A new Salk study, among the first to show how bipolar disorder affects neurons in the brain, also discovers fundamental differences in patient cells.
The brain cells of patients with bipolar disorder, characterized by severe swings between depression and elation, are more sensitive to stimuli than other people’s brain cells, researchers have discovered.
The finding, published October 28, 2015 in the journal Nature, is among the first to show at a cellular level how the disorder affects the brain. Moreover, it reveals why some patients respond to treatment with lithium while others don’t.
“Researchers hadn’t all agreed that there was a cellular cause to bipolar disorder,” says Rusty Gage, a professor in Salk’s Laboratory of Genetics and senior author of the new work. “So our study is important validation that the cells of these patients really are different.”
Bipolar disorder affects more than five million Americans and is often a challenge to treat. If patients’ severe mood swings aren’t helped with lithium, doctors often piece together treatment plans with antipsychotic drugs, antidepressants and mood stabilizers. But they often help only the depressive swings of bipolar or the opposing manic swings, not both.
To study the underlying cause of bipolar disorder, Gage and his colleagues collected skin cells from six bipolar patients, reprogrammed the cells to become stem cells, and then coaxed the stem cells to develop into neurons. They then compared those neurons to ones from healthy people.
“Neurons are normally activated by a stimuli and respond,” says Jerome Mertens, a postdoctoral research fellow and first author of the new paper. “The cells we have from all six patients are much more sensitive in that you don’t need to activate them very strongly to see a response.” And the mitochondria–energy-generating powerhouses–inside the cells were also more active.
Since three of the patients that the cells were collected from had responded well to lithium, and three others hadn’t seen lithium help their mood swings, the researchers next tested how the patient cells reacted to lithium. The team let some of the neurons grow in liquid containing lithium and then re-measured how sensitive the cells were.
Surprisingly–although neurons from the two groups of patients had seemed identical (and equally sensitive) in the first tests–they behaved differently when exposed to the lithium. Cells from lithium responder patients showed weakened excitability after growing in the lithium. But cells from patients who hadn’t been helped by the drug remained hyperexcitable. The findings don’t yet explain why lithium works for some patients and not others, but offers a starting point to probe what the differences between the cells are. And the bipolar neurons also offer a platform to ask other questions about biopolar disorder.
“Now that we have neurons that show differences in excitability, we can use these to screen for better drugs,” Mertens says. If a new drug, for instance, reverses the hyperexcitability at the cellular level, it would likely treat bipolar disorder in patients.
Gage and Mertens next plan to follow the affected cells for longer periods of time to see whether the hyperexcitability they measured is only an initial manic stage of the neurons’ lives or is long-lasting.
“After a few months, it’s possible that this hyperexcitability becomes too much for the cell to handle and it crashes into a less excitable state,” says Gage. “That could signal the shift between the depression and mania that patients experience.”
Funding: The work and the researchers were supported by grants from the National Natural Science Foundation of China, the National Basic Research Program of China, the Engmann Family Foundation, the JPB Foundation, the Leona M. and Harry B. Helmsley Charitable Trust, the G. Harold and Leila Y. Mathers Charitable Foundation, the Glenn Foundation for Medical Research, the National Institute of Mental Health, and the Department of Veterans Affairs.
Source:Salk Institute Image Credit: The image is credited to Salk Institute for Biological Studies Original Research:Abstract for “Differential responses to lithium in hyperexcitable neurons from patients with bipolar disorder” by Jerome Mertens, Qiu-Wen Wang, Yongsung Kim, Diana X. Yu, Son Pham, Bo Yang, Yi Zheng, Kenneth E. Diffenderfer, Jian Zhang, Sheila Soltani, Tameji Eames, Simon T. Schafer, Leah Boyer, Maria C. Marchetto, John I. Nurnberger, Joseph R. Calabrese, Ketil J. Ødegaard, Michael J. McCarthy, Peter P. Zandi, Martin Alba, Caroline M. Nievergelt, The Pharmacogenomics of Bipolar Disorder Study, Shuangli Mi, Kristen J. Brennand, John R. Kelsoe, Fred H. Gage and Jun Yao in Nature. Published online October 28 2015 doi:10.1038/nature15526
Differential responses to lithium in hyperexcitable neurons from patients with bipolar disorder
Bipolar disorder is a complex neuropsychiatric disorder that is characterized by intermittent episodes of mania and depression; without treatment, 15% of patients commit suicide1. Hence, it has been ranked by the World Health Organization as a top disorder of morbidity and lost productivity2. Previous neuropathological studies have revealed a series of alterations in the brains of patients with bipolar disorder or animal models3, such as reduced glial cell number in the prefrontal cortex of patients4, upregulated activities of the protein kinase A and C pathways5, 6, 7 and changes in neurotransmission8, 9, 10, 11. However, the roles and causation of these changes in bipolar disorder have been too complex to exactly determine the pathology of the disease. Furthermore, although some patients show remarkable improvement with lithium treatment for yet unknown reasons, others are refractory to lithium treatment. Therefore, developing an accurate and powerful biological model for bipolar disorder has been a challenge. The introduction of induced pluripotent stem-cell (iPSC) technology has provided a new approach. Here we have developed an iPSC model for human bipolar disorder and investigated the cellular phenotypes of hippocampal dentate gyrus-like neurons derived from iPSCs of patients with bipolar disorder. Guided by RNA sequencing expression profiling, we have detected mitochondrial abnormalities in young neurons from patients with bipolar disorder by using mitochondrial assays; in addition, using both patch-clamp recording and somatic Ca2+ imaging, we have observed hyperactive action-potential firing. This hyperexcitability phenotype of young neurons in bipolar disorder was selectively reversed by lithium treatment only in neurons derived from patients who also responded to lithium treatment. Therefore, hyperexcitability is one early endophenotype of bipolar disorder, and our model of iPSCs in this disease might be useful in developing new therapies and drugs aimed at its clinical treatment.
“Differential responses to lithium in hyperexcitable neurons from patients with bipolar disorder” by Jerome Mertens, Qiu-Wen Wang, Yongsung Kim, Diana X. Yu, Son Pham, Bo Yang, Yi Zheng, Kenneth E. Diffenderfer, Jian Zhang, Sheila Soltani, Tameji Eames, Simon T. Schafer, Leah Boyer, Maria C. Marchetto, John I. Nurnberger, Joseph R. Calabrese, Ketil J. Ødegaard, Michael J. McCarthy, Peter P. Zandi, Martin Alba, Caroline M. Nievergelt, The Pharmacogenomics of Bipolar Disorder Study, Shuangli Mi, Kristen J. Brennand, John R. Kelsoe, Fred H. Gage and Jun Yao in Nature. Published online October 28 2015 doi:10.1038/nature15526