A team of Italian researchers has identified molecular alterations implicated in the cognitive and attention deficits typical of the disease, with the use of machine learning
What happens to the brain when it is affected by a severe psychiatric condition such as schizophrenia, which affects approximately 1% of the world population ?. In the last fifty years, numerous researches have been carried out and as many hypotheses have been formulated to find an explanation. Among these, the possibility that at the base there may be alterations in the chemical communication between neurons in specific areas of the brain, such as the hippocampus and the frontal cortex. In Naples, in the Translational Neuroscience Laboratory of CEINGE-Advanced Biotechnologies, the role of glutamate was investigatedthat is, the sodium salt of glutamic acid, one of the 23 natural amino acids that make up proteins and one of the most abundant amino acids in nature.
Post-mortem tissue analysis
In particular, the researchers of the laboratory directed by Alessandro Usiello, professor of Biochemistry and Clinical Molecular Biology at the University of Campania Luigi Vanvitelli and principal investigator of the Neapolitan Research Center, they analyzed the post-mortem brain tissues of healthy individuals and patients with the diseaseand they found out the existence of widespread biochemical alterations in the complex network of neuronal connections between the synapses of the cortex, which use glutamate as the main transmitter.
Dopamine and glutamate
Let’s try to understand better what it is, with the help of Giancarlo Cervera, psychiatrist and director of the Mental Health Department of the Lodi social and health agency. One of the hypotheses on the nature and causes of schizophrenic pathology that has had great success over the last fifty years is the so-called dopaminergica. That is basically schizophrenia was thought to be possibly the product of a free dysregulation of the neurotransmitter dopamine. Recently another topic has been addressed because it has been seen that there are actually many other neurotransmitters. A very interesting path has come forward from a research point of view: deepen the function of some neuromodulators including glycine but above all glutamate which seems to have an important effect in the progression of schizophrenic pathology because it also regulates the release of dopamine in some way. This paved the way for a number of studies on some drugs with glutamate action which however have not proved so effective and have been abandoned. The glutamatergic hypothesis has not been abandoned, which does not claim to explain schizophrenia in the round but it helps us understand another piece of pathology.
Machine learning
What have the researchers from Naples done? The molecular neurobiology and biochemical experiments carried out in our laboratory at CEINGE – explains Professor Usiello – were subsequently processed through the use of advanced analytical techniques based on “machine learning”, a branch of artificial intelligence. This methodology has made it possible to i
ndividing variations in subjects with schizophrenia, not of single molecules, but of groups of moleculeswhich could act as “dysfunctional complexes” of a fundamental biological structure of the brain, known as glutamatergic synapse.
The brain like an orchestra
The research was carried out in collaboration with Andrea de BartholomewHead of the Laboratory of Molecular and Translational Psychiatry of the University of Naples Federico II and Director of the Uoc of Psychiatry and Psychology of the Frederick Polyclinic and with the research groups led respectively by Andrea Fontanaco-head of the Biostatistics Unit of the Irccs House for Relief of Suffering Foundation, for the University of Bari from Antonio Rampinocoordinator of the Laboratory of Molecular and Genetic Psychiatry, and by Alessandro Bertolinofull professor of Psychiatry.
Let’s try think of the functioning of the human brain as an orchestra in which the instruments taken individually work well, but are not in tune with each other – explains Francesco Errico, professor of Biochemistry at the Department of Agriculture of Federico II and researcher of the Translational Neuroscience Laboratory of CEINGE -. In the case of the studied pathology we can speak of disharmony between groups of moleculeswhich could result in a disordered functioning of the glutamatergic synapse in some brain areas involved in the disorder, such as the prefrontal cortex.
New scenarios
The discovery could open up new scenarios for the identification of new molecular targets for drug therapies. We think that targeting pharmacological treatments not the single elements of the synapse, but the harmonious functioning of groups of these, can allow the development of new pharmacological agents capable of functioning as “good conductors” more than as “silencers” or “amplifiers” of individual instruments, Professor Rampino speculates. Since previous attempts to target single molecules of the glutamatergic synapse have proved unsuccessful – comments Professor de Bartolomeis – this change of perspective could provide new indications in the future in the treatment of this complex psychiatric disorder with innovative molecules.
Predictive molecules
The research results have been published in the prestigious international journal Schizophrenia (
HERE the article
). The approach to analysis consisted of lancio dell’algoritmo “iterative Random Forest”, which is based on the construction of a “random” forest of data classification trees, in an iterative and internally validated way – explains Dr. Fontana -. Not only was it possible through these mathematical algorithms identify the molecules of the cortical glutamatergic synapse that most predict the pathologybut also suggest their functional interactions.
Perspectives to be confirmed
What are the future prospects? The post mortem study was done to see if there were any variations of structures, of compounds that would suggest a different functioning mechanism of some brain areas of people with schizophrenia and normal people – explains Giancarlo Cerveri -. From a superficial analysis no differences seemed to emerge but, using a complex evaluation system that also made use of artificial intelligence, the researchers somehow managed to reach a conclusion by observing that there are more different metabolites in people with schizophrenia than in those who are not. All this opens the way to some considerations: glutamate may actually have something to do with with schizophrenic pathology; one can think of proposing this too as diagnostic system, should the study find confirmations over time. In summary this very rigorous study, of great interest from the speculative point of view for not yet mature to produce a modification of the diagnostic and clinical procedures of schizophrenia.
March 8, 2022 (change March 8, 2022 | 18:35)
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