Substantia nigra ultrastructural pathology in schizophrenia

Schizophrenia is a severe mental illness affecting approximately 1% of the population worldwide. Despite its prevalence, the cause remains unknown, and treatment is not effective in all patients. Dopamine is thought to play a role in schizophrenia pathology, yet the substantia nigra (SN), the origin of dopaminergic pathways, has not been studied extensively in schizophrenia. In this study, electron microscopy was used to examine neurons, oligodendrocytes, and myelinated axons in the SN of normal controls (NCs, n = 9) and schizophrenia subjects with varying response to antipsychotic drugs [SZ, n = 14; treatment resistant (TR) = 6, treatment responsive (RESP) = 6, unknown = 2]. Postmortem tissue was analyzed for qualitative and quantitative markers of ultrastuctural integrity. A significantly higher percentage of axons in the schizophrenia group had inclusions in the myelin sheath compared to NCs (SZ: 3.9 ± 1.7, NC: 2.6 ± 2.0). When considering treatment response, a significantly higher percentage of axons lacked cytoplasm (TR: 9.7 ± 5.5, NC: 3.5 ± 2.3), contained cellular debris (TR: 7.5 ± 3.2, NC: 2.3 ± 1.3) or had protrusions in the myelin sheath (TR: 0.4 ± 0.5, NC: 0.2 ± 0.3). The G-ratio, a measure of myelin thickness, was significantly different between treatment response groups and was greater in TR (0.72 ± 0.02) as compared to NCs (0.68 ± 0.03), indicating decreased myelination in TR. These findings, which suggest myelin pathology in the SN in schizophrenia, are consistent with findings elsewhere in the brain. In addition, our results suggest cytoskeletal abnormalities, which may or may not be associated with myelin pathology.