Schizophrenia found to alter the ‘scaffolding’ that supports the neurones and communication between them

A study published in Molecular Psychiatry and led by the EHU’s Neuropsychopharmacology group, which is also a member of CIBER Mental Health (CIBERSAM) and of the Biobizkaia Health Research Institute, provides new insights into understanding the origins of schizophrenia. The research, led by the EHU lecturer Leyre Urigüen, revealed alterations in the extracellular matrix, the “scaffolding” that supports neurones, and in the synapses, the points of communication between the neurones, thus reinforcing the idea that this is a neurodevelopmental disorder.

This study used a pioneering model based on neural stem cells obtained from the nasal cavity of patients with schizophrenia, more specifically, from the olfactory epithelium. The olfactory epithelium is a region very close to the brain located at the top part of the nostrils, where the olfactory neurones that allow us to smell are located. The olfactory epithelium also contains neural stem cells that can be extracted by means of nasal exfoliation. This simple, non-invasive method enables the extracted neural stem cells to be cultured in the laboratory and grouped together to form structures called neurospheres that mimic the initial stages of neurodevelopment; this is the process of growth, maturity and functional development of the nervous system, which begins during pregnancy and continues until adulthood, enabling cognitive, motor and social skills to be acquired. “That way, we got a unique window to study the disease directly and in a personalised way,” explained Paula Unzueta, the article's lead author.

In fact, the researchers discovered that when neurospheres were generated, alterations were already taking place in genes related to the extracellular matrix. In addition to neurospheres, mature neurones can also be obtained from neural stem cells in the olfactory epithelium, and in these neurones they also detected defects in genes linked to synapses and their interaction with the matrix.

To validate these results, the team measured, in parallel, the levels of certain proteins present in neurones cultured in the laboratory and in post-mortem brain tissue from subjects with schizophrenia. When comparing these levels with those of individuals without schizophrenia, they found that three proteins essential for the formation and functioning of synapses, L1CAM, NPTXR and SCG2, were reduced.

Dr Urigüen stressed that “these findings link neurodevelopmental alterations to specific molecular changes in schizophrenia, and demonstrate that this cell model opens the door to discovering new biomarkers and advancing towards more personalised therapies, not only for schizophrenia, but also for other neuropsychiatric and neurodegenerative diseases”.

Additional information

This research was led by Leyre Urigüen, lecturer at the Faculty of Medicine and Nursing at the University of the Basque Country (EHU), and is the result of Paula Unzueta's PhD thesis, which was co-supervised by Urigüen and Luis F. Callado. Both of them belong to the EHU’s Neuropsychopharmacology group.

The CIBERSAM group at the University of Valencia, coordinated by Juan Nacher, was among those that also collaborated in the study.

Article reference:

Paula Unzueta-Larrinaga, Esteban Cuesta-Vega, Rocío Barrena-Barbadillo, Estibaliz Olabarrieta, Maria Recio-Barbero, Igor Horrillo, Oihane Mentxaka, Rafael Segarra, J. Javier Meana, Juan Nacher, Rebeca Diez-Alarcia, Luis F. Callado & Leyre Urigüen

Extracellular matrix dysfunction and synaptic alterations in schizophrenia

Molecular Psychiatry

https://doi.org/10.1038/s41380-025-03154-2