Researchers at CHU Sainte-Justine and Université de Montréal have discovered a new mechanism involved in the expression of Down syndrome, one of the main causes of intellectual disability and congenital heart defects in children. The study’s findings were published yesterday in Current Biology.
Down syndrome, also called trisomy 21 syndrome, is a genetic condition that affects approximately one in every 800 children born in Canada. In these individuals, many genes are expressed abnormally at the same time, making it difficult to determine which genes contribute to which differences.
For the study, the researchers focused on RCAN1, a gene that is overexpressed in the brains of fetuses with Down syndrome. The team’s work provides insights into how the gene influences the way the condition manifests itself.
The human brain is made up of hundreds of billions of cells known as neurons. They communicate with each other through synapses, which are small gaps between neurons. The ability of synapses to strengthen or weaken over time, known as “synaptic plasticity,” is essential for memory and learning.
“There are two kinds of synaptic plasticity: long-term potentiation, which strengthens synapses and improves interaction between neurons, and long-term depression, which weakens synapses,” says senior author Jannic Boehm, a professor at Université de Montréal and researcher at CHU Sainte-Justine.
“We already knew that synaptic plasticity is influenced by certain proteins,” adds first author Anthony Dudilot. “For example, calcineurin is inhibited when long-term potentiation is induced, but it’s activated when long-term depression begins. But the molecular mechanism underlying calcineurin regulation was less clear.”
The researchers found that the various signaling pathways that trigger synaptic potentiation or depression converge on RCAN1. They also determined that the gene regulates calcineurin activity by inhibiting or facilitating it.
Given its dual role as an inhibitor/facilitator, the researchers deduced that RCAN1 works as a “switch” that regulates synaptic plasticity, thereby affecting learning and memory.
“This is the first time that the molecular mechanism for calcineurin regulation in bidirectional synaptic plasticity has been determined,” Boehm says. “This breakthrough explains how overexpression of the RCAN1 gene could cause intellectual disabilities in individuals with Down syndrome. It also opens up the possibility of developing innovative treatments for affected patients.”