Study sheds new light on early brain development in Down Syndrome

A research team led by scientists at Queen Mary University of London and University College London (UCL), has found new clues about how the brains of people with Down Syndrome develop differently from a very early age.

The study, published in Nature Communications, shows that brain cells with an extra copy of a chromosome (trisomy 21) – the genetic cause of Down Syndrome – have difficulty forming strong, well-coordinated connections with each other.

Down Syndrome affects millions of people worldwide and it is the most common genetic cause of intellectual disability. In the UK, it is estimated that around 50,000 people live with Down Syndrome, equivalent to roughly one in every thousand people nationally. People with Down Syndrome often experience learning, memory and language difficulties, but exactly how these occur during early brain development had not been well understood.

To explore this, researchers grew human brain cells in the laboratory using stem cell technology. These cells were carefully chosen so that some had Down Syndrome and others did not, while everything else about them was the same. This allowed the scientists to directly compare how brain cells develop with and without the extra chromosome.

They found that brain cells with Down Syndrome were less active and less well connected to each other. Some cells struggled to join brain networks at all. As a result, the networks were less coordinated and less able to send signals together in a regular, organised way. These early differences could help explain why learning and memory are affected later in life.

This research, supported by a Wellcome Trust funded Collaborative Award, also found that Down Syndrome brain cells had problems with the tiny electrical signals that allow nerve cells to communicate. In particular, the researchers identified lower levels of a protein called Kv4.3, which helps control how often and how reliably brain cells send signals. When this protein did not work properly, brain networks developed more weakly.

Dean Nizetic, Professor of Cell and Molecular Biology at Queen Mary said: “This achievement is strategically important as it demonstrates that studying the function of brain cells derived from donated skin cells of living patients can pin point a key protein that is defective in real human brain, which might have otherwise been missed by conventional post-mortem brain studies.

“I’m also particularly proud to be contributing to the knowledge about Down syndrome, as this continues the work of the famous scholar of our medical school, John Langdon Down himself, after whom the syndrome is named

Trevor G Smart, Schild Professor of Pharmacology at University College London, said: “This was a complex Wellcome Trust funded collaborative study (Lead PI TG Smart) specifically designed to use patient-derived stem cell-neurons with the goal of advancing research into the neurological aspects of Down Syndrome. We overcame many technical barriers through close collaboration between two major London institutions The outcome is a comprehensive electrophysiological characterisation of an iPSC-neuron line. Our identification of altered levels of Kv4.3 is potentially very significant for future translation, and for revealing genome-wide alterations in key brain proteins involved in Down syndrome.

The lead author of the study, Dr Saad Hannan, Research Fellow at University College London and at the Department of Molecular and Cellular Biology, Harvard said: “Launched at the dawn of patient-derived iPSC neuron research, this project began as a collaboration between UCL and Queen Mary and evolved into a truly international effort spanning Croatia, South Korea and Canada. Beyond advancing fundamental neuroscience and establishing a benchmark for studying the electrical activity of this compelling cellular model, our findings establish Kv4.3 as a valid target. This creates a clear path for therapeutic development and offers the field, including industry partners, a concrete opportunity to translate mechanistic insight into much-needed potential treatments for the neurological aspects of Down syndrome.”

Carol Boys OBE, Chief Executive of Down’s Syndrome Association said: “This is an exciting piece of research from the teams at Queen Mary University of London and University College London. Another step towards a greater understanding of early brain development in people who have Down’s syndrome, which in turn could lead to treatments and interventions for future generations.”

While this study – carried out in a lab – does not lead to a new treatment and will not change the current care for people with Down Syndrome, it provides valuable insight into the early stage of brain development and may help guide future research.

The researchers note that understanding these early changes could, over time, help scientists think more clearly about how best to support learning and development in people with Down Syndrome.