A young brilliant mathematician seen by his colleagues as agitated, socially withdrawn, emotionally flat and paranoid is approached by a Department of Defense agent who requests his assistance with code breaking. Following acceptance of this job, the young professor believes he is being followed and is eventually chased through his university campus, captured and sedated. When the young professor comes to, he is in a psychiatric hospital and forced to realize that his secret work for the Department of Defense is one of his schizophrenic delusions. This is the story of John Nash portrayed in the film A Beautiful Mind. Like many individuals suffering from schizophrenia (1 in every 100 Canadians), John Nash struggles throughout his life with an array of symptoms including delusions and hallucinations.
Can induced pluripotent stem cells (iPSCs) help us understand the underlying mechanism of this devastating and complex condition? Maybe.
Scientists have proposed the use of iPSCs for modeling human disease however; many question the usefulness of iPSCs for modeling complex neurological diseases such as schizophrenia. Last month a team of researchers led by Fred Gage at the Salk Institute published in Nature the first example of modeling a complex neurological disease in a dish.
Skin fibroblasts from schizophrenia patients were obtained from a cell bank and reprogrammed into iPSCs. Patient-derived iPSCs were differentiated into neurons to study the cellular and molecular mechanisms of schizophrenia. The researchers found that patient-derived neurons were electrophysiologically equivalent to control neurons and the levels of a number of synaptic maturation markers were unaffected. However, schizophrenia neurons did show a decrease in the number or neuronal projections, decreased neuronal connectivity and alterations in global gene expression. Over 550 genes were aberrantly expressed in schizophrenia neurons, 25 per cent of which have been previously linked to the disease.
iPSC-derived schizophrenia neurons were treated with five antipsychotic drugs in an attempt to improve neuronal connectivity in vitro. The drugs were administered for the final three weeks of neuronal differentiation. Loxapine, an antipsychotic commonly used to treat schizophrenia was the only antipsychotic drug that significantly increased neuronal connectivity in all patient iPSC derived-neurons.
Interestingly, this is not the first study to investigate the molecular mechanisms of schizophrenia in vitro. A small number of studies have been performed on cultured fibroblasts from skin biopsies of schizophrenia patients. One study identified a cell proliferation defect in patient fibroblasts. While studying patient fibroblasts may provide some insight into disease mechanisms many scientists stress the importance of studying the appropriate cell type in vitro. For example, in the Nature paper noted above, Fred Gage’s group reported increased NRG1 (a protein thought to be involved in schizophrenia) expression in schizophrenia neurons but not SCZD fibroblasts, which they suggest, demonstrates the importance of studying the relevant cell type.
I recently attended a Stem Cell Journal Club session at the Hospital for Sick Children where this paper was presented. Stem cell and neurobiologists in attendance raised a number of concerns about this study includingthe difficulty of modeling a complex systems disease that is thought to be a dynamic process, leading to the dysfunction of many pathways in the brain. How much insight will researchers have into this disease if they are studying only a few types of neurons in a dish? Even though many scientists are skeptical, we can’t disregard that almost all insight into the molecular mechanism of schizophrenia in human patients has come from the study of postmortem brain tissue. iPSCs are the only source of live human neurons available to researchersfor studying this devastating disease and for this reason, scientists should continue to use and optimize neurons from iPSCs.
Angela C. H. McDonald
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