This is what schizophrenia looks like at the molecular level

What you're looking at are neurons grown from a schizophrenic person. An incredible study, published today in Nature, reveals how scientists grew schizophrenic brain cells to understand the inner workings of this still-mysterious neurological disorder.

A team of scientists from research institutes across the US collaborated to conduct this first-of-a-kind experiment. Schizophrenia is known to be a genetic disease in the majority of cases, and the researchers drew their samples from the skin of four people with clear signs of genetic schizophrenia. Three were from families where one parent and all their siblings were also schizophrenic, and one had been diagnosed with schizophrenia at the age of 6. The scientists "reprogrammed" these cells to become stem cells, then neurons, creating small colonies of cells whose genetic profile exactly matches schizophrenic neurons.


Over a period of weeks, they watched the cells develop, testing them to see how they differed from a control group of cells. They already knew from previous studies that schizophrenic neurons don't form many connections with other neurons, and indeed this was exactly what they found. Neural connections, which are electrical and chemical links between cells called synapses, allow your brain to form new memories, learn, and come up with new ideas. (You can see them in the fine threads between neurons in the pictures that illustrate this story.) But schizophrenic neurons don't reach out to each other.

And the research team now has a much better picture of why this is. Partly it's because schizophrenic neurons are low on proteins that help build those connections. But the researchers also found unusual behavior in genes needed to regulate two cell processes (called "signalling pathways") that help neurons communicate with each other. What it all boils down to is that schizophrenic neurons suffer from a number of problems, all of which make it harder for them to create the kind of dense neural network your brain needs.


At left, you can see two neural cultures - on the left is the control group and on the right are the schizophrenic cells. Note that the schizophrenic cells have formed far fewer connections than the control group has.


The researchers also tested 5 antipsychotic drugs on the neurons, and found that only loxapine helped the cells form more connections with each other.

In a technical summary, the authors write:

Schizophrenic human-induced pluripotent stem cell neurons showed diminished neuronal connectivity in conjunction with decreased neurite number, PSD95-protein levels and glutamate receptor expression. Gene expression profiles of SCZD hiPSC neurons identified altered expression of many components of the cyclic AMP and WNT signalling pathways. Key cellular and molecular elements of the SCZD phenotype were ameliorated following treatment of SCZD hiPSC neurons with the antipsychotic loxapine.


So what's the upshot? We know that most of the problems in schizophrenic neurons come from an inability to form neural connections, and now we know that these problems are caused by a very complicated set of factors. There is no "schizophrenia gene." And there is no one type of neurological damage that leads to schizophrenia. The good news is that we have a detailed cellular model of one form of schizophrenia now, and what these researchers have found will help others in the field get closer and closer to a therapy that might one day reprogram schizophrenic neurons to be more like typical neurons, forming a web of connections with their fellow cells in the brain.

Read the full scientific paper via Nature


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