Major discovery in the genetics of Down syndrome

Summary: Study explains how an overexpression of the RCAN1 gene may cause intellectual disabilities in people with Down syndrome.

Source: University of Montreal

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 today in Current Biology.

Down syndrome (SD), 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.

Professor Jannic Boehm’s research team 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.

Synaptic plasticity, memory and learning

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 is known as “synaptic plasticity.” It’s an important biological phenomenon because it’s 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,” said Boehm, a professor at Université de Montréal and researcher at CHU Sainte-Justine.

“We already knew that synaptic plasticity is influenced by certain proteins,” added Anthony Dudilot, one of the study’s first authors. “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.”

This shows DNA
Down syndrome (SD), 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. Image is in the public domain.

The research team found that the various signalling 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.

A better future for all patients

“This is the first time that the molecular mechanism for calcineurin regulation in bidirectional synaptic plasticity has been determined,” said Boehm. “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.”

About the study

“RCAN1 regulates bidirectional synaptic plasticity” was published in Current Biology in February 2020. The first authors are Anthony Dudilot and Emilie Trillaud-Doppia, PhD candidates supervised by Jannic Boehm. The senior author is Jannic Boehm, PhD, an associate professor at UdeM’s Department of Neurosciences and researcher at CHU Sainte-Justine. The study was backed by the Canadian Institutes of Health Research (CIHR), Fonds de recherche du Québec – Santé (FRQS), the Alzheimer Society of Canada and Université de Montréal.

About this genetics research article

Source:
University of Montreal
Media Contacts:
Julie Gazaille – University of Montreal
Image Source:
The image is in the public domain.

Original Research: Open access
“RCAN1 Regulates Bidirectional Synaptic Plasticity”. Anthony Dudilot, Emilie Trillaud-Doppia, Jannic Boehm.
Current Biology doi:10.1016/j.cub.2020.01.041.

Abstract

RCAN1 Regulates Bidirectional Synaptic Plasticity

Highlights
• Inhibiting GSK3β-dependent phosphorylation of RCAN1 increases synaptic transmission
• Inhibiting GSK3β-dependent phosphorylation of RCAN1 blocks LTD induction
• Inhibiting phosphorylation of RCAN1 at a PKA site blocks LTP induction
• RCAN1 regulates bidirectional synaptic plasticity through its regulation of calcineurin

Summary
Synaptic plasticity, with its two most studied forms, long-term potentiation (LTP) and long-term depression (LTD), is the cellular mechanism underlying learning and memory. Although it has been known for two decades that bidirectional synaptic plasticity necessitates a corresponding bidirectional regulation of calcineurin activity, the underlying molecular mechanism remains elusive. Using organotypic hippocampal slice cultures, we show here that phosphorylation of the endogenous regulator-of-calcineurin (RCAN1) by GSK3β underlies calcineurin activation and is a necessary event for LTD induction, while phosphorylation of RCAN1 at a PKA site blocks calcineurin activity, thereby allowing LTP induction. Our results provide a new mechanism for the regulation of calcineurin in bidirectional synaptic plasticity and establish RCAN1 as a “switch” for bidirectional synaptic plasticity.

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