Discovery would help specify role of genetics in the development of neuropsychiatric disorders

Neurobiologists from I.M. Sechenov First Moscow State Medical University confirmed that stress in early age affects the mice with activated and deactivated CDH13 gene in different ways. Different variants of this gene are associated with the development of ASDs, ADHD, and depression. The discovery would help specify the role of genetics in the development of neuropsychiatric disorders. The results of the study were published in the Progress in Neuro-Psychopharmacology & Biological Psychiatry journal.

CDH13 codes the protein called cadherin 13 that participates in many processes in the brain, from cell migration in embryos to the axon guidance and target finding as well as synaptogenesis in adults. Different variations of this gene are associated with ASDs, ADHD, depression, memory loss, and other disorders. However, it's been unclear whether these consequences are caused by enhancement or suppression of cadherin 13 functions.

To evaluate the influence of the absence of cadherin 13 on the development in cases of early exposure to stress, neurobiologists experimented on mice in which the CDH13 was deactivated. The stress factor was separation from the mother. During the first two weeks of life the mice with activated and deactivated CDH13 gene were left in their cells alone every day. They were separated from the mothers for three hours, but the conditions in the cells, namely comfortable temperature and humidity, were kept the same. Young mice from the control group (with various versions of the CDH13 gene) were not exposed to any stress. When the mice grew up, both the experimental and the control group underwent a number of behavioral tests to assess their anxiety levels, exploratory activity, and fear susceptibility. A thorough study of the structure of the brain called the hippocampus was also carried out.

According to the tests, the animals without cadherin 13 were different from conrols with the normal CDH13 function. Early exposure to stress, such as short-term separation from the mother, usually makes the mice more stress-resistant in adult age, and this was confirmed by the behavior of the mice with the working gene. The animals that were separated from their mothers during the first weeks of life quickly adapted to the new conditions in the majority of tests and were more active than the mice with the same genotype but without any stressful experience. However, short-term stress had no positive effect on the mice whose bodies did not produce cadherin 13. They were more anxious and less eager to show risky behavior during tests. For example, they didn't want to leave the lighted area in a light and dark transition chamber and were slow to explore unknown spaces.

"Our earlier study of mice with CDH13 deficiency showed that it contributes to the development of the brain serotonin system. Mice like that exhibit higher density of serotonin neurons and increased innervation of the cerebral cortex. These symptoms have long been suspected to represent one of the pathogenetic mechanisms causing autism," says Klaus-Peter Lesch, head of the Laboratory of Psychiatric Neurobiology at the Institute of Molecular Medicine, Sechenov University. "In our recent work we've demonstrated that CDH13 dysfunction impairs adaptation to early-life stress. Additionally, the assessment of gene expression in the brain suggests CDH13 as a neuroprotective factor impacting synaptic plasticity. Together, these findings show that the interaction of risk multiple genes and environmental factors is important for the pathophysiology of neuropsychiatric disorders. CDH13 gene variation in humans can be identified by genotyping for common and rare variants. However, the low penetrance and the small effect size these variants does not justify screening individuals for diagnostic purposes, preventive measures or therapeutic intervention".



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