Q&A with Gordon Fishell, Ph.D.
Professor of Cell Biology
Coordinator of the Smilow Neuroscience Program

When Gordon Fishell thinks about birthdays, he usually isn’t entertaining thoughts of balloons and cake. Instead, he is thinking about how neurons are born in the brain, and how the date of their birth influences what they become. His laboratory has created novel methods for tracking the birth of specific neurons among billions of cells in the developing brains of mice. His studies have led to a better understanding of the molecules and genes involved in cementing the identities of neurons that are crucial to brain function.

Recently, Dr. Fishell and his colleagues showed that the timing of a gene’s activity controls whether so-called inhibitory interneurons—small neurons that interconnect nerve cells—become one or another class of cell. By eliminating the Nkx2-1 gene during a specific point in development, they were able to influence the fate of cells in mice normally destined to become interneurons in the outer layer of the brain. These cells instead differentiated into what are known as striatal medium spiny projection neurons, which are normally derived from another population of developing cells. The finding expands our knowledge about the underlying mechanisms of development that shape the identities of neurons at birth.

Q: What are interneurons?

A: Interneurons make up 20 percent of the cells in the brain and are inherently very interesting. As opposed to being the long tracks of neurons that carry information form one brain area to another, interneurons are involved with localized activity. It is only recently that interneurons have really popped onto the radar— they are increasingly being linked to the brain’s ability to process information. For instance, schizophrenia and autism have been tied to the way interneurons develop.

Q: How has this particular study shed more light on the birth of neurons during development?

A: There is an idea out there in neuroscience that neurons are committed to their fate right about the time they stop dividing. While this notion is dogma, it is actually a tricky thing to prove since early tampering with genes produces developmental changes beyond what we care to study. But in this study, we figured out a clever way to accurately time the elimination of a gene in a particular kind of cell class in mice. Timing this gene deletion at a particular time in the cell’s life—its last division—resulted in class switching; the cell went from one kind of interneuron to another kind of interneuron. In other words, when the cell reached a final fork in the road of development, the gene decided which direction to take depending on whether it was on or off. We could verify what cell it became according to the shape it took, the proteins it expressed, and the way it electrically fired.

Q: What does this say about the fate of brain cells and development?

A: It is remarkable that you can have gene expression in a cell before it is born and before locking onto a genetic program for the rest of its life. The expression of the Nkx2-1 gene is a decision that’s made at a specific time when the cell’s state is changing one last time—a decision that permanently establishes the cell’s identity. Nkx teaches us when neurons really gain their identity—right at birth.

Q: How do you see this aspect of cellular development as clinically significant?

A: I have a pilot grant from the Simons Foundation that is based on the premise that interneurons are a good place to look when searching for the causes of autism. We are making a series of genetic models that may connect the aberrant development of interneurons to this disorder. Malfunction of specific types of interneurons may well account for some forms of autism. Indeed, when you consider the fact that 30 percent of autistic kids have epilepsy, a possible link between autism and interneuron development is well worth exploring.