Schizophrenia is a serious mental disorder, which can cause a combination of hallucinations, delusions, and disturbances in thinking and behavior in those who suffer from it. Although it has been widely associated with problems with brain activity and connectivity, as well as with environmental factors, its exact cause is unknown.
This is the focus of a collaborative investigation spearheaded by veronica palm Y Magdalena Sanhuezaacademics of Department of Biology of the Faculty of Sciences of the University of Chilewho have made important findings on the origin of this disease.
One of his most recent discoveries was published by the prestigious magazine Frontiers in Cell and Developmental Biology, an article in which they state that the conditions for the development of the pathology would be associated with the formation of the nervous system in the fetal stage, so that this risk factor could be detected in the early stages of life in the future. The experiments, carried out in the laboratories of professors Palma and Sanhueza by researchers Sophia Puvogel Y Chris Blanchardused induced pluripotent stem cells (hiPSC) from patients with schizophrenia to reproduce what happens with neuronal communication in the brain of these people in an in vitro model.
The specialist explains that, from the early stages of formation of the nervous system, the emerging neural networks of people with this potential to develop the disease present altered communication, that is, less coordinated and dynamic, which would increase the risk of suffering schizophrenia in the face of stressful events. The work, in this sense, contributes to the understanding of the etiology of schizophrenia, a mental disorder of multifactorial origin in which genetic and environmental factors converge. Added to this is another recent investigation by Dr. Palma’s laboratory in which the incidence of the vascular system, in addition to the nervous system, in the emergence of schizophrenia was also determined, a finding published in the journal Molecular Psychiatry of the group Nature.
The discovery of this communication problem between neurons in early stages of life is of great relevance “Because there are a series of pathologies of the nervous system where the functioning of neural networks is affected from the moment it is being formed”explains the academic and director of the Department of Biology of the Faculty of Sciences of the University of Chile, Dr. Verónica Palma.
A new study model
The research also presents a new approach to model the development of this disease within the uterus, a scientific contribution that opens a new path for the creation of early detection strategies and possible treatments for schizophrenia during embryonic neuronal development, as well as for the evaluation of the effect of various environmental factors. “Our cell model will allow laboratory studies to be carried out leading to the development and testing of preventive treatments in people with a history of schizophrenia or, even, with other neurodevelopmental diseases, such as autism spectrum disorders,” says Professor Palma.
Dr. Magdalena Sanhueza, for her part, highlights the originality and the important contribution that this study makes to science, since “the pathology of schizophrenia is analyzed through functional studies in populations of interconnected neurons, generated in vitro in the laboratory , from stem cells obtained from skin cells of adult patients with schizophrenia. The electrical activity of the neurons is monitored through fluorescence images that reflect increases in intracellular calcium, which are subsequently analyzed and integrated into a mathematical model that allows the dynamic properties of the network as a whole to be extracted.”
Along the same lines, the doctoral student in Molecular Cellular Biology and Neurosciences at the Faculty of Sciences of the University of Chile, Sofía Puvogel, thesis student of the project and co-first author of the article, explained that through this novel system they have been able to “to study the communicational dynamics in these neural networks that preserve the genetic information of patients and simulate the first stages of neurodevelopment, and to compare their behavior with that of neural networks from healthy subjects”.
An essential contribution to this work was made by Dr. in Molecular, Cellular and Neuroscience Biology, Kris Blanchard, co-first author of the publication, who designed the calcium imaging acquisition system, performed the electrophysiological recordings, and together with the thesis student Sofía Puvogel, carried out and analyzed the dynamics of communication in neural networks.
Communicational dynamics of neurons
The specialists explain that the dynamics of the in vitro networks presented a surprising similarity with the alterations observed in different regions of the brain of patients with schizophrenia. These findings could have global implications for our understanding of the functional properties of neurons from patients with schizophrenia. Additionally, this system constitutes a valuable tool to investigate the organization of emerging neural networks in normal or pathological conditions.
The student of Engineering in Molecular Biotechnology of the Faculty of Sciences, Sebastián Arizabalos, who is conducting his title seminar on this subject and participates in the research, explains that “Since we cannot directly study the brain of a person living with schizophrenia, we must look for other methods to answer the questions. In this article, hiPSCs were used, from which we are able to generate neuronal cultures and study how neurons interact with each other.”
To study the communicational dynamics between the neurons that make up the network, a mathematical model was developed, originally proposed by Dr. Robyn Miller, an international collaborator, to study brain images. The team is also made up of Dr. Bárbara Casas and the Molecular Biotechnology Engineering thesis student from the Faculty of Sciences, Delia Garrido-Jara.
One of the limitations of this work, Kris Blanchard states, is that the calcium indicators used did not allow recurrent monitoring of neuronal activity, as the neuronal networks develop in the culture. “This implies that the differences we observe are limited to a fixed time window, like a photograph that integrates and reflects the dynamics of communication at a given moment of neuronal development.“, details the researcher.
For this reason, in the future, the team will expand its range of exploration and study communication dynamics, also including other stages of development, earlier and later, and see how they evolve over time. To do this, they are currently using genetically modified calcium indicators in their experiments.
“This allows us to have a series of photographs that reflect the properties of neuronal communication at different moments of development, and -therefore- we can recreate a movie that reflects how neuronal circuits are formed and evolve, thus broadening our understanding of the processes that govern the generation and evolution of neuronal communication during the development of these circuits, both in normal and pathological conditions,” he explains.
Myths around schizophrenia
The Casa de Bello researchers explained that schizophrenia is a psychiatric disorder and is mainly associated with anomalies in the nervous system. That is why the neural networks in the brain of a person diagnosed with schizophrenia tend to work differently. In the article, this point of view is discussed from a concept called “functional connectivity”which opens a scientific opportunity to study and develop other treatments, before schizophrenia is triggered.
Regarding the origin of schizophrenia, the experts clarify that, although there are genetic factors, the fact that the father or mother or someone in the family lineage has schizophrenia does not necessarily predispose another family member to suffer from it. In that sense, the causes associated with this condition, the scientists clarify, are a combination of genetics and the environment that contribute to the development of this disorder. The risk factors that can trigger this disease are family history, consumption of psychoactive or psychotropic drugs during adolescence and traumatic acts of violence or violation in the environment, but the causes can be varied and multiple.
The team behind these investigations is also made up of the Dr. Barbara Casas and the thesis student of the Molecular Biotechnology Engineering career of the Faculty of Sciences of the U. de Chile, Delia Garrido-Jara.