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Headlines 13 T he 1918 influenza pandemic caused by an H1N1 virus affected about 500 million people worldwide. In the following years, the medical community noticed a marked rise in patients with mental disorders and other symptoms, causing scientists to suspect a link between viruses and neuropsychiatric disorders. Much has been discovered since, including the knowledge that exposure to a viral or bacterial infection while in the womb (maternal immune activation) increases offspring’s risk of developing schizophrenia and autism. Fast forward to 2022, and the ongoing COVID-19 pandemic caused by SARS-CoV-2 has also resulted in over 500 million infections worldwide, among them pregnant women. It's a worrisome scenario, says Professor Liu. "Given the known link between maternal immune activation and offspring's risk of developing neuropsychiatric diseases (such as schizophrenia and autism), the impact of the COVID-19 pandemic on offspring will be a critical health issue on a global scale," Professor Liu says. "There is an urgent need to develop new preventive and therapeutic strategies for COVID-19 infected pregnant women and their offspring. However, it is important to note that little is known of the long-term effects of COVID-19 on the mother and the baby at this stage." Researchers such as Professor Liu have explored the link between viruses and neurological disorders for decades, giving the scientific community a significant head start. So how is a virus linked to neurodevelopmental disorders? Research suggests it is to do with an amino acid called arginine. Arginine is metabolised into agmatine by the human body, and agmatine (decarboxylated arginine) appears to modulate chemicals and pathways in the brain. The immune response that kicks in when a foetus contracts a virus causes alterations in arginine metabolism and microglia – the innate immune cells in the brain – having a critical role in neurodevelopment. Professor Liu’s research has demonstrated that these changes persist until adulthood in rat offspring with maternal immune activation, along with behavioural changes mimicking symptoms of schizophrenia patients. Professor Liu has led much of the agmatine and arginine research in the fields of learning, memory, aging, Alzheimer’s disease and schizophrenia, with support from the Neurological Foundation. Since 2000, she has received eight grants ($1.23m in total) from the Neurological Foundation, supporting her career development from Postdoctoral Fellow to Professor. Each grant has allowed Professor Liu to build her research and test new ideas. For instance, an initial focus for Professor Liu was the role of nitric oxide in the brain, critical for synaptic plasticity, learning, memory, and cerebral blood flow. The findings from this research led to her interest in agmatine, which is an important regulator for nitric oxide production. In 2014 she was granted funding to explore whether changes in arginine metabolism after contracting a virus while pregnant is linked to schizophrenia in offspring. And in 2018, she successfully applied for a grant to broaden her arginine research to neurodegenerative disorders, including Alzheimer’s and other dementias. Her current project explores agmatine's preventative and/or therapeutic potential for offspring with prenatal exposure to viral infections. "By inducing a viral-like immune response in pregnant rats or mice, a number of behavioural and neural features of schizophrenia was evident in their offspring," Professor Liu says. "The information obtained from this project may offer strategies to reduce the heightened neuropsychiatric burden in children with prenatal exposure to viral infections." Her research has implications beyond COVID-19. It may also help diagnose and treat Alzheimer's disease, schizophrenia, and many other neurodevelopment conditions. A COVID-19 head start Professor Ping Liu's pioneering research on viruses and long-term neurological damage Professor Ping Liu works in the Department of Anatomy at the University of Otago. She completed her PhD at Otago in 1998 after eight years of clinical work as a geriatrician in China. Over the next two decades, she pioneered research into the role of arginine metabolism in ageing and neurodegenerative and psychiatric diseases, becoming an international expert in this field. A focus on the interplay between viruses and the brain has provided a head-start on understanding COVID-19's long-term neurological impacts. GLOSSARY Arginine: an essential amino acid that helps your body build protein. It is found widely in our body, including in our brain. Maternal Immune Activation: a maternal immune system response triggered by pathogens or inflammation that may affect foetal neurodevelopment. Arginine metabolism: the body's process of metabolising arginine for important functions including cell division, wound healing, immune function, the release of hormones, and learning and memory.