Is schizophrenia reversible?
A group from Columbia University, New York, led by Joseph Gogos identified the SETD1A gene as the main regulator of schizophrenia risk. The protein it encodes affects the expression of many other genes, including other genes responsible for the development of schizophrenia. Surprisingly, the deviations that occurred in mice were reversible.
Researchers have identified both common and rare genetic variations that contribute to the development of schizophrenia. The SETD1A mutation is one of the few known gene factors uniquely associated with the development of schizophrenia. Thus, the presence of one mutant copy of SETD1A is sufficient to significantly increase the risk of disease.
To find out exactly how a mutation in SETD1A affects brain cells and the connection between neurons, Gogos and colleagues modeled mice carrying a mutation that halves the expression of this gene. The mice could not cope with the tasks of spatial orientation in the maze for the sake of getting food. This test is designed to evaluate the working memory of animals – the ability to remember information and extract it to determine behavior, often impaired in schizophrenia.
Image of spikes on a neuron process in animals with normal (left) and impaired (right) function of the SETD1A gene. Spikes are necessary for relaying signals. Source: Columbia University.
The mutant gene also changed the cellular mechanism by which neurons communicate with each other. So, he stopped the growth and branching of the processes and reduced the number of spikes on the processes, which are necessary for the transmission of chemical signals between neighboring cells.
As the researchers have shown, the reason for the disruption of the growth and functioning of neurons lies in the change in the regulation of many other genes with which it is associated caused by the SETD1A mutation. The expression of whole classes of genes decreased, while the expression of others was excessive.
Experimental restoration of normal expression of the SETD1A gene in adult mice led to normalization of working memory function. Moreover, suppression of the expression of the LSD1 gene, which counteracts SETD1A, also led to the restoration of all behavioral and neuronal disorders in animals. Given that many of the mechanisms identified in the mouse brain were developed during evolution, they probably play similar roles in humans.
Researchers believe that reactivating SETD1A function or countering the side effects of SETD1A deficiency in the adult brain, including using LSD1 inhibitors, may be a promising method of treating cognitive deficits in schizophrenia.
Nevertheless, it is worth remembering that the mutation of the SETD1A gene is present in a small percentage of all patients with schizophrenia.
Article by J. Mukai et al. Recapitulation and Reversal of Schizophrenia-Related Phenotypes in Setd1a-Deficient Mice is published in the journal Neuron.
Aminat Adzhieva, portal "Eternal Youth" http://vechnayamolodost.ru based on NIH materials: Schizophrenia risk gene linked to cognitive deficits in mice.