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Interview with Hilleke Hulshoff Pol and Jeroen Pasterkamp

Psychiatry and molecular biology: linked by neuronal unbalance

"Crossroads in neuroscience."

“Psychiatry owes a lot to progress made in visualizing and mapping neurobiological processes,” says Hilleke Hulshoff Pol, who leads the neuroimaging research group. Her work benefits from research in Jeroen Pasterkamp’s group, which uncovers the fundamentals of brain wiring. How do neurons interact? What systems do they form? What happens if neuronal connectivity does not function as it does in the majority of people? It’s their groups’ mutual interest: neuronal unbalance setting off disorders, from schizophrenia to neurological diseases. In twin studies, Hulshoff Pol looks into brain development from genetic, environmental and visualizing angles. “A few hundred twins participate and we’ve been working with them for many years. We’ve already learned a lot from scanning their brains using structural and functional MRI at 9, 12 and 16 years of age or in adulthood.” One of the questions her group wants to answer is why identical twins have a fifty percent chance of developing schizophrenia when the other half of the twin is schizophrenic – as opposed to the overall chance being only one percent.

Brain areas and disease

“But getting a clear picture is only the first step. We can see for example that, as our brain develops, our cortex gradually gets thinner: a process that starts during puberty. In patients with schizophrenia, this thinning is more progressive. How? Why? We don’t know yet.”

“We now know that, through contributions of both genes and environment, brains of people with schizophrenia are 3 percent smaller than those of people without. It also seems that some brain areas are more isolated in people with schizophrenia and make less contact with other brain areas. Also, they have one percent less white matter than people without schizophrenia, which adds up, since white matter forms connections between anatomically distant brain areas, and is a means of transmitting neural information throughout the brain’s network.”

Integrated approach

This approach entails a new lab equipped for experiments in induced pluripotent stem cells. “This technology allows us for the first time to make and manipulate neurons from human patients. The advantage is that these cells will have the genetic make-up of the patient, allowing us to dissect disease mechanisms or to test therapies. The first results of our work on neurons obtained from ALS-patients are promising. We and others plan to make schizophrenia-models in a similar way.” Hulshoff Pol: “This is a great opportunity, because it complements brain imaging with reprogrammed cells from living patients.”

Jeroen Pasterkamp is after biological insight into neuronal connectivity. “We work at a molecular and cellular biological level, providing basic neurobiological knowledge for translational studies into disease. Our focus is on developmental disorders as well as neurological diseases such as epilepsy and ALS. In the latter, specific neuronal connections disappear or change because of genetic defects and dysfunctioning proteins. When it comes to schizophrenia, defects in single genes are unlikely to explain the disease. We need an integrated approach, covering different disciplines. Hilleke’s research reveals the biological substrate of the disease; we deliver the molecular knowledge, while others focus on genetics.” getting a clear picture is only the first step.

Cross-talks

Such joint ventures are what the Brain Center Rudolf Magnus aims for- Pasterkamp: “Valuable findings in one disease can clarify things about other disorders too –our work usually has a beneficial impact on other fields of expertise.”

The monthly cross-talks, meant for everyone working within the Brain Center are a practical means to an end,” says Hulshoff Pol. “Such talks are invigorating; they give room to new ideas for combining research in ways that you, on your own, would never have come up with.”

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