Altering the balance of excitatory and inhibitory inputs in the brains of mice disrupts the animals' social interactions.

The mammalian brain—a giant, unruly mass of neurons and the cells that support them buried beneath a protective skull—guards its secrets well. Figuring out what goes awry in psychiatric disorders, which, unlike neurodegenerative diseases, often leave no observable trace, is particularly difficult. But Howard Hughes Medical Institute scientists have used light-activated proteins to home in on and manipulate specific neurons in the brains of mice, uncovering a mechanism that appears to be involved in social dysfunctions that are relevant to autism and other social-behavior disorders.

“In psychiatry, in particular, we are seeking insight,” says HHMI early career scientist Karl Deisseroth. “We don’t know what the brain is doing at the circuit level, we don’t understand its constraints at that level, and we don’t know what its failure modes are. We need deep insights into how circuits aren’t working, and this is a very significant challenge.”

These results take a step toward supporting a unifying hypothesis that could explain certain devastating and complex psychiatric symptoms, including the social dysfunction we see in autism.

Karl Deisseroth

Deisseroth, a psychiatrist and neuroengineer at Stanford University, pioneered a field known as optogenetics, in which light-sensitive proteins called opsins are delivered to nerve cells and—in combination with light of the right wavelength—can help control the behavior of those cells. When Deisseroth began his first experiments that launched the field in 2004, he had to start at square one: figuring out how to introduce the opsins into the right cells, how to design different opsins with the right properties, and how to get light deep into the brain.

“The undercurrent of it all for me has not been just developing the technology but bringing it to bear on the understanding of neural systems and how they can fail to function, particularly in complex neuropsychiatric disease models,” he says. Seven years later, his methods are already beginning to bear fruit. “It’s been exciting to finally start addressing psychiatry issues,” Deisseroth says.

In the past year alone, he has already looked at the neural underpinnings of anxiety and addiction. Now, in research published online July 27, 2011, in the journal Nature, Deisseroth and his colleagues set their sights on social-dysfunction disorders such as autism and schizophrenia. Using novel, long-lasting opsins, they investigated the activity of excitatory and inhibitory neurons in the mouse prefrontal cortex—the area of the brain that researchers believe may responsible for social behaviors and high-level planning.

Autism and other diseases of social dysfunction can arise from diverse unrelated genetic abnormalities that somehow cause the same class of psychiatric symptoms. One idea that’s surfaced to explain is that each of these abnormalities may throw off the relative balance of influence from excitatory and inhibitory neurons in the pre-frontal cortex. That model suggests that if the brain is unable to keep activity from excitatory neurons in check, the overload can lead to seizures and overstimulation. To test this hypothesis, Deisseroth used optogenetics to step up the activity of prefrontal cortex neurons—first the excitatory and then the inhibitory ones—and examined how this affected the social interactions of mice.

Most opsins remain active for only a short time, so the researchers first had to create a way to make the neural changes they induced last long enough for them to assess prolonged social interactions. And because they were looking at the balance of excitatory versus inhibitory neurons, they had to create two different opsins that were activated by two separate wavelengths of light: One to help upregulate excitatory neurons, and one to do the same for inhibitory ones. They used a virus to target the opsins to the pertinent neurons, then activated only the excitatory neurons with a pulse of light just above the medial prefrontal cortex.

When they examined its effects on social interactions, they found that an overabundance of excitatory neuron activity nearly eliminated a mouse’s tendency to investigate unfamiliar mice. “Many things were normal about animals that were stepped up this way in excitation/inhibition balance. They moved about normally, they weren’t unusually anxious, and they responded to novel objects equally well. But they were severely deficient in social interactions,” Deisseroth says. Normally, when mice are introduced to strange juvenile mice of the same gender, they go through a long, enthusiastic period of interaction. “But the test animal runs over, looks, and then stops exploration. The whole period of social interaction is virtually gone. It’s a profound effect.”

Going a step further, the researchers then administered a second pulse of light, this one with a wavelength to activate the opsins attached to inhibitory neurons. Once the ratio of excitatory to inhibitory neurons was brought back into balance, the mice’s social functions were at least partially restored.

“These results take a step toward supporting a unifying hypothesis that could explain certain devastating and complex psychiatric symptoms, including the social dysfunction we see in autism,” Deisseroth says. “This gives us a causal, precise insight into how a major class of dysfunction could happen. And that may help us identify better treatments, it may help us understand patients better, it may help reduce the stigma, and may help people understand how physical and biological these disorders are. And as a psychiatrist, I know that for patients even small steps forward are important.”

Going forward, Deisseroth hopes to delve deeper into the neural circuitry to understand how information is being processed, and to learn how basic circuits fail when a fine-tuned balance of excitation and inhibition is disrupted. He also is training his sights on depression, another psychiatric disorder that affects millions of people. “The most limiting factor in psychiatry is understanding of the mammalian brain at the circuit level,” he says. “Because the system is so complicated, our first and most important task is to seek deeper insight that can arise from tests of unifying or simplifying hypotheses.”

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