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Protein Required for Flexible Behavior Is Identified

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24 May 2012
Doug Cavener in his lab, 2012

Department head and professor of biology at Penn State University, Douglas Cavener, pictured in his lab. Credit: Penn State University

Researchers have identified a protein that is necessary for maintaining behavioral flexibility. The protein, named PERK, adjusts behaviors for new circumstances that are similar, but not identical, to previous experiences. The findings may offer new insights for addressing such afflictions as autism and schizophrenia, which are marked by impaired behavioral flexibility. Douglas Cavener, department head and professor of biology at Penn State University, is a coauthor of a research paper describing the discovery, which will be published on 24 May 2012 in the journal Cell Reports.

"A major obstacle to investigating the role of the PERK protein in regulating behavior is that many other body functions also are dependent upon this protein," Cavener said. "To overcome this problem, my lab developed a mouse strain that allows us to mutate the PERK gene specifically in a single organ or cell type, while the PERK gene remains normal in other parts of the body." The research studies described in the Cell Reports paper employed a special strain of mice in which the PERK gene -- and therefore the PERK protein -- was missing only from the forebrain. "This mouse strain allowed us to investigate the function of the PERK protein in the brain without the severe complications of other dysfunctions in the body," Cavener said.

"Genetic mutations of the PERK gene result in several severe dysfunctions in humans and mice, known as the Wolcott Rallison Syndrome," Cavener said. "We also have used similar mouse strains, in which the PERK gene was removed from the pancreas, to show that PERK also plays a dominant role in regulating insulin synthesis and secretion." The forebrain-specific mouse strain was developed by Cavener in collaboration with Mimi Trinh and Eric Klann at New York University (NYU).

In one experiment in the study, the mice were asked to navigate a water maze, which included elevating themselves onto a platform to get out of the water. Normal mice, and those lacking the PERK protein in their forebrains, learned to complete this task. However, in a second step, the researchers tested the mice's behavioral flexibility by moving the maze's platform to another location, thereby requiring them to respond to a change in the terrain. Here, the normal mice located the platform, but those lacking the PERK in their forebrains were unable to do so or took significantly more time to complete the task.

A second experiment used a different test of the role of the PERK protein in aiding behavioral flexibility. In this test, both normal and mutant mice heard an audible tone that was followed by a mild foot shock. At this stage, all of the mice developed a normal fear response -- freezing at the tone in anticipation of the mild shock. However, the researchers subsequently removed the foot shock from the procedure and the mice heard only the tone. Eventually, the normal mice adjusted their responses so they did not freeze after hearing the tone. However, the mutant mice continued to respond as if they expected a foot shock to follow.

The researchers sought additional support for their conclusion that the absence of the PERK protein may contribute to impaired behavioral flexibility in human neurological disorders. To do so, they conducted postmortem analyses of human cells from the frontal cortex of people without schizophrenia with frontal-cortex cells from schizophrenic patients, who often exhibit behavioral inflexibility. The samples from the non-schizophrenic group showed normal levels of PERK protein while those from the schizophrenic patients had significantly reduced levels of the protein.

"A rapidly expanding list of neurological disorders and neurodegenerative diseases, including Alzheimer's disease, Parkinson's disease, and Fragile X syndrome, already have been linked to aberrant protein synthesis," explained Eric Klann, a professor in NYU's Center for Neural Science and one of the study's co-authors. "Our results show the significance of PERK in maintaining behavioral flexibility and how its absence might be associated with schizophrenia. Further studies clarifying the specific role of PERK-regulated protein synthesis in the brain may provide new avenues to tackle such widespread and often debilitating neurological disorders."

The study's other co-authors are: Mimi Trinh, who recently completed her Ph.D. in NYU's Center for Neural Science; Hanoch Kaphzan, a former post-doctoral fellow in NYU's Center for Neural Science and now at the University of Haifa in Israel; Ronald Wek, a professor at Indiana University School of Medicine; and Philippe Pierre, a group leader at France's Université de la Méditerranée.

Funding of this work was from the National Institutes of Health, the FRAXA Research Foundation, and the Bill and Melinda Gates Foundation.

[ James Devitt / Barbara K. Kennedy ]

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