Using a genetically modified mouse model, researchers have shown that a mutation in the Plau gene – which is involved in the migration of newly formed nerve cells and the pruning of excess neural connections – causes changes in behaviour and brain structure characteristic of autism spectrum disorders. Animals carrying the mutation displayed heightened anxiety, reduced social interaction with peers, but outperformed healthy controls in solving complex tasks. The mouse model of autism created by the authors will enable testing of new diagnostic and therapeutic approaches and help unravel the molecular causes of the condition. The findings were published in the journal Frontiers in Cell and Developmental Biology.
The study was conducted by researchers from Lomonosov Moscow State University, the Mental Health Research Centre, and the Russian University of Medicine of the Russian Health Ministry.
Using CRISPR/Cas9 genome editing, the scientists introduced a mutation into the mouse Plau gene, replacing a single nucleotide in the functional centre of the corresponding enzyme. This substitution increased the activity of the Plau‑derived protein by 40% compared with normal levels, and significantly altered the behaviour of the mutant mice. The animals spent very little time interacting with peers, preferring isolation, and displayed heightened anxiety, aggression and behavioural stereotypies – repetitive motor patterns. These social and behavioural deficits are typical of several autism spectrum disorders.
However, under stressful conditions – when searching for an escape from a water maze – the mutant mice performed significantly faster and more successfully than normal mice. The researchers said this feature is difficult to interpret unequivocally: it may reflect extreme anxiety or, alternatively, an exceptional ability to focus attention on overcoming a life‑threatening challenge.
The researchers also compared brain structure between healthy mice and those carrying the Plau mutation. Analysis revealed that the mutation caused thickening of the somatosensory cortex – a region responsible for processing visual, auditory and tactile information. Similar changes have been described in some patients with autism spectrum disorders.
“We have not only identified another new genetic alteration that can lead to autism spectrum disorders, but have also created a convenient model for studying this group of conditions and testing new drugs for their correction and treatment,” said Maxim Karagyur, project leader, head of the Postgenomic Technologies Laboratory and associate professor at the Department of Biochemistry and Regenerative Medicine of the Medical Research and Education Institute at Lomonosov Moscow State University.
“In the future, we plan to investigate the brain structure and function of these mice in greater detail, and to determine at the cellular and pathway level how it differs from the brain of healthy animals. From our perspective, a promising next step would be to evaluate the possibility of pharmacological prevention and correction of hereditary forms of autism spectrum disorders using this genetic model.”