Lithium reduced calcium influx by suppressing the functions of several genes. Credit: Benjavisa/ iStock/ Getty Images
Neurologists have provided new insights into how lithium, a mood-stabilising drug, dampens hyperactive neurons in patients with bipolar disorder1.
Lithium treatment is known to soothe an agitated bipolar brain but is only effective in one-third of patients. The rest show limited or no response.
To understand why, scientists at the National Centre for Biological Sciences-TIFR GKVK campus in Bengaluru treated lab-grown cortical cells of the human forebrain with specific neurotransmitters, such as serotonin.
These neurotransmitters bind to receptors on the neurons, activating an enzyme called phospholipase C (PLC). This converts a lipid molecule phosphatidylinositol 4,5-bisphosphate (PIP2) into inositol 1, 4, 5-triphosphate (IP3). This mimicked overstimulated cells in a bipolar brain.
The researchers then added lithium to the mix. This delayed the re-synthesis of PIP2, slowing the formation of IP3. This, in turn, reduced calcium influx and dampened the neurons’ activity.The experiments showed that lithium interacts with an enzyme called Inositol monophosphatase 1 (IMPA1), preventing it from catalysing the formation of IP3. Removing IMPA1 from a group of nerve cells made these cells go into overdrive which lithium could not modulate.
The researchers also found that lithium reduced calcium influx by suppressing the functions of several genes that orchestrate different pieces of the calcium channels. This suggests that an altered calcium level is a likely basis for bipolar disorder.
The results of this study will help to develop lab tests that could be used to detect patients with bipolar disorder who will respond to lithium treatment, the researchers say.
