Lithium was the first effective mood stabiliser for bipolar disorder (BD) and still the first-line treatment, but it is effective only in about 30% of patients, while the remainder are unresponsive. A new study implicates the decreased activation of a certain gene.
The study shows that decreased activation of a gene called LEF1 disrupts ordinary neuronal function and promotes hyperexcitability in brain cells—a hallmark of BD. The findings could lead to development of a new drug target for BD as well as a biomarker for lithium nonresponsiveness.
“Only one-third of patients respond to lithium with disappearance of the symptoms,” says Renata Santos, co-first author on the study. “We were interested in the molecular mechanisms behind lithium resistance, what was blocking lithium treatment in nonresponders. We found that LEF1 was deficient in neurons derived from nonresponders. We were excited to see that it was possible to increase LEF1 and its dependent genes, making it a new target for therapeutic intervention in BD.”
The study built on a previous one which discovered differences in the neurons of those with lithium unresponsiveness.
Using stem cell technology, the team grew neurons sampled from patients’ blood, who had BD and were responsive or unresponsive to lithium, and from normal patients. They compared the genetic characteristics and behaviour of those neurons.Lithium enables beta-catenin to pair with LEF1 to promote neural regulation in the normal controls and lithium responders.
Administration of valproic acid, a typical treatment for non-responders, increased LEF1 levels as well as activation of related genes. Silencing the LEF1 gene also deactivated related genes.”When we silenced the LEF1 gene, the neurons became hyperexcitable,” says Shani Stern, co-first author on the study. “And when we used valproic acid, expression of LEF1 increased, and we lowered the hyperexcitability. That shows there is a causative relationship, and that’s why we think LEF1 may be a possible target for drug therapy.”
The team wants to look at other types of cells, such as astrocytes, to better understand the role of LEF1 in the bipolar neural network.”LEF1 works in various ways in different parts of the body, so you can’t just turn it on everywhere,” said co-corresponding author Carol Marchettor. “You want to be more specific, either activating LEF1 on a targeted basis or activating downstream genes that are relevant for lithium nonresponsiveness.”
Source: Medical Xpress
