Social Deficits Linked to Autism, Schizophrenia Stimulated in Mice with New Technology

The research shows that the mice in the study displayed a brain-wave pattern that has been associated with autism and schizophrenia in human beings.

With the help of a technology which allows scientists to influence nerve activity in the brain, Stanford University School of Medicine researchers have found a way to “flip the switch” on certain social-behavior deficits in mice akin to similar deficits observed in humans who suffer from both autism and schizophrenia.

The research shows that the mice in the study displayed a brain-wave pattern called gamma oscillation, a pattern that has been associated with autism and schizophrenia in human beings.

According to the researchers, these findings mark the first demonstration that elevating the brain’s susceptibility to stimulation can produce social deficits resembling those of autism and schizophrenia, and that then restoring the balance eases those symptoms.

Separately, autism spectrum disorder and schizophrenia affect nearly 1% of humanity, and as of now, there are no existing drugs which can effectively alleviate the social-behavioral deficits of either disorder.

While the syndromes are very different from each other, both schizophrenia and autism are multifaceted and encompass diverse deficits, including social dysfunction.

Social behavior can’t be ascribed to a single brain region, according to senior author Karl Deisseroth, MD, PhD, associate professor of psychiatry and behavioral sciences and of bioengineering. “To form a coherent pattern of another individual, you need to quickly integrate all kinds of sensations. And that’s just the tip of the iceberg,” reported Deisseroth, who is also a practicing psychiatrist who routinely sees autistic-spectrum patients.

“It’s all changing, millisecond by millisecond, as both you and the other individual act and react,” continued Deisseroth. “You have to constantly alter your own predictions about what’s coming next. This kind of interaction is immensely more uncertain than, for example, predator/prey activity. It seems that it has to involve the whole brain, not just one or another part of it.”

Deisseroth and his team performed this experiment in order to test a theory known as the “excitation/inhibition-balance” hypothesis, which holds that social deficits connected to both autism and schizophrenia may be caused by a distorted balance in the “propensity of excitatory versus inhibitory nerve cells in the brain to fire”, as the study authors noted, which ultimately results in a general hyper-responsiveness to stimulation.

Researchers state that this hypothesis holds water due to evidence supporting it, such as the higher seizure rate seen in autistic patients. Also, both schizophrenics and autistics display social deficits and increased levels of gamma oscillation in the brain.

Deisseroth also called to attention the fact that “autistic kids seem to be over-responding to environmental stimuli,” as most autistic children will be overwhelmed by direct eye contact, and have a tendency to cover their ears if there is a lot of noise around them.

Until this study, there was no way to directly test this hypothesis, but Deisseroth and his team discovered a method with a new technology, which was created in his laboratory and is known as optogenetics. The technology works by selectively bioengineering specific kinds of nerve cells so that they respond to light, and with just the flick of a light switch, the researchers were able to activate a nerve circuit in the brain—or inhibit it.

The investigators in this study targeted the excitatory and inhibitory nerve cells in the medial prefrontal cortex, the most advanced part of the mouse brain. According to Deisseroth, this area of the brain is linked to every other region in the brain, and also plays a role in processes such as planning, execution, personality, and social behavior.

“We didn’t want to precisely direct the firing patterns of excitatory or inhibitory cells,” Deisseroth said. “We wouldn’t know where to start, because we don’t know the neural codes of behavior. We just wanted to bias excitability.”

The investigators bioengineered the nerve cells to react to particular wavelength bands of light by becoming either more or less likely to fire. “Nerve cells have an all-or-nothing tipping point,” Deisseroth said. “Up to that point, they won’t do much. But at a certain threshold, they fire.”

The study’s two first co-authors, postdoctoral researcher Ofer Yizhar, PhD, and Lief Fenno, a graduate student, planned out methods of activating or inhibiting brain circuits by a light pulse for up to a half-hour in order to allow for a long enough time period to have the experimental mice take part in a variety of tests of social behavior.

The researchers assessed the bioengineered mice according to these tests of rodent behavior and compared the outcomes using control mice.

According to the findings, the experimental mice and the control mice had similar results concerning tests of their anxiety levels, their mobility, or their innate curiosity when new objects were introduced to them.

The researchers found, however, that the mice whose medial prefrontal cortex excitability had been optogenetically stimulated lost nearly all interest in engaging with other mice. The control mice, which were genetically unaltered, were much more curious about one another.

“Boosting their excitatory nerve cells largely abolished their social behavior,” Deisseroth said.

Further, the brains of the genetically altered mice displayed similar gamma-oscillation patterns which are seen in many autistic and schizophrenic patients.

“When you raise the firing likelihood of excitatory cells in the medial prefrontal cortex, you see an increased gamma oscillation right away, just as one would predict it would if this change in the excitatory/inhibitory balance were in fact relevant,” added Deisseroth.

When the researchers restored that balance by increasing inhibitory nerve-cell firing in the medial prefrontal cortex, they observed a moderate but considerable recovery of social function in the engineered mice.

“The behavioral results and the correspondence of gamma-oscillation changes to alterations in the animals’ excitatory/inhibitory balance suggest that that what we’re observing in animals could be relevant to people,” concluded Deisseroth.

This study was published in the July 27 issue of the journal Nature.