Abstract
Psychiatric symptoms of schizophrenia suggest alteration of cerebral neurons. However, the physical basis of the schizophrenia symptoms has not been delineated at the cellular level. Here, we report nanometer-scale three-dimensional analysis of brain tissues of schizophrenia and control cases. Structures of cerebral tissues of the anterior cingulate cortex were visualized with synchrotron radiation nanotomography. Tissue constituents visualized in the three-dimensional images were traced to build Cartesian coordinate models of tissue constituents, such as neurons and blood vessels. The obtained Cartesian coordinates were used for calculating curvature and torsion of neurites in order to analyze their geometry. Results of the geometric analyses indicated that the curvature of neurites is significantly different between schizophrenia and control cases. The mean curvature of distal neurites of the schizophrenia cases was ~1.5 times higher than that of the controls. The schizophrenia case with the highest neurite curvature carried a frame shift mutation in the GLO1 gene, suggesting that oxidative stress due to the GLO1 mutation caused the structural alteration of the neurites. The differences in the neurite curvature result in differences in the spatial trajectory and hence alter neuronal circuits. It has been shown that the anterior cingulate cortex analyzed in this study has emotional and cognitive functions. We suggest that the structural alteration of neurons in the schizophrenia cases should reflect psychiatric symptoms of schizophrenia.
Highlights
Schizophrenia is a chronic mental disorder that affects~1% of the population[1]
Three-dimensional tissue structure The cerebral cortex tissues analyzed in this study were taken from the left hemispheres of autopsied brains of four schizophrenia cases S1–S4 and four age/gender-matched control cases N1–N4 (64 ± 5 years; Page 4 of 12 85 two males and two females)
In the S4 schizophrenia case, the high curvature and short radius of the neurites should stem from the GLO1 frameshift mutation[44]
Summary
Clinical symptoms of schizophrenia include hallucinations, delusions, emotional disorders, and cognitive dysfunction. The development of these symptoms suggests alterations in the connectivity between cerebral neurons. It has been reported that dendritic spines of neurons are significantly decreased in the external pyramidal layer of the cerebral cortex of schizophrenic brains[2,3,4]. The reduced neuropil hypothesis[5] posits that reductions in neuron size and arborization are the explanation for the reduced brain volume observed in schizophrenia[6,7,8,9]. The reductions in neuron size and arborization can perturb the neuronal structures, resulting in changes to the neuronal circuits
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