ALTERED CYTOSKELETAL ORGANIZATION AND SECRETION IN OLFACTORY NEURONAL PRECURSORS FROM SCHIZOPHRENIA PATIENTS

Schizophrenia, a severe mental disorder with high global prevalence, is among the most disabling health conditions. Diagnosis typically occurs between ages 15 and 35, after the first psychotic episode, when symptoms are already advanced. Classical antipsychotics targeting dopamine D2 receptors reduce positive symptoms but do not adequately address negative symptoms or cognitive deficits, which emerge before psychotic episodes and are now recognized as a core feature of schizophrenia, reflecting profound alterations in neuronal circuits. The pathophysiology of schizophrenia involves multiple neurotransmitter systems, highlighting the importance of understanding neurotransmitter secretion and its regulation.
Here we studied secretion from olfactory neuronal precursors (ONPs), a model that mirrors key processes of the central nervous system and can be obtained from living patients, allowing analysis of cellular alterations associated with schizophrenia. Using the fluorescent dye FM1-43, we found that patient-derived ONPs exhibit exacerbated secretion, with higher amplitude and faster kinetics than ONPs from healty control subjects. Considering the role of the actin cytoskeleton in vesicle mobilization and fusion, its organization was studied through immunofluorescence and novel image analysis methods. While total actin levels were similar, patient cells showed increased filamentous actin intensity, altered microfilament orientation, and disorganized actin distribution. Pilot experiments further suggested greater structural instability of actin during secretion.
These results suggest that cytoskeletal alterations may contribute to the exacerbated secretion observed in patients. This work provides evidence of altered cellular mechanisms in schizophrenia and establishes analytical tools that could be instrumental in developing biomarkers for early detection of mental disorders.