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Dec 18, 2013

Teen Gene Discovery Offers Hope for Mentally Ill Young

  • Scientists at the Douglas Institute Research Center, affiliated with McGill University, say they have isolated a gene, DCC, which is responsible for dopamine connectivity in the medial prefrontal cortex during adolescence. Working with mouse models, they have shown that dysfunction of this gene during adolescence has behavioral consequences which carry into adulthood. This project has implications for humans since it has long been known that during the teenage phase of brain development, adolescents are particularly vulnerable to psychiatric disorders, including schizophrenia, depression, and drug addiction.

    According to the researchers, this finding provides the first clues towards a fuller understanding of this important phase of brain development. “Certain psychiatric disorders can be related to alterations in the function of the prefrontal cortex and to changes in the activity of the brain chemical dopamine,” says Cecilia Flores, Ph.D., senior author on the study and professor at McGill's department of psychiatry. “Prefrontal cortex wiring continues to develop into early adulthood, although the mechanisms were, until now, entirely unknown.”

    “Adolescence is a period of heightened susceptibility to psychiatric disorders of medial prefrontal cortex (mPFC) dysfunction and cognitive impairment. mPFC dopamine (DA) projections reach maturity only in early adulthood, when their control over cognition becomes fully functional,” wrote the investigators in an article (“DCC orchestrates the development of the prefrontal cortex during adolescence and is altered in psychiatric patients”) in Translational Psychiatry. “The mechanisms governing this protracted and unique development are unknown. Here we identify DCC as the first DA neuron gene to regulate mPFC connectivity during adolescence and dissect the mechanisms involved. Reduction or loss of DCC from DA neurons by Cre-lox recombination increased mPFC DA innervation.”

    Even subtle variations in DCC during adolescence produce significant alterations in prefrontal cortex function later on. To determine whether the findings of such basic research can translate to human subjects, researchers examined DCC expression in postmortem brains of people who had committed suicide. Remarkably, these brains showed higher levels of DCC expression—about 48% higher when compared to control subjects.

    “The prefrontal cortex is associated with judgment, decision making, and mental flexibility, or with the ability to change plans when faced with an obstacle,” explained Dr. Flores. “Its functioning is important for learning, motivation, and cognitive processes. Given its prolonged development into adulthood, this region is particularly susceptible to being shaped by life experiences in adolescence, such as stress and drugs of abuse. Such alterations in prefrontal cortex development can have long term consequences later on in life.”

    By identifying the first molecule involved in how the prefrontal dopamine system matures, researchers now have a target for further investigation for developing pharmacological and other types of therapies. “We know that the DCC gene can be altered by experiences during adolescence,” continued Dr. Flores. “This already gives us hope, because therapy, including social support, is itself a type of experience, which might modify the function of the DCC gene during this critical time and perhaps reduce vulnerability to an illness.”



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