Researchers have identified a protein criticial to flexibility in behavior, affording new insights into autism and schizophrenia.
In the study, which appears in the journal Cell Reports, researchers at New York University noted that behavioral flexibility allows us to adjust our behavior when faced with a situation that is similar — but not identical — to one we have encountered in the past.
The ability to adapt is partly driven by protein synthesis, which produces experience-dependent changes in neural function and behavior, the researchers said.
They note this process is impaired for many people, including those who are afflicted with autism and schizophrenia, preventing an adjustment in behavior when faced with different circumstances.
To find out why, the researchers focused on the kinase PERK, an enzyme that regulates protein synthesis. PERK is known to modify eIF2alpha, which is required for proper protein synthesis, according to the scientists.
The experiments compared normal lab mice, which possessed the enzyme, with those that lacked it. The mice were tasked with navigating a water maze, which included elevating themselves onto a platform to get out of the water. Normal mice and those lacking PERK learned to complete this task.
However, in a second step, the researchers tested the mice’s behavioral flexibility by moving the platform to another location. Normal mice located the platform, but those lacking PERK were unable to do so or took significantly more time to complete the task, the researchers said.
In a second experiment, both normal and mutant mice heard a tone that was followed by a mild foot shock. All of the mice developed a normal fear response, freezing at the tone in anticipation of the foot shock. The researchers then removed the foot shock 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.
Seeking additional support for their conclusion that the absence of PERK may contribute to impaired behavioral flexibility in human neurological disorders, the researchers conducted postmortem analyses of human frontal cortex samples from patients with schizophrenia, who often exhibit behavioral inflexibility, and unaffected individuals.
The samples from the control group showed normal levels of PERK, while those from the schizophrenic patients had significantly reduced levels of the protein, according to the researchers.
“A rapidly expanding list of neurological disorders and neurodegenerative diseases, including Alzheimer’s disease, Parkinson’s disease, and Fragile X syndrome, have already been linked to aberrant protein synthesis,” explained Eric Klann, Ph.D., 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.”
Source: New York University