Autism may reflect excitation-inhibition imbalance in brain

Stanford Medicine| Wed Aug 02 11:27:10 EDT 2017
Autism may reflect excitation-inhibition imbalance in brain

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.

“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 social interaction. 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 neurons, 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.

In all of psychiatry, there’s no lab test that can diagnose this condition.

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 inhibitory neurons 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 pyramidal neurons.

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 mice 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 medial prefrontal cortex may be significant in normal social behavior and in autism.”

Other Stanford study co-authors are postdoctoral scholars Christina Kim, PhD, and Masatoshi Inoue, PhD; former postdoctoral scholars Soo Yeun Lee, PhD, and Thomas Davidson, PhD; laboratory technician Alice Hong; graduate student Isaac Kauvar; laboratory manager Charu Ramakrishnan; former graduate student Lief Fenno, PhD; and psychiatry instructor Matthew Wright, MD, PhD.

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