Post by Deborah Joye
What's the science?
Bipolar disorder (BD) is a complex affective disorder that can be trademarked by repetitive episodes of mania and depression. One of the most common, pharmacological treatments for individuals experiencing BD is lithium. Although lithium has been used for decades to successfully treat BD, the mechanism by which lithium works to treat symptoms is not clear and not every patient responds to lithium treatment. Recently developed induced pluripotent stem cell (iPSC) technology allows researchers to take living cells (like skin cells or white blood cells) from BD patients and turn them into specific types of neurons, allowing for the investigation of cellular differences in individuals with BD versus healthy controls. Previous research using this methodology has found cellular differences in the dentate gyrus region of the hippocampus, where cells derived from BD patients are hyperexcitable, exhibiting longer durations of increased firing activity relative to cells from controls. This week in Biological Psychiatry, Stern and colleagues use induced pluripotent stem cells technology to demonstrate that CA3 hippocampal pyramidal cells can also be hyperexcitable in BD due to differences in potassium currents and that lithium treatment can reduce this hyperexcitability.
How did they do it?
The authors collected cells from 6 BD patients (3 known to respond to lithium and 3 non-responders) and 4 individuals without BD (controls). Using iPSC methodology, the authors created CA3 hippocampal cells from each participant and then used whole-cell patch-clamp electrophysiology to study the cell’s a) electrical properties, b) response to lithium and c) response to specific potassium channel blockers The authors also used quantitative polymerase chain reaction (qPCR) to investigate the expression of specific genes within each cell.
What did they find?
As with cells from the dentate gyrus, the authors found that CA3 BD neurons were hyperexcitable, but only when derived from patients that responded to lithium. This cellular hyperexcitability correlated with higher amplitude potassium currents and with faster kinetics. Faster potassium currents can result in hyperexcitability because the cell is able to recover faster from each action potential and therefore produce more action potentials for a given input. The authors also found that neurons derived from lithium-responding BD patients exhibited overexpression of genes Kcnc1 and Kcnc2, which code for subunits of voltage-gated potassium channels. When the authors applied potassium channel blockers to cells, hyperexcitability was reduced, further supporting the role of potassium channels in BD-derived CA3 cell hyperexcitability. Chronically treating cells with lithium also decreased hyperexcitability in cells derived from lithium responders, which was associated with an increase in sodium currents and a reduction in fast potassium currents. Fast potassium currents slow a cell’s ability to re-polarize after firing an action potential and increase the amount of time before another action potential can fire. While CA3 cells from lithium non-responders did not exhibit hyperexcitability, they did display altered physiology compared to healthy controls, including reduced sodium currents and increased fast and slow potassium currents as well as a unique distribution of highly excitable and very low excitability neurons. Changes to these features suggest that, in general, BD patients may have altered cellular physiologies, but that CA3 hyperexcitability was specific to lithium responders.
What's the impact?
This study uncovers neuron-specific physiological changes that can occur in the brains of individuals with BD and provides critical insight into how lithium might successfully treat bipolar disorder in a subset of patients. Due to the slow progress of BD research, treatment options for those suffering from this complex disorder have not changed much in decades. This study demonstrates important differences in hippocampal cell function in BD patients who respond to lithium, relative to both lithium non-responders and healthy controls, providing important avenues for future therapeutics.
Stern et al., Mechanisms underlying the hyperexcitability of CA3 and dentate gyrus hippocampal neurons derived from bipolar disorder patients, Molecular Psychiatry (2019). Access the original scientific publication here.