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A study conducted by National Centre for Biological Sciences (NCBS) researchers has revealed how lithium acts on brain cells to change neural activity. This finding, according to NCBS, could offer a potential pathway for the development of new treatments and precision medicine for bipolar disorder.
“Bipolar disorder stands as the sixth leading cause of disability globally demanding effective therapeutic intervention. While mood stabilisers like lithium are the go-to treatment to soothe a bipolar brain, only about one-third of patients benefit from lithium treatment. The remaining patients with bipolar disorder show limited or no response to lithium treatment,” said NCBS.
How lithium acts
One of the reasons for this inability to predict the response of an individual to treatment is a lack of clear understanding of how lithium acts on the brain leading to an improvement in a patient’s condition, it added.
“To understand why some patients do not respond to lithium treatment, we need to know how lithium exerts its effects,” said Sankhanil Saha, lead author of the study.
In the brain, communication between cells leading to normal behaviour occurs through chemicals called neurotransmitters. These neurotransmitters, such as serotonin or glutamate bind to receptors in the neural cell membrane that switch on an enzyme called phospholipase C (PLC).
Breaking down molecule
The role of PLC is to break down a lipid molecule–phosphatidylinositol 4,5-bisphosphate (PIP2) into inositol1,4,5-trisphosphate (IP3) which orchestrates changes in calcium levels within the cells. Calcium performs many functions within the brain and previous studies that altered calcium levels within neurons is a likely basis for bipolar disorder.
“In individuals with Bipolar Affective Disorder (BPAD), the PIP2 pathway is in hyperactive mode which leads to elevated calcium levels in the cell,” Mr. Sankhanil said.
To understand lithium’s stabilising effect, they treated lab-grown cortical cells of the human forebrain with neurotransmitters to mimic the activity of a bipolar patient’s brain cells. This activated the PLC, mimicking the overstimulated cells of a bipolar brain. On adding lithium to the mix, the team observed a delay in the re-synthesis of PIP2. Consequently, it slowed down the formation of IP3 and reduced calcium influx that dampened the activity of neurons.
Delayed synthesis
The research team further investigated how lithium delayed the PIP2 re-synthesis. In subsequent experiments, they discovered that lithium interacts with an enzyme IMPA1, suppressing it from catalysing the formation of Inositol, essential for a continuous supply of PIP2 in the cells. When they removed the IMPA1 from a group of cells, it turned out that lithium could not modulate the hyperexcitability of the brain cells.
“The insights from our study into how lithium acts on human brain cells will pave the way for lab tests to help doctors predict which bipolar patients will respond to lithium. It will be valuable for doctors to clearly predict which patient will respond to a given medicine to devise a treatment uniquely suited for that individual; this is a very exciting area called precision medicine that is expanding worldwide,” said Raghu Padinjat, professor, NCBS.
