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Putative presynaptic dopamine dysregulation in schizophrenia is supported by molecular evidence from post-mortem human midbrain.

ABSTRACT: The dopamine hypothesis of schizophrenia posits that increased subcortical dopamine underpins psychosis. In vivo imaging studies indicate an increased presynaptic dopamine synthesis capacity in striatal terminals and cell bodies in the midbrain in schizophrenia; however, measures of the dopamine-synthesising enzyme, tyrosine hydroxylase (TH), have not identified consistent changes. We hypothesise that dopamine dysregulation in schizophrenia could result from changes in expression of dopamine synthesis enzymes, receptors, transporters or catabolic enzymes. Gene expression of 12 dopamine-related molecules was examined in post-mortem midbrain (28 antipsychotic-treated schizophrenia cases/29 controls) using quantitative PCR. TH and the synaptic dopamine transporter (DAT) proteins were examined in post-mortem midbrain (26 antipsychotic-treated schizophrenia cases per 27 controls) using immunoblotting. TH and aromatic acid decarboxylase (AADC) mRNA and TH protein were unchanged in the midbrain in schizophrenia compared with controls. Dopamine receptor D2 short, vesicular monoamine transporter (VMAT2) and DAT mRNAs were significantly decreased in schizophrenia, with no change in DRD3 mRNA, DRD3nf mRNA and DAT protein between diagnostic groups. However, DAT protein was significantly increased in putatively treatment-resistant cases of schizophrenia compared to putatively treatment-responsive cases. Midbrain monoamine oxidase A (MAOA) mRNA was increased, whereas MAOB and catechol-O-methyl transferase mRNAs were unchanged in schizophrenia. We conclude that, whereas some mRNA changes are consistent with increased dopamine action (decreased DAT mRNA), others suggest reduced dopamine action (increased MAOA mRNA) in the midbrain in schizophrenia. Here, we identify a molecular signature of dopamine dysregulation in the midbrain in schizophrenia that mainly includes gene expression changes of molecules involved in dopamine synthesis and in regulating the time course of dopamine action.

SUBMITTER: Purves-Tyson TD

PROVIDER: S-EPMC5545725 | biostudies-literature | 2017 Jan

REPOSITORIES: biostudies-literature

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Putative presynaptic dopamine dysregulation in schizophrenia is supported by molecular evidence from post-mortem human midbrain.

Purves-Tyson T D TD Owens S J SJ Rothmond D A DA Halliday G M GM Double K L KL Stevens J J McCrossin T T Shannon Weickert C C

Translational psychiatry 20170117 1

The dopamine hypothesis of schizophrenia posits that increased subcortical dopamine underpins psychosis. In vivo imaging studies indicate an increased presynaptic dopamine synthesis capacity in striatal terminals and cell bodies in the midbrain in schizophrenia; however, measures of the dopamine-synthesising enzyme, tyrosine hydroxylase (TH), have not identified consistent changes. We hypothesise that dopamine dysregulation in schizophrenia could result from changes in expression of dopamine syn ...[more]

PMID: 28094812

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Project description:Elevated in vivo markers of presynaptic striatal dopamine activity have been a consistent finding in schizophrenia, and include a large effect size elevation in dopamine synthesis capacity. However, it is not known if the dopaminergic dysfunction is limited to the striatal terminals of dopamine neurons, or is also evident in the dopamine neuron cell bodies, which mostly originate in the substantia nigra. The aim of our studies was therefore to determine whether dopamine synthesis capacity is altered in the substantia nigra of people with schizophrenia, and how this relates to symptoms. In a post-mortem study, a semi-quantitative analysis of tyrosine hydroxylase staining was conducted in nigral dopaminergic cells from post-mortem tissue from patients with schizophrenia (n = 12), major depressive disorder (n = 13) and matched control subjects (n = 13). In an in vivo imaging study, nigral and striatal dopaminergic function was measured in patients with schizophrenia (n = 29) and matched healthy control subjects (n = 29) using (18)F-dihydroxyphenyl-L-alanine ((18)F-DOPA) positron emission tomography. In the post-mortem study we found that tyrosine hydroxylase staining was significantly increased in nigral dopaminergic neurons in schizophrenia compared with both control subjects (P < 0.001) and major depressive disorder (P < 0.001). There was no significant difference in tyrosine hydroxylase staining between control subjects and patients with major depressive disorder, indicating that the elevation in schizophrenia is not a non-specific indicator of psychiatric illness. In the in vivo imaging study we found that (18)F-dihydroxyphenyl-L-alanine uptake was elevated in both the substantia nigra and in the striatum of patients with schizophrenia (effect sizes = 0.85, P = 0.003 and 1.14, P < 0.0001, respectively) and, in the voxel-based analysis, was elevated in the right nigra (P < 0.05 corrected for family wise-error). Furthermore, nigral (18)F-dihydroxyphenyl-L-alanine uptake was positively related with the severity of symptoms (r = 0.39, P = 0.035) in patients. However, whereas nigral and striatal (18)F-dihydroxyphenyl-L-alanine uptake were positively related in control subjects (r = 0.63, P < 0.001), this was not the case in patients (r = 0.30, P = 0.11). These findings indicate that elevated dopamine synthesis capacity is seen in the nigral origin of dopamine neurons as well as their striatal terminals in schizophrenia, and is linked to symptom severity in patients.

Project description: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 < 0.05). Gene expression of somatostatin (SST) was unchanged (p = 0.485). We confirmed the reduction in GAD at the protein level (34%, p < 0.05). When stratifying by inflammation, only 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 < 0.001) but not controls (GABRA2; r < - 0.200, GABRA3; r < 0.310, all 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.

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Putative presynaptic dopamine dysregulation in schizophrenia is supported by molecular evidence from post-mortem human midbrain.

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Putative presynaptic dopamine dysregulation in schizophrenia is supported by molecular evidence from post-mortem human midbrain.

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