“I’d avoided the brain for a long time because it isn’t my area of expertise,” says Dr. Duester. “But when a new postdoc joined my lab who had studied the brain and stem cells in mice during graduate school, we decided it was time.”
This new postdoctoral researcher, Dr. Christina Chatzi, started with mice lacking Raldh3, one of several enzymes that produce retinoic acid. She then took a look at what’s happening in that model’s basal ganglia, the part of the brain that sits right below the cerebral cortex. The cortex contains excitatory neurons that drive learning and memory, while inhibitory neurons in the basal ganglia keep those cortical functions in check. As Drs. Duester and Chatzi show in a paper published online April 12 by the journal PLoS Biology, one region of the basal ganglia – the primitive part that fish have, too – requires retinoic acid to make inhibitory neurons. Another part, the more advanced section that came about later in evolution, doesn’t.
That’s a pretty cool finding because neurobiologists are beginning to appreciate that proper brain function relies on a careful balance of inhibitory and excitatory neurons. An imbalance has been implicated in some neurological disorders.
Here’s where Dr. Chatzi’s previous experience with stem cells also came in handy. With funding from the California Institute for Regenerative Medicine (CIRM), she developed a retinoic acid recipe that, when added to embryonic stem cells, generates the most common type of inhibitory brain cells – the GABAergic neurons. These neurons might be useful for alleviating symptoms in Huntington’s disease, autism, schizophrenia, epilepsy and bipolar disorder – diseases that are hard to treat, but believed to be caused by a loss of inhibitory neuron function.
“To us, this is a basic science story and that’s what’s most important,” Dr. Duester says. “We just want to know how things normally work during development. But what we found here suggests that others could use retinoic acid to make inhibitory neurons to treat disease, just the way an embryo does it naturally.”
As if that wasn’t enough, this paper also contains an interesting side story. While Drs. Duester and Chatzi were getting ready to submit their findings for publication, a group at the University of California, San Francisco (UCSF) published a big paper in the journal Cell claiming that normal development of the cerebral cortex requires retinoic acid generated in the meninges, the protective sac surrounding the brain.
While not exactly stealing their thunder, Drs. Duester and Chatzi worried that the Cell paper’s focus on retinoic acid in the cortex would surely overshadow their findings in the basal ganglia. But it didn’t keep them down for long. They decided to check out the cortex for themselves, turning to a different mutant mouse model that’s missing another retinoic acid enzyme, Raldh2. Without Raldh2, the meninges do not produce any retinoic acid. In the model used in the Cell paper, retinoic acid was only partially missing from the meninges. Those mice had severe brain defects, which the authors attributed to the cortex’s need for retinoic acid to stimulate neuron production.
However, Drs. Duester and Chatzi found that retinoic acid in the meninges wasn’t necessary for cortical development after all. Instead, they point out that defects in the UCSF group’s mice were likely due to complete loss of retinoic acid production in the neural crest – an early step in embryonic development that occurs before any cortical neurons are made. The UCSF researchers hadn’t considered that loss of retinoic acid produced by the neural crest (and later in the meninges) might be indirectly distorting cerebral cortex growth.
And in the end, Drs. Duester and Chatzi ended up with a more thorough – and accurate – paper on retinoic acid’s role in brain development.
Chatzi, C., Brade, T., & Duester, G. (2011). Retinoic Acid Functions as a Key GABAergic Differentiation Signal in the Basal Ganglia PLoS Biology, 9 (4) DOI: 10.1371/journal.pbio.1000609