According to David A. Lewis, MD, who spoke at the American Psychiatric Association Institute on Psychiatric Services on October 31 in San Francisco, California, impairment in working memory is a key finding in schizophrenia, and this impairment is present before onset of psychosis, persists during the illness, and helps predict functional outcome. Furthermore, research in post-mortem brains and animal models shows that layer 3 of the dorsolateral prefrontal cortex is crucial to working memory.
In a lecture titled “Developmental trajectories in cortical circuits: Identifying sensitive periods for the emergence of schizophrenia,” Dr. Lewis, director of the Translational Neuroscience Program and chair of the department of psychiatry at the University of Pittsburgh, described research that has begun to explain why schizophrenia tends to strike people in late adolescence and early adulthood. A circuit consisting of pyramidal cells and inhibitory GABAergic cells, which is recorded electrophysiologically as the “gamma oscillation,” matures during childhood and early adolescence. In this complex process, which involves GABA, NMDA and cannabinoid receptors, some synapses are strengthened and others pruned. During this “sensitive period,” as Lewis called it, exposure to environmental insults can have a profound effect. One manifestation is that people with schizophrenia end up with 20% fewer dendritic spines, which are post-synaptic structures, on the pyramidal cells in cortical layer 3 than unaffected people.
Epidemiologic data consistently show that youth who use marijuana before 16 years of age double or triple their risk for developing schizophrenia. Tetrahydrocannabinol (THC), which binds to cannabinoid receptors on pyramidal and GABAergic neurons in the cortex, affects visual working memory in many people who use it. In an effort to mimic human teenagers’ regular use of marijuana, Dr. Lewis’ lab gave a group of young rhesus monkeys frequent doses of THC. Compared to non-exposed peers, monkeys who had a 6-month exposure to THC developed impairments in spatial working memory similar to enduring deficits exhibited by humans with schizophrenia. The researchers also looked at a second cognitive task that targets object working memory, which depends upon the ventral prefrontal cortex, an area of the brain that matures earlier. This function was unaffected by exposure to THC.
Dr. Lewis emphasized that timing is crucial and may help explain why certain exposures or traumas have major impact at one time in development and minor impact at another. The impact of treatments likewise may vary by developmental stage, and he said that those that aren’t targeted and timely may have unintended consequences.