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

Autor: Christin Weissleder, Cynthia Shannon Weickert, Debora A. Rothmond, Amelia M. Brown, Tertia D. Purves-Tyson
Rok vydání: 2021
Předmět:
Male
Vesicular Inhibitory Amino Acid Transport Proteins
Cohort Studies
GABA
chemistry.chemical_compound
0302 clinical medicine
Neuroinflammation
Mesencephalon
GABAergic Neurons
Neurotransmitter
gamma-Aminobutyric Acid
Parvalbumin
GAD1
Glutamate Decarboxylase
GABAA receptor
Dopaminergic
Middle Aged
Parvalbumins
Female
Somatostatin
medicine.drug
Adult
medicine.medical_specialty
Psychosis
Tyrosine 3-Monooxygenase
GAD65/67
Substantia nigra
Biology
Neurotransmission
Young Adult
03 medical and health sciences
Cellular and Molecular Neuroscience
Dopamine
Internal medicine
mental disorders
medicine
Humans
RNA
Messenger
GABRA
RC346-429
Molecular Biology
Aged
Dopamine transporter
Inflammation
Dopamine Plasma Membrane Transport Proteins
Dopaminergic Neurons
Research
Receptors
GABA-A
medicine.disease
030227 psychiatry
Protein Subunits
Endocrinology
Gene Expression Regulation
chemistry
Neuroinflammatory Diseases
Schizophrenia
biology.protein
Neurology. Diseases of the nervous system
Tyrosine hydroxylase
Biomarkers
030217 neurology & neurosurgery
Zdroj: Molecular Brain
Molecular Brain, Vol 14, Iss 1, Pp 1-19 (2021)
ISSN: 1756-6606
Popis: 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 GABAA 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 GABAA receptor in people with schizophrenia compared to controls (p SST) was unchanged (p = 0.485). We confirmed the reduction in GAD at the protein level (34%, p GABRA3 mRNA exhibited more pronounced changes in high compared to low inflammatory subgroups in schizophrenia. GABRA3 protein was expressed by 98% of tyrosine hydroxylase-positive neurons and was 23% lower in schizophrenia, though this did not reach statistical significance (p > 0.05). Expression of transcripts for GABAA receptor alpha subunits 2 and 3 (GABRA2, GABRA3) were positively correlated with tyrosine hydroxylase (TH) and dopamine transporter (DAT) transcripts in schizophrenia cases (GABRA2; r > 0.630, GABRA3; r > 0.762, all p GABRA2; r GABRA3; r p > 0.05). Taken together, our results support a profound disruption to inhibitory neurotransmission in the substantia nigra regardless of inflammatory status, which provides a potential mechanism for disinhibition of nigrostriatal dopamine neurotransmission.
Databáze: OpenAIRE
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