Using Induced Pluripotent Stem Cells to Model Mental Diseases in a Dish

The brains of patients who suffer from neurological disorders like autism or schizophrenia work differently than those who do not have such conditions. The precise functional differences in the neurons of those who suffer from such conditions are not completely understood, but stem cell technology has provided a way to study this very question. Scientists have literally been able to “turn back the clock” on the neurons of schizophrenic patients and see some of the abnormalities they display during development.

Researchers isolated skin cells from schizophrenia patients and converted the skin cells into induced pluripotent skins cells (iPSCs) by utilizing using genetic engineering technologies. They then treated these iPSCs with various growth factors to reprogram them into neurons, which are the cells in the central and peripheral nervous systems that generate nerve impulses and are responsible for thinking, reasoning, emotion, and other basic and higher brain functions. Once they made the cultured neurons, they subjected them to various physiological tests and measured the ability of neurons made from the iPSCs derived from patients with schizophrenia, and compared them to neurons made by the same protocol from patients who do not suffer from schizophrenia. The results were telling.

Neurons made from iPSCs derived from skin cells from schizophrenia patients looked normal, but the connections they made with other neurons were abnormal. Neurons connect with each other through special connections called “synapses.” Synapses consist of the end of the neuron, which is called the “axon terminus,” and the cell that receives the neural impulse from the signaling neuron. Neurons can give their input to the front part of another neuron, or they can give their input to other parts of a neuron. Synapses consist of a host of special proteins that dock the neurons together and facilitate the reception of signals from one neuron to another. Defects in synapses lead to abnormalities in nerve impulse conduction, and the neurons from schizophrenic patients showed structural abnormalities in the synapses that they made with other neurons and also produced fewer synapses with other neurons in general.

If that was not enough, Gage and his co-workers went the next step. They treated these cultured neurons with drugs that are normally used to treat schizophrenia. These drugs reversed the abnormalities found in the cultured neurons. This completely contradicts some of the current thinking regarding the treatment of schizophrenia, which asserts that by regulating the amount of particular neurotransmitters like dopamine and serotonin, psychiatrists can ameliorate the symptoms of schizophrenia. Now it appears that the drugs actually induce structural changes in the neurons and the synaptic junctions they make with other neurons and this is the reason these drugs mitigate schizophrenia symptoms.

Lead researcher, Fred (Rusty) Gage, professor of genetics at the Salk Institute for Biological Studies and a member of the executive committee of the Kavli Institute for Brain and Mind (KIBM) at the University of California, San Diego, said: “This allows us to identify subtle changes in the functioning of neuronal circuits that we never had access to before.” Gage continued: “As we accumulate models for these diseases – bipolar disease, schizophrenia, depression, autism – we are going to be able to explore if there are really differences between them that exist on a cellular or gene expression level.” — Fred Gage

Gage also noted that the need to induce structural changes in the neurons in order to assuage the symptoms of schizophrenia might explain why schizophrenia drugs take time before they actually help the patient. In fact, this might explain why other psychoactive drugs take so long to work as well. For example, if depression was simply a matter of modulating the concentration of a particular neurotransmitter, then an anti-depressant should have immediate effects. However, such drugs like antidepressants often take weeks to work. Could it be that such medications work at the structural level and not only at the neurotransmitter level?

When asked what technological advances are needed to explore this further, Gage responded: “One limitation is we haven’t differentiated the cells into specific cell types—neuronal subtypes. Right now we’re just laying these neurons down and allowing them to form connections as they might. Looking ahead, it’s going to be important for us to differentiate the cells. For example, to differentiate and model the cortical neurons, which are responsible for thinking tasks, or the hippocampal neurons, which are responsible for memory tasks. I can one day see us using microfluidic chambers to achieve this. They will allow us to compartmentalize microscopically specific subtypes of neurons in certain locations, and then regulate how they connect to each other. That way you can simulate in a more accurate manner how these subtypes connect with each other in the brain. The future of this is really exciting because the dish is going to get much more complicated.”

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Professor of Biochemistry at Spring Arbor University (SAU) in Spring Arbor, MI. Have been at SAU since 1999. Author of The Stem Cell Epistles. Before that I was a postdoctoral research fellow at the University of Pennsylvania in Philadelphia, PA (1997-1999), and Sussex University, Falmer, UK (1994-1997). I studied Cell and Developmental Biology at UC Irvine (PhD 1994), and Microbiology at UC Davis (MA 1986, BS 1984).