New Clues to the Causes of Bipolar Disorder

by Jim Schnabel

February 16, 2016

Aging-related brain diseases such as Alzheimer’s get far more attention from the media and even from scientists, but bipolar disorder—featuring episodes of mania that are often followed by depression—arguably takes a greater toll on human health and productivity. At any one time it afflicts almost 3 percent of the US adult population—about ten million people—and it disproportionately affects those who are in the prime of life: Bipolar’s prevalence among 18–29 year olds appears to be about six percent. Moreover, bipolar disorder decreases life expectancy—to about the same degree as cigarette smoking—largely because of an elevated risk of suicide but also, for reasons that aren’t understood, due to elevated rates of “natural causes” of death.

Treatments such as lithium, risperidone, and valproate help many bipolar patients. However, scientists don’t really know how they work—because they lack a fundamental understanding of the disease’s biological mechanisms—and in any case none of these medications comes close to curing the disease.

“It’s remarkable how little we know about the biological bases of affective disorders such as bipolar,” said Rusty Gage, a researcher at the Salk Institute and member of the Dana Alliance for Brain Initiatives. His and other laboratories are beginning to zero in on those biological bases, using new types of cell and animal model.

Overexcitable hippocampal cells

Gage, who has helped to pioneer the use of stem cell-related techniques to study brain diseases, recently teamed up with bipolar disorder researchers to examine how neurons from bipolar patients differ from those of people without the disorder.

The researchers started by harvesting skin cells from six patients with bipolar “type 1,” which predominantly features the hyperactivity, sleeplessness, and euphoria of mania. In the lab, the team reprogrammed the cells to become neurons—specifically granule neurons of the type normally found in the dentate gyrus of the hippocampus, a key memory- and learning-related region.

“We targeted the hippocampus because it has been reported to be atrophied in bipolar disorder,” Gage said, “and we’ve learned over the years that we usually should pick a specific cell type—if we just differentiate the patient cells into ‘neurons,’ the variability is very high.”

Analyses of gene expression patterns and other features of the new neurons revealed some key differences, compared with dentate gyrus neurons derived from non-bipolar volunteers. Above all, the “type 1 bipolar” neurons were more active and excitable.

When the researchers exposed these overexcitable neurons to lithium, the first-line therapy for bipolar disorder, their excitability returned to normal—but only for the neurons derived from patients whose bipolar symptoms had responded to lithium therapy. Neurons from lithium non-responders remained abnormal. That hints strongly that the overexcitability seen in the bipolar patient neurons is not just an incidental finding but is relevant to the disorder. The mania experienced by bipolar disorder patients involves an overabundance of restless energy as well as racing thoughts and speech, which plausibly could be driven by overexcitable neurons and their associated networks in the brain.

Gage and his team plan to investigate other types of neurons derived from bipolar patients, including the dopamine and serotonin-producing neurons that are thought to be affected by risperidone and other treatments.

The scientists are also trying to find out more precisely how the overactivity of dentate gyrus neurons arises. One clue is that mitochondria—the tiny oxygen reactors that fuel most cellular operations and are particularly important for sustaining neurons’ activity and health—are much more active in the neurons from bipolar patients, and are also smaller, making them more swiftly transportable along the neurons’ output stalks (axons). Whether these mitochondrial abnormalities lead or follow the overall neuronal overexcitability remains to be seen.

How people who are manic eventually swing back to a normal mood, or even to the lowered mood of depression, also remains a mystery. However, Gage and his colleagues have observed that as their patient-derived and normal control neurons mature in the lab dish, the patient-derived neurons start out more excitable than the controls, but eventually become less and less excitable—until, several weeks later, “the bipolar neurons drop in their excitability below the level of the controls,” Gage said.

A rise and fall in the excitability of these neurons during maturation would be potentially relevant to the disorder because the dentate gyrus is one of the only places in the adult brain where new neurons are continually being produced and maturing.

Gage and his team are now trying to understand what causes this apparent drop from overexcitable to underexcitable. It isn’t clear that the neurons themselves are dying early. “The cell density in the dish does not appear to be changing,” Gage said. “On the other hand the cells may still be there but not functioning, so that the only ones [whose activity] we’re seeing are cells that are relatively young.”

The researchers are also investigating whether these apparent wavelike rhythms in excitability occur over periods of months rather than just the weeks studied so far.

“We’re all pretty cautious about all this, but it’s the hypothesis we’re following up on,” Gage said.

The circadian and dopamine connections

Gage’s investigation of hippocampal neurons proceeded from observations that the hippocampus appears to shrink faster with aging in people with bipolar disorder compared to people without the disorder. There also have been observations in bipolar patients that point to the involvement of other brain areas.

For example, mania episodes often follow incidental disruptions to the normal daily (“circadian”) sleep-wake cycle—from staying up late, traveling by air across multiple time zones, etc. Mania episodes also typically worsen circadian abnormalities by making sleep difficult or impossible. Lithium and valproic acid are thought to alleviate mania episodes in part by helping to restore normal circadian rhythms.

“There are a lot of things pointing to the fact that circadian rhythms in bipolar patients are disrupted, and changes to these rhythms can really precipitate episodes, so that it’s really beneficial for these patients to have very stable circadian rhythms,” said Colleen McClung, a researcher at the University of Pittsburgh.

Mania episodes also commonly feature compulsive, disinhibited activity—excessive gambling, hypersexuality, or other socially inappropriate behavior—of the type that has also been reported in people who take dopamine-boosting therapies or recreational drugs.

A recent study led by McClung suggests that these circadian and dopamine links to bipolar disorder could be intertwined.

McClung’s group had previously discovered that mice with a particular mutation in the Clock gene, an essential enforcer of circadian rhythms, cycle between apparently normal behavior at night (when mice ordinarily are awake and active) and mania-like behavior during the day (when mice ordinarily sleep).

In the new study, the researchers found that the key to the daytime mania-like behavior was a surge in dopamine levels in the ventral tegmental area (VTA), a major node in the pleasure-seeking circuitry of the brain. VTA dopamine levels spiked because levels of tyrosine hydroxylase—an enzyme that mediates dopamine production—rose sharply.

Why did tyrosine hydroxylase levels increase? McClung’s team discovered that the Clock protein normally suppresses the transcription of the tyrosine hydroxylase gene. Thus, when this function of Clock was disrupted by the mutation, the usual daytime brakes were off, tyrosine hydroxylase production surged, VTA dopamine levels surged—and with this neurochemical change came the mania-like behaviors of the mice.

“There’s apparently something about having surges of dopamine at the wrong time of day, when the mice are supposed to be sleeping, that the circuitry in the mouse brain is not able to handle in the way that it would when the mouse is supposed to be awake,” said McClung.

She and her colleagues found that they could reproduce these mania-like behaviors by artificially driving VTA dopamine neuron activity in mice using optogenetics techniques. Importantly, they could also inhibit the daytime mania-like behavior of Clock-mutant mice by administering a compound, AMPT, that inhibits tyrosine hydroxylase activity.

McClung suspects that in bipolar patients, as in the Clock-mutant mice, a disruption of circadian rhythms leads to a spike in dopamine levels during the normal sleep-time, and that sleep-time dopamine spike, through some yet-unknown mechanism, triggers the mania episode. She and her colleagues are now trying to determine that dopamine-to-mania mechanism—and conceivably that search will lead to findings that help explain the Gage team’s recent results in hippocampal neurons.

“It’s not just dopamine, there’s something else going on downstream of dopamine, whether it’s in the hippocampus, the nucleus accumbens, the prefrontal cortex—wherever—that is seemingly unable to handle that excess dopamine and is thus involved in triggering the manic episode,” McClung said.“But we don’t know exactly what that is yet.”


Blood Calcium

Greg Marlow

11/1/2017 1:05:21 PM

Could changes in blood calcium level change neuronal excitability in bipolar patients?


Jen Thomas

8/17/2017 10:25:36 AM

Hi. I read your article with interest and appreciate the information. I am a clinical counselor and interested in learning more about Bipolar disorder, so I read your article. I am hoping to find out whether things that naturally increase dopamine should be avoided by someone diagnosed with bipolar disorder? The article says that spikes in dopamine at certain times seem to lead to a manic period.