"Maniac" mice helped to understand one of the causes of mental disorders
Transgenic mice on guard of human health
Alexandra Bruter, <url>A group of American scientists have created mice with a mutation that causes mice to behave maniacally and causes them to have seizures.
This mutation is analogous to the mutation found in humans. And indeed, there were two patients with the same mutation and similar symptoms.
The researchers proposed a solution to the problem: a long-used drug put the mice in order.
The most common mutations are changes in the genetic code by one or more "letters": substitutions, insertions and dropouts. Depending on the location, they may not have any effect, or cause an effect of varying severity. In addition to these mutations, there are others. For example, duplications – doubling of some fragments of the genome. They occur due to errors during crossing-over and homologous recombination, or due to the activity of retrotransposons, mobile genetic elements similar to viruses that have settled in the genomes of more complex organisms and are sometimes activated. Generally speaking, gene duplications play a very important role in evolution. When two copies of the same gene appear in the body, one of them can safely mutate, and such mutations do not affect the viability of the organism. Most often, of course, this does not lead to anything good, but sometimes genes encoding new useful proteins or improved versions of the original protein can be obtained.
In particular, in the described article published in Nature (Han et al., SHANK3 overexpression causes manic-like behavior with unique pharmacogenetic properties), the doubling of the gene encoding the SHANK3 protein is considered. This protein is involved in the formation of synapses from the postsynaptic side and the conduction of nerve signals. Previously, it was shown that mutations in his gene that reduce his activity lead to autism spectrum disorders, schizophrenia and mental retardation. In the same article, we are not talking about a decrease in activity, but, on the contrary, about its growth due to the fact that there are now two genes, not one.
There are several people with duplication of a large section of the 22nd chromosome containing more than 20 genes, including SHANK3, who have been diagnosed with Asperger's syndrome, attention deficit hyperactivity disorder (ADHD) or schizophrenia. But it was still unknown which gene duplication was responsible for this effect.
Therefore, the authors decided to check what would happen if only the SHANK3 gene was doubled. To do this, they created the corresponding transgenic mice. Transgenic mice behaved hyperactively while sitting in a cage, and when released, they ran faster and more. Since one of the patients with duplication had ADHD, the authors decided to check whether there was a direct causal relationship. They began to give the mice a drug against ADHD – a substance of the amphetamine series, but it did not help.
At the same time, the authors of the study were looking for people with a doubling of a small area that does not affect other genes other than SHANK3. And they found it. It turned out to be an 11-year-old girl diagnosed with ADHD, who, like mice, was not helped by standard therapy, and a 35-year-old man with manic-depressive psychosis and epilepsy. It should be noted here that psychiatric diagnoses, especially in children, are often conditional. The clinical picture is often blurred and fits several diagnoses. Indeed, the behavior of mice and both patients with duplication of a small section of the 22nd chromosome is quite similar to manic manifestations of manic-depressive psychosis, accompanied by seizures. After discovering this, the authors gave the mice valproic acid, an anticonvulsant and normotimic that stabilizes mood. Valproic acid managed to overcome the symptoms caused by an additional copy of the SHANK3 gene.
This article clearly shows how, when conducting interdisciplinary research, animal experiments can help in the study of human diseases. Since there can be many mice, and there are only a few patients with a mutation, and mice can be studied in much more detail, the creation of transgenic mice with the same mutation makes it easier to assess the effect of this mutation on the phenotype, a detailed explanation of cause-and–effect relationships and the selection of innovative drugs.
Portal "Eternal youth" http://vechnayamolodost.ru29.10.2013