{"id":25741,"date":"2020-02-19T10:31:23","date_gmt":"2020-02-19T18:31:23","guid":{"rendered":"https:\/\/vermont.salk.edu\/?post_type=disclosure&p=25741"},"modified":"2024-01-30T14:42:10","modified_gmt":"2024-01-30T22:42:10","slug":"altered-potassium-levels-in-neurons-may-cause-mood-swings-in-bipolar-disorder","status":"publish","type":"disclosure","link":"https:\/\/www.salk.edu\/es\/news-release\/altered-potassium-levels-in-neurons-may-cause-mood-swings-in-bipolar-disorder\/","title":{"rendered":"Altered potassium levels in neurons may cause mood swings in bipolar disorder"},"content":{"rendered":"

LA JOLLA\u2014People with bipolar disorder experience dramatic shifts in mood, oscillating between often debilitating periods of mania and depression. While a third of people with bipolar disorder can be successfully treated with the drug lithium, the majority of patients struggle to find treatment options that work.<\/p>\n

Now, a sweeping new set of findings by Salk researchers reveals previously unknown details explaining why some neurons in bipolar patients swing between being overly or under excited. In two papers published in the journal Biological Psychiatry<\/em> in Febrero 2020<\/a> y Octubre 2019<\/a>, Salk researchers used experimental and computational techniques to describe how variations in potassium and sodium currents in the brain cells of people with bipolar disorder may help to further explain why some patients respond to lithium and others do not.<\/p>\n

\"Healthy
Healthy CA3 pyramidal neurons stained to show the cell body (blue) and axons (green).<\/p>\n

Haga clic aqu\u00ed<\/a> para obtener una imagen en alta resoluci\u00f3n.<\/p>\n

Cr\u00e9dito: Instituto Salk<\/figcaption><\/figure>\n

\u201cThis is exciting progress toward understanding the cellular mechanisms that cause bipolar disorder,\u201d says Salk Professor\u00a0Rusty Gage<\/a>, the study\u2019s senior author and president of the Institute. \u201cIt also brings us one step closer to being able to develop new therapeutics to treat the disorder.\u201d<\/p>\n

In 2015<\/a>, Gage and his colleagues discovered for the first time the initial differences between brain cells of patients who respond to lithium and those who don\u2019t. In both cases, neurons from the brain\u2019s dentate gyrus (DG) region were hyperexcitable\u2014more easily stimulated\u2014compared to DG neurons from people without bipolar disorder. But when exposed to lithium, only the cells from known lithium-responders were calmed by the drug.<\/p>\n

In the new research, Gage\u2019s team\u2014curious whether the results held true across different brain areas\u2014conducted similar experiments but with more in-depth probes and using a different type of neuron than before. They grew the neurons\u2014called CA3 pyramidal neurons\u2014from six people with bipolar disorder, three of whom responded to lithium.<\/p>\n

While in previous studies DG neurons from all bipolar patients were hyperexcitable, in the new study, only CA3 neurons from lithium responders were hyperexcitable all the time.<\/p>\n

\u201cThe neurons were very different between responders and non-responders,\u201d says Salk research associate Shani Stern, first author of both papers. \u201cIt\u2019s almost as if it\u2019s two different diseases.\u201d<\/p>\n

Studying the CA3 neurons from lithium responders more closely, the team found that these cells had higher than usual numbers of potassium channels as well as stronger potassium currents through these channels. The increased potassium currents, the scientists showed, were responsible for the hyperactivity of the CA3 neurons: when they exposed the cells to a potassium channel blocker, the hyperactivity disappeared. Intriguingly, when they exposed the cells to lithium, the drug not only reversed the hyperactivity but reduced potassium currents at the same time.<\/p>\n

\"From
From left: Shani Stern and Rusty Gage<\/p>\n

Haga clic aqu\u00ed<\/a> para obtener una imagen en alta resoluci\u00f3n.<\/p>\n

Cr\u00e9dito: Instituto Salk<\/p>\n

<\/figcaption><\/figure>\n

In addition, the team initially observed that the CA3 neurons from lithium non-responders, on average, had normal excitability. But when they looked more closely at individual cells over time, they found a different story.<\/p>\n

\u201cThere were days I\u2019d measure the cells and the whole group would be hyperexcitable, and other days they\u2019d all be hypoexcitable,\u201d says Stern. \u201cAnd then there were times when the cells would be split; some would be very hyperexcitable and others very hypoexcitable.\u201d<\/p>\n

To better understand what was causing these fluctuations, the researchers designed a computational simulation of CA3 neuron activity. The computer simulation revealed that drastic reductions in sodium currents and an increase in the amplitude of potassium currents could lead to the same kind of neuronal instability in CA3 neurons\u2014explaining both hyperexcitability and hypoexcitability. When the researchers then exposed CA3 neurons from non-responders to potassium channel blockers, their excitability became closer to control levels. The findings strengthened the case that potassium currents play a role in bipolar disorder\u2014in both lithium responders and non-responders\u2015and can help researchers understand how to better target drugs.<\/p>\n

The team is planning additional studies on what happens to large networks of neurons when they alternate between hyperexcitable and hypoexcitable phases to understand if these shifts may be driving the manic and depressive moods seen in bipolar disorder.<\/p>\n

Other researchers on the papers were Anindita Sarkar, Dekel Galor, Tchelet Stern, Arianna Mei, Yam Stern, Ana P. D. Mendes, Lynne Randolph-Moore, Renata Santos, Maria C. Marchetto, Gabriela Goldberg, Thao Nguyen and Yongsung Kim of Salk; Guy Rouleau of the McGill University; Anne Bang of Sanford Burnham Prebys Medical Discovery Institute; and Martin Alda of Dalhousie University.<\/p>\n

The work and researchers involved were supported by the\u00a0National Cancer Institute, the National Institutes of Health,\u00a0the National Cooperative Reprogrammed Cell Research Groups, the Leona M. and Harry B. Helmsley Charitable Trust, the JPB Foundation, Annette C. Merle-Smith, the Robert and Mary Jane Engman Foundation and the Canadian Institutes of Health.<\/p>\n

Publication Information<\/strong><\/p>\n

Journal<\/strong>
\nBiological Psychiatry<\/em><\/p>\n

Title<\/strong>
\nMechanisms underlying the hyperexcitability of CA3 and dentate gyrus hippocampal neurons derived from bipolar disorder patients.<\/em><\/p>\n

Authors<\/strong>
\nShani Stern, Anindita Sarkar, Tchelet Stern, Arianna Mei, Ana P. D. Mendes, Yam Stern, Gabriela Goldberg, Dekel Galor, Thao Nguyen, Lynne Randolph-Moore, Yongsung Kim, Guy Rouleau, Anne Bang, Martin Alda, Renata Santos, Maria C. Marchetto, Fred H. Gage<\/p>\n

DOI<\/strong>
\n10.1016\/j.biopsych.2019.09.018<\/a><\/p>\n

\n

Journal<\/strong>
\nBiological Psychiatry<\/em><\/p>\n

Title<\/strong>
\nA physiological instability displayed in hippocampal neurons derived from lithium non-responsive bipolar disorder patients<\/em><\/p>\n

Authors<\/strong>
\nShani Stern, Anindita Sarkar, Dekel Galor, Tchelet Stern, Arianna Mei, Yam Stern, Ana P. D. Mendes, Lynne Randolph-Moore, Guy Rouleau, Anne Bang, Renata Santos, Martin Alda, Maria C. Marchetto, Fred H. Gage<\/p>\n

DOI<\/strong>
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