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Human Forebrain Circuits Wiring-up - in a Dish


Dr. David Panchision: Induced pluripotent stem cells, like those scientists can make from your skin or blood, are revolutionary for two reasons: First, because they provide unique information about your own biology, and second, because they have the ability to self-organize into many tissues and organs. In fact, when these structures self-organize in a dish they’re often called organoids, or spheroids. Scientists have been trying to get organoids that represent the different regions of the human brain – and the diverse cell types that interact -- but the process has been very haphazard and variable. You need to have this work consistently in order to learn anything. What this group from Stanford did was clever – they decided to grow these as spheres separately, under growth conditions that are known to normally instruct them to become one of two important forebrain regions: the cortex, which is the main region responsible for our higher thought processes, and a region right below it. This lower region is responsible for a lot of things, but one thing it does is generate a very important cell type called an interneuron. When these interneurons are generated in the brain during normal development, they do something very remarkable, which is to migrate -- using these characteristic stop-and-start, leaping motions – into the cortex, and THEN….they wire up with the neurons already in the cortex and start communicating. These different neurons have different roles – the ones that were born already in the cortex always excite other neurons, which is why they’re called excitatory neurons. However, the migrating interneurons’ job, once they wire up, is to inhibit those excitatory neurons to keep them from being over-active. It’s this balance of excitation and inhibition that allows the normal processing of information within the brain. So…the Stanford group was able to generate these two different types of spheres that actually contained these two different types of neurons. The next clever thing they did is they fused these two types of spheres together, and the interneurons actually did migrate from the lower sphere into the cortex sphere.  And they did it using the same stop-and-start migration that is seen in a real brain. Even more remarkable is that they wired up with the neurons already in the cortex and did what inhibitory interneurons are supposed to do, which is to tamp down the activity of the excitatory neurons to keep them from being over-active. Induced pluripotent stem cells that are made from you, and therefore the organoids made from them, provide unique information about your own biology. So the Stanford team decided to find out if these fused brain-like spheres could teach them something about the underlying biology of a medical condition. They looked at cells from kids with a serious condition called Timothy Syndrome – these kids often die early from cardiac problems, and those that survive often have autism and epileptic seizures. Timothy Syndrome occurs when a specific gene – one that codes for a Calcium channel – is mutated so that it doesn’t work properly. What the team found is that, within the fused spheroids, the migration of these Timothy syndrome interneurons was different – they were ‘jumpier’ but less efficient in moving forward. In fact, when the team applied a drug known to block this mutated calcium channel, it restored normal migration to these cells. While finding a result in a dish is only a first step to understanding a disorder or even finding a treatment that can be given to patients, this result with fused forebrain spheres is a crucial step in the right direction. Why? It allows complex biological events like migration and forming of connections to be studied in a way that’s more similar to the way they occur in the developing human body. This makes it more likely that they’ll provide insight into both the mechanisms of disease and effective treatments.