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The substantia nigra (SN) provides the largest dopaminergic input to the brain, projects to the striatum (the primary locus of action for antipsychotic medication), and receives GABAergic and glutamatergic inputs. This study used western blot analysis to compare protein levels of tyrosine hydroxylase (TH), glutamate decarboxylase (GAD67), and vesicular glutamate transporters (vGLUT1 and vGLUT2) in postmortem human SN in schizophrenia subjects (n = 13) and matched controls (n = 12). As a preliminary analysis, the schizophrenia group was subdivided by (1) treatment status: off medication (n = 4) or on medication (n = 9); or (2) treatment response: treatment resistant (n = 5) or treatment responsive (n = 4). The combined schizophrenia group had higher TH and GAD67 protein levels than controls (an increase of 69.6%, P = 0.01 and 19.5%, P = 0.004, respectively). When subdivided by medication status, these increases were found in the on-medication subjects (TH 88.3%, P = 0.008; GAD67 40.6%, P = 0.003). In contrast, unmedicated schizophrenia subjects had higher vGLUT2 levels than controls (an increase of 28.7%, P = 0.041), but vGLUT2 levels were similar between medicated schizophrenia subjects and controls. Treatment-resistant subjects had significantly higher TH and GAD67 levels than controls (an increase of 121.0%, P = 0.0003 and 58.7%, P = 0.004, respectively). These data suggest increases in dopamine and GABA transmission in the SN in schizophrenia, with a potential relation to treatment and response.

Certain cognitive deficits in schizophrenia, such as impaired working memory, are thought to reflect alterations in the neural circuitry of the dorsolateral prefrontal cortex (DLPFC). Gamma oscillations in the DLPFC appear to be a neural corollary of working memory function, and the power of these oscillations during working memory tasks is lower in individuals with schizophrenia. Thus, gamma oscillations represent a potentially useful biomarker to index dysfunction in the DLPFC circuitry responsible for working memory in schizophrenia. Postmortem studies, by identifying the cellular basis of DLPFC dysfunction, can help inform the utility of biomarker measures obtained in vivo . Given that gamma oscillations reflect network activity of excitatory pyramidal neurons and inhibitory GABA neurons, we review postmortem findings of alterations to both cell types in the DLPFC and discuss how these findings might inform future biomarker development and use.

Several schizophrenia brain regions exhibit decreased dysbindin. Dysbindin modulates copper transport crucial for myelination, monoamine metabolism, and cellular homeostasis. Schizophrenia patients (SZP) exhibit increased plasma copper, while copper-decreasing agents produce schizophrenia-like behavioral and pathological abnormalities. Therefore, we sought to determine dysbindin and copper transporter protein expression and copper content in SZP. We studied the copper-rich substantia nigra (SN) using Western blot and inductively-coupled plasma mass spectrometry. We characterized specific protein domains of copper transporters ATP7A, CTR1, ATP7B, and dysbindin isoforms 1A and 1B/C in SZP (n = 15) and matched controls (n = 11), and SN copper content in SZP (n = 14) and matched controls (n = 11). As a preliminary investigation, we compared medicated (ON; n = 11) versus unmedicated SZP (OFF; n = 4). SZP exhibited increased C-terminus, but not N-terminus, ATP7A. SZP expressed less transmembrane CTR1 and dysbindin 1B/C than controls. ON exhibited increased C-terminus ATP7A protein versus controls. OFF exhibited less N-terminus ATP7A protein than controls and ON, suggesting medication-induced rescue of the ATP7A N-terminus. SZP exhibited less SN copper content than controls. These results provide the first evidence of disrupted copper transport in schizophrenia SN that appears to result in a copper-deficient state. Furthermore, copper homeostasis may be modulated by specific dysbindin isoforms and antipsychotic treatment.