Brain Awareness Week 2021: Understanding rare genetic changes in brain biology
Posted on: 18 March 2021
Professor Louise Gallagher and her research group are beginning to understand how changes in brain structure and function may lead to brain conditions such as autism, epilepsy and psychosis. Here, she explains the background to this research and her group’s involvement in a pan-European study on autism biomarkers.
Conditions that affect the brain are among the leading causes of global disability and premature mortality. Major advances in genomics and neuroscience research are providing us with a growing understanding of the biology underlying these conditions which promises new advances in drug therapies and improved interventions.
A key area where our knowledge has expanded relates to the biology at the synapse. The synapse is a fundamental structure in the brain that allows signals to pass from one neuron, or brain cell, to the next. This leads to the formation of key connections or brain circuits that underlie complex brain functions. Through genomics research we now understand that genes that influence the development and functioning of the synapse are disrupted in many brain conditions such as intellectual disability, autism, psychosis and epilepsy.
Increasingly we see people with brain conditions who carry rare genetic changes to genes that are involved in brain development, particularly in synaptic genes. In my research group, we use an approach called deep phenotyping to understand the impact of these genetic changes on the brain. Deep phenotyping means that we collect detailed information on behavioural symptoms, conduct tests of brain functions (cognitive tests) and study brain electrical activity, structure and function. Through this we are beginning to understand how changes in brain structure and function may lead to the brain conditions we study. We also study the genetic background of carriers of rare genetic changes to see how it influences the degree to which people are affected.
One gene that we are currently focusing on is called Neurexin 1 (NRXN1) which encodes for a protein that is situated at excitatory and inhibitory synapses. These synapses fine tune excitation and inhibition of brain cell functioning. If there is too much or too little excitation this disturbs brain connections and can lead to psychiatric and neurological conditions. Deletions of NRXN1 affect only a tiny number of people, and many, although not all, may have learning difficulties, speech and language delays, autism or psychosis.
By participating in our research studies, people with NRXN1 deletions allow us to understand differences in brain functioning, and how this relates to cognitive, behavioural and clinical characteristics. Our neuroimaging research shows differences in the brains of people with NRXN1 deletions compared with people without that seems to show alterations in connectivity in brain regions that are important for attention and visual networks.
To make a connection to underlying biology, we also need to study NRXN1 at the cellular level. Studying the cellular basis of brain conditions is challenging as we don’t have ready access to tissues. Approaches that are used instead include studying the effects of NRXN1 deletions in preclinical animal models, e.g. a mouse who is not expressing the gene. However, there are limitations to using mice to study human brain disorders, so more recently researchers are focusing on induced pluripotent stem cells (IPSCs). IPSCs are immature cells that can be differentiated into any cell type in the body. Our collaborator, Prof. Sanbing Shen at NUIG has created neuronal cells from skin taken from NRXN1 deletion carriers who participate in our studies. In this research we showed that there are differences in calcium signalling in these cells, a process that regulates synaptic activity.
We are now involved in a large pan-European study, AIMS-2-TRIALS, which is focused on biomarker discovery in autism and clinical trials of new drug therapies. Many new drugs that are now being tested for autism and related rare neurodevelopmental disorders are targeted at molecules that impact on excitation or inhibition. For example, Arbaclofen, a drug that increases inhibition in the brain, is currently undergoing clinical trials in the AIMS-2-TRIALS network.
Major advances in our understanding of brain biology in relation to brain conditions, aided by studies in conditions linked to rare genetic mutations, is leading to better treatments for brain conditions. Future studies will be needed to help us understand who will benefit from these therapies and how and when drug therapies should be administered.
An exciting question that needs to be studied is how drug therapies and psychological therapies may be used together to produce better outcomes. Most importantly, we need investment in research in brain disorders and strong collaborations to promote new discoveries and reduce the global burden of brain conditions.
Professor Louise Gallagher is Professor in Child and Adolescent Psychiatry at Trinity’s School of Medicine and the Trinity College Institute of Neuroscience (TCIN).