Using human induced pluripotent stem cells (hiPSCs), researchers have gained new insight into what may cause schizophrenia by revealing the altered patterns of neuronal signaling associated with this disease. They did so by exposing neurons derived from the hiPSCs of healthy individuals and of patients with schizophrenia to potassium chloride, which triggered these stem cells to release neurotransmitters, such as dopamine, that are crucial for brain function and are linked to various disorders. By discovering a simple method for stimulating hiPSCs to release neurotransmitters, the findings in the International Society for Stem Cell Research's journal Stem Cell Reports, published by Cell Press, could provide new insights into how neurons communicate with each other and could lead to a better understanding of the neural mechanisms underlying a range of brain disorders.
"This study is novel because it shows that stem cell neurons derived from patients can provide new insight into neurotransmitter mechanisms occurring in brain disorders such as schizophrenia," says senior study author Vivian Hook of the University of California, San Diego. "The approach of this study has broad opportunities for uncovering the neurochemistry of brain cell communication in numerous brain disorders, via these studies of human disease in a dish. Findings from these studies will lead to new therapeutic strategies for brain disorders, especially those mental and neurological diseases for which no drug treatments exist today."
hiPSCS are cells that are taken from adults, genetically reprogrammed to an embryonic stem cell-like state, and then converted into specialized cells such as neurons. Patient-derived hiPSCs offer the possibility of modeling an individual's disease in a dish and assessing which drugs will most effectively treat the disease. Because dysfunction in neural communication is linked to brain disorders such as schizophrenia, Hook and Fred Gage of The Salk Institute and Kristen Brennand of the Icahn School of Medicine at Mount Sinai set out to determine whether hiPSC-derived neurons can be induced to release important brain signaling chemicals, allowing disease mechanisms to be studied in a dish.
To address this question, the researchers exposed hiPSC-derived neurons from healthy individuals and patients with schizophrenia to a chemical known to stimulate the release of neurotransmitters. They found that these cells contained neurotransmitter-producing enzymes and were capable of secreting dopamine, norepinephrine, and epinephrine--neurotransmitters that are crucial for brain function and that are linked to various disorders. Moreover, secretion of the three neurotransmitters was enhanced in hiPSC-derived neurons from schizophrenia patients compared with those from healthy individuals.
"The significance of this study is that patient-derived stem cell neurons can uncover previously unknown neurotransmitter brain mechanisms occurring in schizophrenia," Hook says. "Because in vivo human brain research is limited, hiPSC neurons derived from patients create new opportunities to understand changes occurring in brain cells occurring in nervous system disorders. These approaches can potentially define new drug targets for the development of therapeutic agents to improve the lives of schizophrenia patients."
Stem Cell Reports, Hook et al.: "Human iPSC Neurons Display Activity-Dependent Neurotransmitter Secretion: Aberrant Catecholamine Levels in Schizophrenia Neurons."