Schizophrenia (SZ) is a devastating mental illness with genetic and environmental risk factors that affects 1% of the world population. Pathology exists in multiple grey and white matter areas and neurotransmitter systems, making the search for a cause(s) and effective treatment elusive. Exploring new pathological mechanisms is paramount in trying to advance our understanding of SZ. Copper, which is required for proper monoamine metabolism, neurotransmission, mitochondrial activity, and myelination, is implicated in SZ but so far not studied in the brain. There is substantial evidence that copper is increased in the blood of patients with SZ. Interestingly, experimental manipulations that decrease copper produce demyelination, increases in dopamine, and behavioral impairments reminiscent of some SZ symptoms. Dysbindin is an upstream modulator of copper via the dysbindin/BLOC-1-copper metabolism interactome. It is encoded by the gene DTNBP1, which is a top candidate gene for SZ. A consequence of dysfunctional dysbindin in mice is a decrease in the copper transporters ATP7A and CTR1, which facilitate copper transport between the blood and the brain. To date, in spite of compelling evidence for a role of dysbindin in SZ, no one has linked a decrease in dysbindin function with abnormal copper homoeostasis in SZ. My overall hypothesis is that copper homeostatic and transport system alterations contribute to SZ pathology, potentially through decreased dysbindin expression. In support of this, we have observed decreased ATP7A and CTR1 protein in postmortem SZ substantia nigra (SN). SA1) In postmortem brain, we will test the hypothesis that SZ cases have lower levels of brain copper, ATP7A and/or CTR1, and dysbindin. We will study the SN and hippocampus, because these areas are implicated in SZ and have decreased dysbindin levels. We will use western blot protein analyses, quantitative immunohistochemistry to localize copper transporters, copper and dysbindin. SA2) In SZ patients and controls, we will test the hypothesis that medication nave subjects with SZ at first psychotic break will show markers of decreased dysbindin function, lower levels of ATP7A and/or CTR1, and higher levels of copper in blood or saliva. To do this we will get saliva/and or blood from SZ subjects in two different first episode clinics before and after treatment, and healthy controls. SA3) In an animal model with a knockout of the dysbindin gene, we will test the hypothesis that rescue of impairments in behaviors relevant to SZ, via antipsychotic drugs (APD), will require an increase in ATP7A and/or CTR1. We will treat dysbindin KO, heterozygotes and WT littermates with APDs, test behavior before and after treatment, then analyze the brain for levels of copper, ATP7A and CTR1. These studies will provide the first evidence of the state of copper in SZ brain. Although no one single abnormality will be the cause or cure of SZ, our studies will provide new data about the effects of copper transporters (a previously unstudied pathway in SZ), the role of dysbindin and its and a potential mechanism of antipsychotic rescue of copper starvation deficits, which could yield novel targets for drug development.
Schizophrenia (SZ) is a devastating mental illness that affects 1% of the world population. Abnormalities in copper can cause SZ like symptoms and pathology in animal models. We propose a novel, translational and multidisciplinary set of studies to address potentially abnormal copper homoeostasis in SZ. We will look at: 1) an upstream modulator of copper, the schizophrenia-susceptibility gene coding for dysbindin, one of the top candidate genes in schizophrenia; 2) the copper transporters and 3) levels of copper in patients, postmortem brain and an animal model with a knockout of dysbindin..