Autism may reflect excitation-inhibition imbalance in brain, study finds

August 2, 2017, Stanford University Medical Center
Using a technique called optogenetics to directly activate specific brain regions, researchers reversed behavioral symptoms in mouse models of autism spectrum disorder. Credit: A. Selimbeyoglu et al., Science Translational Medicine (2017)

A study by Stanford University investigators suggests that key features of autism reflect an imbalance in signaling from excitatory and inhibitory neurons in a portion of the forebrain, and that reversing the imbalance could alleviate some of its hallmark symptoms.

In a series of experiments conducted on a mouse model of the disorder, the scientists showed that reducing the ratio of excitatory to inhibitory signaling countered hyperactivity and deficits in social ability, two classic symptoms of autism in humans.

The study will be published Aug. 2 in Science Translational Medicine. Karl Deisseroth, professor of bioengineering and of psychiatry and behavioral sciences, is the study's senior author. The lead author is former graduate student Aslihan Selimbeyoglu, PhD.

In 2011, Deisseroth's group published a study in Nature showing that autismlike behavioral deficits could be induced in ordinary mice by elevating the ratio of excitatory to inhibitory neuronal firing patterns in the mice's medial prefrontal cortex. The new study shows that decreasing that ratio restores normal behavior patterns in a strain of bioengineered to mimic human autism. These mice carry a mutation equivalent to a corresponding mutation in humans that is associated with .

Autism incidence increasing

For reasons that are not understood, the incidence of autism spectrum disorder has increased steadily in recent years, said Deisseroth, a practicing psychiatrist. Around 1 in 80 American children may be diagnosed with the disorder, which is characterized by repetitive behaviors and difficulty with social interaction. To date, there are no medications that treat the fundamental underpinnings of the disorder.

"In all of psychiatry, there's no lab test that can diagnose this condition," said Deisseroth. "It's been associated with numerous genetic variants, many of which appear to exert only small individual influences."

Deisseroth, who holds the D.H. Chen Professorship, notes that UCSF psychiatrist John Rubenstein and his colleagues, among others, have theorized that an excitation-inhibition imbalance might account for these phenomena. While myriad genetic variations contribute to autism, many of them may do so by impairing, in diverse ways, a single process or a small number of processes necessary for overall healthy brain function, such as a balance between excitatory and inhibitory signaling in key brain regions. One of those regions is the medial prefrontal cortex, which plays a major role in executive functions, such as planning, prediction, attention and integrating information from other individuals' behaviors and speech for clues as to what they might be thinking.

Testing the hypothesis

"Social interaction may be the hardest thing a mammal can do," Deisseroth said. "It's an immensely complex phenomenon that requires rapid, highly integrated communication among disparate, distant parts of the brain. Specific brain states well-suited for rich information handling may be needed for effective social communication and behavior."

To test the excitation-inhibition balance hypothesis, the Stanford scientists launched a set of experiments employing the mutant mice, which display hyperactive behavior and impaired . Interestingly, these mice also share a less visible characteristic with humans carrying the equivalent mutation: a shortage, compared with normal mice and humans, of parvalbumin , a particular category of inhibitory nerve cell found throughout the brain. In a 2009 Nature paper, Deisseroth and his team reported that parvalbumin neuron activity can improve the information-handling capacity of forebrain neurons.

The researchers used optogenetics, an advanced laboratory technology that Deisseroth pioneered, to insert genes for two types of light-sensitive proteins, or opsins, into two distinct sets of neurons in the medial prefrontal cortex of the mice. The researchers inserted one type of opsin into parvalbumin in that region of the mice's brains. It made the neuron more excitable if it received a pulse of blue light, delivered via an implanted optical fiber.

The other opsin, also activated with a pulse of blue light, had the opposite effect: When activated, it rendered the neuron on which it sat more resistant to firing. The scientists put this inhibitory opsin in a set of excitatory medial prefrontal cortex neurons called .

Reducing the excitation-inhibition ratio by either diminishing the excitability of the pyramidal neurons or by increasing the excitability of the parvalbumin neurons led to the same result in the mice: more time spent engaging in social encounters with other mice and less hyperactivity during those encounters or when the were by themselves.

"Excitation-inhibition balance can take many forms and may be important at different stages of life," Deisseroth said. "Together, these findings suggest that this form of regulating the ratio of excitatory- to inhibitory-cell firing in the may be significant in normal social behavior and in autism."

Explore further: Social deficits associated with autism, schizophrenia induced in mice with new technology

More information: A. Selimbeyoglu el al., "Modulation of prefrontal cortex excitation/inhibition balance rescues social behavior in CNTNAP2-deficient mice," Science Translational Medicine (2017). stm.sciencemag.org/lookup/doi/ … scitranslmed.aah6733

Related Stories

Social deficits associated with autism, schizophrenia induced in mice with new technology

July 27, 2011
Researchers at Stanford University School of Medicine have been able to switch on, and then switch off, social-behavior deficits in mice that resemble those seen in people with autism and schizophrenia, thanks to a technology ...

Serotonin improves sociability in mouse model of autism

June 21, 2017
Scientists at the RIKEN Brain Science Institute (BSI) in Japan have linked early serotonin deficiency to several symptoms that occur in autism spectrum disorder (ASD). Published in Science Advances, the study examined serotonin ...

Low doses of antianxiety drugs rebalance the autistic brain

March 19, 2014
New research in mice suggests that autism is characterized by reduced activity of inhibitory neurons and increased activity of excitatory neurons in the brain, but balance can be restored with low doses of a well-known class ...

Molecule may help maintain brain's synaptic balance

June 13, 2017
Many neurological diseases are malfunctions of synapses, or the points of contact between neurons that allow senses and other information to pass from finger to brain. In the brain, there is a careful balance between the ...

The brain's balancing act: Researchers discover how neurons equalize between excitation and inhibition

June 22, 2014
Researchers at the University of California, San Diego School of Medicine have discovered a fundamental mechanism by which the brain maintains its internal balance. The mechanism, described in the June 22 advanced online ...

Recommended for you

Researchers investigate changes in white matter in mice exposed to low-frequency brain stimulation

June 19, 2018
A team of researchers at the University of Oregon has learned more about the mechanism involved in mouse brain white matter changes as it responds to stimulation. In their paper published in Proceedings of the National Academy ...

Left, right and center: mapping emotion in the brain

June 19, 2018
According to a radical new model of emotion in the brain, a current treatment for the most common mental health problems could be ineffective or even detrimental to about 50 percent of the population.

Cell type and environment influence protein turnover in the brain

June 19, 2018
Scientists have revealed that protein molecules in the brain are broken down and replaced at different rates, depending on where in the brain they are.

Often overlooked glial cell is key to learning and memory

June 18, 2018
Glial cells surround neurons and provide support—not unlike hospital staff and nurses supporting doctors to keep operations running smoothly. These often-overlooked cells, which include oligodendrocytes and astrocytes, ...

Electrically stimulating the brain may restore movement after stroke

June 18, 2018
UC San Francisco scientists have improved mobility in rats that had experienced debilitating strokes by using electrical stimulation to restore a distinctive pattern of brain cell activity associated with efficient movement. ...

Neuroscientists map brain's response to cold touch

June 18, 2018
Carnegie Mellon University neuroscientists have mapped the feeling of cool touch to the brain's insula in a mouse model. The findings, published in the June 15 issue of Journal of Comparative Neurology, provide an experimental ...

1 comment

Adjust slider to filter visible comments by rank

Display comments: newest first

BubbaNicholson
1 / 5 (1) Aug 04, 2017
250mg of healthy adult male facial skin surface lipid taken by mouth one time diminishes symptoms of Autism. n=1

Please sign in to add a comment. Registration is free, and takes less than a minute. Read more

Click here to reset your password.
Sign in to get notified via email when new comments are made.