Study pinpoints schizophrenia-causing receptor

A Yale study has identified the neuroreceptor whose malfunction is thought to cause cognitive diseases such as schizophrenia.

Published in the Feb. 20 issue of the journal Neuron, the study examines the role NMDA receptors in the prefrontal cortex of the brain play in determining the onset of illness. Yale neurobiology professor and paper senior author Amy Arnsten said scientists already knew genetic defects led to NMDA defects, adding that the study examined why genetic alterations to NMDA receptors were associated with thought disorders. Arnsten said understanding the function of NMDA receptors is key to understanding mental illness.

“That’s the receptor you need for highly developed circuits [in the brain] to talk to each other,” she said. “This will provide clarity for therapeutic development.”

Arnsten said the study was based on “wonderful collaboration” between Yale’s Psychiatry and Mathematics departments, along with the Mount Sinai School of Medicine, where the electron microscopy necessary for the project was conducted. Working under Psychiatry Department chair John Krystal MED ’84, the Yale laboratory exposed human subjects to low doses of the anesthetic ketamine, which researchers discovered affected NMDA receptors and induced schizophrenia-like symptoms in the subjects. Although these symptoms were transient, the human subjects demonstrated impaired cognitive functions typical of the disease.

“When healthy people get a low dose of ketamine, it produces behavioral changes resembling schizophrenia,” Krystal said. “[The anesthetic] also doesn’t activate the prefrontal cortex [of the brain] when it’s having its effect.”

Xiao-Jing Wang, formerly a Yale neurobiology professor and now a faculty member at New York University, provided the mathematical models of brain circuits examined in the study. These models predicted that NMDA receptors would be utilized by these circuits. Wang said he conducted his mathematical modeling research after realizing working memory must be mathematical. He defined working memory as the memory retained once there is no immediate stimulus present, such as remembering a particular telephone number.

“The ability to hold something in your mind when the stimulus is not there grants the freedom to do what you want without the stimulus,” he said.

Krystal said the project was initiated decades ago through his interactions with Arnsten and the late Yale neuroscience professor Patricia Goldman-Rakic.

“[Goldman-Rakic] was a pioneer in seeing how the prefrontal cortex guides behavior,” he said.

He said this study continued Goldman-Rakic’s research hypothesis that nerve cells retained activity when ideas were generated.

Arnsten said her future research will focus on other molecules that might weaken or impair cognition.

“We are in great need of better understanding and better treatment of serious mental illness,” she said. “The only way to do that is to understand molecular influences on higher cognitive functions.”

Eight of the 10 authors of the paper published in Neuron are affiliated with Yale.

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