Enzyme linked to mania and schizophrenia impairs higher brain functions

Overactivity of protein kinase C (PKC), an enzyme that is implicated in bipolar disorder and schizophrenia, markedly impairs higher brain functions in animals, according to a Yale study published Oct. 29 in Science.

The research adds to mounting evidence that excessive activity of PKC may underlie the distractibility, impaired judgment, impulsivity, and disturbed thinking seen in bipolar disorder (also known as manic depressive illness), and in schizophrenia.

The study also shows that exposure to mild stress can activate PKC, which may lead to worsening of symptoms in patients with these disorders. The findings may explain how upsetting events in the environment can lead to deterioration in higher brain function, and why patients with schizophrenia or bipolar disorder may be particularly susceptible to stress-induced dysfunction. PKC inhibitors may be useful in treating these illnesses, according to Amy Arnsten, associate professor, Department of Neurobiology at Yale School of Medicine and senior author of the study.

“These new findings may also help us understand the impulsivity and distractibility observed in children with lead poisoning,” Arnsten said. “Very low levels of lead can activate PKC, and this may lead to impaired regulation of behavior.”

Recent genetic and biochemical studies indicate that bipolar disorder and schizophrenia are associated with overactivity of PKC, and many medications that treat schizophrenia and bipolar disorder reduce PKC activity. However, the link between PKC overactivity and neuropsychiatric symptoms had not been understood.

This study examined the effects of increasing PKC activity in the prefrontal cortex of animals performing working memory tasks. The prefrontal cortex is a brain region that allows for the regulation of thoughts, behaviors and feelings. The prefrontal cortex becomes dysfunctional in both bipolar disorder and schizophrenia. In animals, either direct or indirect activation of PKC dramatically impaired prefrontal cortical function, while inhibition of PKC protected prefrontal function. No changes in performance were seen on cognitive tasks that did not rely on the prefrontal cortex.