson, PhD, suggested that the loss of a single gene in this regulatory network is enough to generate seizures.
Axons might also play a role in some of these safety measures. When the signals sent zooming down the axon don’t make it to its end, these measures don’t deploy. “Axons are complicated, they have many branches,” said Huguenard. “At each of these branches is a potential site where this failure can happen.” The research suggests each branch competes for the signal as it passes, and this challenge sometimes stops it in its tracks.
Another theory suggests that failure can occur even if the signal meets no roadblocks. Once cued by an electrical signal, axons send out chemicals to deliver messages between cells. If the packaging and delivery of these chemicals is disrupted, this exchange of information freezes.
Once the reasons behind these failures are better understood, the researchers hope to work toward preventing them. A recent study in rodent models, led by graduate student Jordan Sorokin, demonstrated how neural firing might be controlled to stop seizures in real-time — to basically switch them off like a light. “Using gene therapy allows us to first identify brain cells and circuits that are important in the seizures, then make those cells sensitive to manipulation,” said Huguenard. These methods are fairly successful in animal models, he said, and the goal is to someday make them clinically useful for humans.
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