Reductions in midbrain GABAergic and dopamine neuron markers are linked in schizophrenia

• Published in: Molecular brain 2021-06, Vol.14 (1), p.96-96, Article 96
• Main Authors: Purves-Tyson, Tertia D, Brown, Amelia M, Weissleder, Christin, Rothmond, Debora A, Shannon Weickert, Cynthia
• Format: Article
• Language: English
• Subjects: Adult; Aged; Biomarkers - metabolism; Cohort Studies; Cytokines; Dopamine; Dopamine Plasma Membrane Transport Proteins - genetics; Dopamine Plasma Membrane Transport Proteins - metabolism; Dopamine receptors; Dopamine transporter; Dopaminergic Neurons - pathology; Enzymes; Female; GABA; GABAergic Neurons - pathology; GABRA; GAD1; GAD65/67; gamma-Aminobutyric Acid; Gene expression; Gene Expression Regulation; Glutamate; Glutamate decarboxylase; Glutamate Decarboxylase - genetics; Glutamate Decarboxylase - metabolism; Humans; Hydroxylase; Immunoblotting; Inflammation; Inflammation - genetics; Inflammation - pathology; Male; Mental disorders; Mesencephalon; Mesencephalon - pathology; Middle Aged; Neuroinflammatory Diseases - genetics; Neuroinflammatory Diseases - pathology; Neurons; Neurotransmission; Parvalbumin; Parvalbumins - metabolism; Pharmaceutical industry; Phenols; Protein expression; Protein Subunits - metabolism; Protein transport; Proteins; Psychosis; Receptors, GABA-A - genetics; Receptors, GABA-A - metabolism; RNA; RNA, Messenger - genetics; RNA, Messenger - metabolism; Schizophrenia; Schizophrenia - genetics; Schizophrenia - pathology; Somatostatin; Somatostatin - genetics; Somatostatin - metabolism; Statistical analysis; Substantia nigra; Tyrosine; Tyrosine 3-monooxygenase; Tyrosine 3-Monooxygenase - genetics; Tyrosine 3-Monooxygenase - metabolism; Vesicular Inhibitory Amino Acid Transport Proteins - genetics; Vesicular Inhibitory Amino Acid Transport Proteins - metabolism; Young Adult; γ-Aminobutyric acid A receptors
• ISSN: 1756-6606; 1756-6606
• DOI: 10.1186/s13041-021-00805-7

Reductions in the GABAergic neurotransmitter system exist across multiple brain regions in schizophrenia and encompass both pre- and postsynaptic components. While reduced midbrain GABAergic inhibitory neurotransmission may contribute to the hyperdopaminergia thought to underpin psychosis in schizophrenia, molecular changes consistent with this have not been reported. We hypothesised that reduced GABA-related molecular markers would be found in the midbrain of people with schizophrenia and that these would correlate with dopaminergic molecular changes. We hypothesised that downregulation of inhibitory neuron markers would be exacerbated in schizophrenia cases with high levels of neuroinflammation. Eight GABAergic-related transcripts were measured with quantitative PCR, and glutamate decarboxylase (GAD) 65/67 and GABA alpha 3 (α3) (GABRA3) protein were measured with immunoblotting, in post-mortem midbrain (28/28 and 28/26 control/schizophrenia cases for mRNA and protein, respectively), and analysed by both diagnosis and inflammatory subgroups (as previously defined by higher levels of four pro-inflammatory cytokine transcripts). We found reductions (21 - 44%) in mRNA encoding both presynaptic and postsynaptic proteins, vesicular GABA transporter (VGAT), GAD1, and parvalbumin (PV) mRNAs and four alpha subunits (α1, α2, α3, α5) of the GABA receptor in people with schizophrenia compared to controls (p  0.630, GABRA3; r > 0.762, all p