Stress Impairs Thinking via Mania-Linked
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.
Also participating in the study were: Dr. Peixiong Yuan, NIMH;
Dr. Min Wang, Susheel Vijayraghavan, Allyson Bloom, Douglas Davis,
Kevin Gobeske, Yale University; Dr. David Sweatt, Baylor College
To learn more, visit the following links:
NIMH and NIA are part of the National Institutes of Health (NIH),
the Federal Government's primary agency for biomedical and behavioral
research. NIH is a component of the U.S. Department of Health and