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.
Jules Asher | EurekAlert!
Cancer diagnosis: no more needles?
25.05.2018 | Christian-Albrechts-Universität zu Kiel
Less is more? Gene switch for healthy aging found
25.05.2018 | Leibniz-Institut für Alternsforschung - Fritz-Lipmann-Institut e.V. (FLI)
The more electronics steer, accelerate and brake cars, the more important it is to protect them against cyber-attacks. That is why 15 partners from industry and academia will work together over the next three years on new approaches to IT security in self-driving cars. The joint project goes by the name Security For Connected, Autonomous Cars (SecForCARs) and has funding of €7.2 million from the German Federal Ministry of Education and Research. Infineon is leading the project.
Vehicles already offer diverse communication interfaces and more and more automated functions, such as distance and lane-keeping assist systems. At the same...
A research team led by physicists at the Technical University of Munich (TUM) has developed molecular nanoswitches that can be toggled between two structurally different states using an applied voltage. They can serve as the basis for a pioneering class of devices that could replace silicon-based components with organic molecules.
The development of new electronic technologies drives the incessant reduction of functional component sizes. In the context of an international collaborative...
At the LASYS 2018, from June 5th to 7th, the Laser Zentrum Hannover e.V. (LZH) will be showcasing processes for the laser material processing of tomorrow in hall 4 at stand 4E75. With blown bomb shells the LZH will present first results of a research project on civil security.
At this year's LASYS, the LZH will exhibit light-based processes such as cutting, welding, ablation and structuring as well as additive manufacturing for...
There are videos on the internet that can make one marvel at technology. For example, a smartphone is casually bent around the arm or a thin-film display is rolled in all directions and with almost every diameter. From the user's point of view, this looks fantastic. From a professional point of view, however, the question arises: Is that already possible?
At Display Week 2018, scientists from the Fraunhofer Institute for Applied Polymer Research IAP will be demonstrating today’s technological possibilities and...
So-called quantum many-body scars allow quantum systems to stay out of equilibrium much longer, explaining experiment | Study published in Nature Physics
Recently, researchers from Harvard and MIT succeeded in trapping a record 53 atoms and individually controlling their quantum state, realizing what is called a...
25.05.2018 | Event News
02.05.2018 | Event News
13.04.2018 | Event News
25.05.2018 | Event News
25.05.2018 | Machine Engineering
25.05.2018 | Life Sciences