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.

Dopamine and glutamate in schizophrenia: biology, symptoms and treatment

“…Two PET studies have found that its levels were increased in the ventral brainstem of individuals with schizophrenia, but found no differences compared to controls in the striatum or thalamus. This is in contrast to the post‐mortem studies discussed above, but in keeping with a study showing increased VMAT2 density within platelets from individuals with schizophrenia.…”

“…Post‐mortem studies have also examined the substantia nigra. In these studies evidence regarding dopamine function is inconsistent, with some studies suggesting an increase in tyrosine hydroxylase levels in patients, but others finding no difference. Other studies have found abnormal nuclear morphology of substantia nigra neurons, reduced dopamine transporter (DAT) and vesicular monoamine transporter (VMAT) gene expression, and increased monoamine oxidase A expression.…”

mTOR-Related Brain Dysfunctions in Neuropsychiatric Disorders

“…Such an abnormal DA release produces peaks of extracellular DA, which cannot be taken up within nerve terminals, because METH inhibits and reverts the direction of the dopamine transporter (DAT). In line with this, recent studies suggest that DAT expression is significantly reduced in the midbrain of postmortem schizophrenic samples [150], which is reminiscent of the METH-addicted brain [151,152]. Upon METH administration, the massive amount of extracellular DA is followed by DA depletion, which translates into a pulsatile stimulation of post-synaptic DA receptors.…”

Increased Macrophages and C1qA, C3, C4 Transcripts in the Midbrain of People With Schizophrenia

“…Note the group sizes are different in the cohorts as different cases were excluded due to either poor quality RNA and/or protein. A single schizophrenia case in this mRNA cohort was lost from the mRNA cohort published previously ( 7 ) due to failure of cDNA synthesis . * p < 0.05 .…”

“…Human tissue experiments were approved by the University of New South Wales Human Research Ethics Committee (HREC #17826). Midbrain tissue was provided by the New South Wales Brain Tissue Resource Center (30/30 control/schizophrenia cases) and processed as previously described to generate mRNA and protein midbrain cohorts ( 7 ). The final midbrain mRNA cohort in this manuscript comprised 28 schizophrenia cases and 28 controls and the final midbrain protein cohort comprised 26 schizophrenia cases and 28 controls ( Table 1A ).…”