Increased cortical expression of the zinc transporter SLC39A12 suggests a breakdown in zinc cellular homeostasis as part of the pathophysiology of schizophrenia

Our expression microarray studies showed messenger RNA (mRNA) for solute carrier family 39 (zinc transporter), member 12 ( SLC39A12 ) was higher in dorsolateral prefrontal cortex from subjects with schizophrenia (Sz) in comparison with controls. To better understand the significance of these data we ascertained whether SLC39A12 mRNA was altered in a number of cortical regions (Brodmann’s area (BA) 8, 9, 44) from subjects with Sz, in BA 9 from subjects with mood disorders and in rats treated with antipsychotic drugs. In addition, we determined whether inducing the expression of SLC39A12 resulted in an increased cellular zinc uptake. SLC39A12 variant 1 and 2 mRNA was measured using quantitative PCR. Zinc uptake was measured in CHO cells transfected with human SLC39A12 variant 1 and 2. In Sz, compared with controls, SLC39A12 variant 1 and 2 mRNA was higher in all cortical regions studied. The were no differences in levels of mRNA for either variant of SLC39A12 in BA 9 from subjects with mood disorders and levels of mRNA for Slc39a1 2 was not different in the cortex of rats treated with antipsychotic drugs. Finally, expressing both variants in CHO-K1 cells was associated with an increase in radioactive zinc uptake. As increased levels of murine Slc39a12 mRNA has been shown to correlate with increasing cellular zinc uptake, our data would be consistent with the possibility of a dysregulated zinc homeostasis in the cortex of subjects with schizophrenia due to altered expression of SLC39A12 . Cell biology: Zinc transport protein could alter brain function in schizophrenia Changes in the expression of a protein that regulates zinc levels could alter brain function and boost schizophrenia risk. Schizophrenia is thought to occur in people with a genetic predisposition to the disorder in response to environmental factors that alter the expression of certain genes. One possible candidate is SLC39A12, which encodes a zinc transporter protein that regulates zinc levels within and between cells of the central nervous system. Brian Dean at the Florey Institute of Neuroscience and Mental Health in Australia and colleagues found increased expression of SLC39A12 in the brains of people with schizophrenia–but not those with bipolar disorder or major depressive disorder–and confirmed that increased expression is associated with enhanced zinc transport into cells. Further experiments suggest that these changes are unlikely to be the result of antipsychotic drugs.