Stress impairs thinking via mania-linked enzyme

An errant enzyme linked to bipolar disorder, in the brain’s prefrontal cortex, impairs cognition under stress, an animal study shows. The disturbed thinking, impaired judgment, impulsivity, and distractibility seen in mania, a destructive phase of bipolar disorder, may be traceable to overactivity of protein kinase C (PKC), suggests the study, funded by the National Institutes of Health’s (NIH) National Institute of Mental Health (NIMH) and National Institute on Aging (NIA), and the Stanley Foundation. It explains how even mild stress can worsen cognitive symptoms, as occurs in bipolar disoder, which affects two million Americans.

Abnormalities in the cascade of events that trigger PKC have also been implicated in schizophrenia. Amy Arnsten, Ph.D. and Shari Birnbaum, Ph.D. of Yale University, and Husseini Manji, M.D., of NIMH, and colleagues, report on their discovery in the October 29, 2004 issue of Science.

"Either direct or indirect activation of PKC dramatically impaired the cognitive functions of the prefrontal cortex, a higher brain region that allows us to appropriately guide our behavior, thoughts and emotions," explained Arnsten. "PKC activation led to a reduction in memory-related cell firing, the code cells use to hold information in mind from moment-to-moment. Exposure to mild stress activated PKC and resulted in prefrontal dysfunction, while inhibiting PKC protected cognitive function."

"In the future, drugs that inhibit PKC could become the preferred emergency room treatments for mania," added Manji, currently Director of NIMH’s Mood and Anxiety Disorders Program, who heads a search for a fast-acting anti-manic agent. "All current treatments – lithium, valproate, carbamazepine and antipsychotics – take days, if not weeks, to work. That’s because they’re likely acting far upstream of where a key problem is, namely in the PKC pathway. Since PKC inhibitors could act more directly, they might quench symptoms more quickly. Patients could carry PKC inhibitors and take them preventively, as soon as they sense a manic episode coming on."

Clinical trials of a PKC inhibitor, the anti-cancer drug tamoxifen, are currently underway in bipolar disorder patients. However, these may be more important for proof-of-concept than therapeutic utility, according to Manji, who says side effects will likely rule out tamoxifen itself as a practical treatment for mania. "While there are likely other pathways involved, PKC appears to be very important for bipolar disorder," he noted.

The fact that the current anti-manic drugs ultimately reduce PKC activity suggests that PKC may be a final common target of these treatments and may play a key role in bipolar disorder. Studies have also found signs of increased PKC activity in bipolar patients’ blood platelets and in the brain cells of deceased patients. Susceptibility to bipolar disorder may involve variants of genes that code for a key PKC precursor and for a stress-sensitive signaling protein that normally puts the brakes on PKC activity.

The new study shows how PKC triggers cognitive symptoms in response to stress. When the stress-sensitive messenger chemical norepinephrine binds to receptors on cell membranes in the prefrontal cortex, it activates PKC through a cascade of events. The enzyme then travels out to the cell membrane, opening ion channels that heighten the cell’s excitability, and stoking protein machinery that propels neurotransmitters into the synapse. PKC also moves into the cell’s nucleus, where it turns-on genes.

To tease out PKCs role, the researchers selectively targeted the prefrontal cortex in rats and monkeys performing working memory tasks with PKC activators, inhibitors, norepinephrine-like and stress inducing drugs – alone and in combination. They also found that by blocking PKC, the anti-manic drugs lithium and carbamazepine protected monkeys’ prefrontal cortex functioning from impairment by a norepinephrnine-like drug.

The researchers traced impairment to a reduction in memory-related firing of single cells in the prefrontal cortex, which was reversible by a PKC inhibitor.

Genetic and biochemical studies indicate that PKC may also be overactive in the brains of patients with schizophrenia. Antipsychotics, which are used to treat bipolar disorder as well as schizophrenia, block receptors in the brain that activate PKC.