The substantia nigra in the pathology of schizophrenia: A review on post-mortem and molecular imaging findings.

• Dopamine synthesis in the substantia nigra appears to be increased in schizophrenia. • There is evidence for increased glutamatergic functioning and reduced GABAergic functioning in the substantia nigra. • Reduced GABAergic inhibition and excessive glutamatergic excitation might underlie the increased dopamine synthesis in the nigrostriatal pathway. Dysregulation of striatal dopamine is considered to be an important driver of pathophysiological processes in schizophrenia. Despite being one of the main origins of dopaminergic input to the striatum, the (dys)functioning of the substantia nigra (SN) has been relatively understudied in schizophrenia. Hence, this paper aims to review different molecular aspects of nigral functioning in patients with schizophrenia compared to healthy controls by integrating post-mortem and molecular imaging studies. We found evidence for hyperdopaminergic functioning in the SN of patients with schizophrenia (i.e. increased AADC activity in antipsychotic-free/-naïve patients and elevated neuromelanin accumulation). Reduced GABAergic inhibition (i.e. decreased density of GABAergic synapses, lower VGAT mRNA levels and lower mRNA levels for GABA A receptor subunits), excessive glutamatergic excitation (i.e. increased NR1 and Glur5 mRNA levels and a reduced number of astrocytes), and several other disturbances implicating the SN (i.e. immune functioning and copper concentrations) could potentially underlie this nigral hyperactivity and associated striatal hyperdopaminergic functioning in schizophrenia. These results highlight the importance of the SN in schizophrenia pathology and suggest that some aspects of molecular functioning in the SN could potentially be used as treatment targets or biomarkers. [ABSTRACT FROM AUTHOR]