The Humane Research Trust is funding a research project to advance understanding of the causes of neurodevelopmental conditions. Using human cortex cells grown in the laboratory, the University of Edinburgh scientists will look at the role of a specific gene in affecting the balance of different neuron types. This will reveal new insights into the factors that could contribute to the development of conditions like autism.
Neurodevelopmental conditions occur in the brain and central nervous system, affecting around 3-4% of people in the UK. They manifest in childhood and are characterised by differences in brain development and functioning. This group includes autism spectrum conditions (ASC), attention deficit hyperactivity disorder (ADHD), learning disability, and schizophrenia.
These conditions affect a part of the brain called the cortex, which is responsible for brain functions such as sensory, motor, and cognitive processes. The cortex includes two major types of nerve cells: excitatory and inhibitory neurons. Excitatory neurons activate target cells, whilst inhibitory neurons interfere with the function of other neurons.
Scientists think that an imbalance between these neuron types could contribute to these conditions. “There are no effective treatments for these conditions available. That's why it's important to study the formation of the balance between excitatory and inhibitory neurons,” says Dr Thomas Theil. Dr Theil is Reader at the Centre for Discovery Brain Sciences at the University of Edinburgh.
He thinks that the primary cilium, a specialised subunit of the cortical cells, could be an important controller of this balance. The cilium is a tiny hair-like structure that comes out of a cell’s surface. It acts as an antenna for communicating with other cells. So, to learn more about neurodevelopmental conditions, Dr Theil is studying the relationship between cilia function, excitation/inhibition balance, and the effect on the functionality of the neurons.
Research into neurodevelopmental conditions often involves animals such as mice. However, mice models do not adequately capture the complexity of the human brain, and the conditions that can affect it. Additionally, these experiments use a huge quantity of animals and cause a high degree of suffering. Between 2014 and 2023 alone, 2.58 million live animals were used and killed in British neurological research projects.
“Animal models have limitations, as there are key species differences in neural stem cell types, neuronal maturation, and synaptic connectivity,” explains Dr Theil. “We need a human brain model system to study human cortical development and the causes of neurodevelopmental conditions.”
The Humane Research Trust is funding research at the University of Edinburgh to develop a human brain model. The scientists, led by Dr Theil, are using 'cortical organoids'. These are brain-like structures grown in the lab from human stem cells. Using this approach, the scientists will study how disruptions in the primary cilia influence the development of excitatory and inhibitory neurons. Further, they will reveal how this can affect the overall function of the neural network.
Using CRISPR gene editing technology, they will engineer their organoids to have a gene mutation called CEP41. This gene is strongly associated with autism and encodes a protein that is important in primary cilia development. Using imaging techniques, the scientists will study the impact of this gene on the morphology and activity of neurons, and the synapses between junctions.
Together, these analyses will offer valuable insights into the impact of this autism-specific gene on the structure and function of neurons in the cortex. This will deepen our understanding of the role of the primary cilia in neurodevelopmental conditions, laying the groundwork for discovering ways to enhance cortical functionality. Ultimately, it is hoped that this will help enhance the lives of autistic people and those with other neurodevelopmental conditions.
Dr Thomas Theil
Principal investigator
Dr Thomas Theil is a Reader at the Centre for Discovery Brain Sciences at the University of Edinburgh. His research group is investigating the molecular mechanisms that control how the cortex in the brain develops and functions. His group use 3D cell culture techniques to delve into the changes that occur in neurodevelopmental conditions and genetic disorders which affect the cilium.
Dr Kerstin Hasenpusch-Theil
Postdoctoral researcher
Kerstin is a Postdoctoral Research Associate at the University of Edinburgh. She has extensive experience establishing and using organoids to study human brain development and neurodevelopmental conditions. Most recently, she's been investigating a novel role of primary cilia in cortical stem cells.
