TY - JOUR
T1 - The substantia nigra in the pathology of schizophrenia
T2 - A review on post-mortem and molecular imaging findings
AU - van Hooijdonk, Carmen F. M.
AU - van der Pluijm, Marieke
AU - Bosch, Iris
AU - van Amelsvoort, Therese A. M. J.
AU - Booij, Jan
AU - de Haan, Lieuwe
AU - Selten, Jean-Paul
AU - Giessen, Elsmarieke van de
N1 - Funding Information: None. Publisher Copyright: © 2022
PY - 2023/3/1
Y1 - 2023/3/1
N2 - 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.
AB - 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.
KW - Dopamine
KW - Glutamate & GABA
KW - Molecular imaging
KW - Post-mortem studies
KW - Schizophrenia
KW - Substantia nigra
UR - http://www.scopus.com/inward/record.url?scp=85146347946&partnerID=8YFLogxK
U2 - https://doi.org/10.1016/j.euroneuro.2022.12.008
DO - https://doi.org/10.1016/j.euroneuro.2022.12.008
M3 - Review article
C2 - 36640734
SN - 0924-977X
VL - 68
SP - 57
EP - 77
JO - European neuropsychopharmacology
JF - European neuropsychopharmacology
ER -