Striking the right balance between excitation and inhibition
La Jolla, CA – Neurons in the brain and spinal cord come in two flavors, excitatory neurons that transmit and amplify signals, and inhibitory neurons that inhibit and refine those signals. Although investigators have long appreciated that these two classes of neurons exist in the central nervous system, little is known about how cells decide to become inhibitory or excitatory during embryonic development. Researchers at the Salk Institute for Biological Studies have now uncovered a pathway that plays a central role in regulating this choice.
That path is described in a study from Martyn Goulding, PhD., an associate professor in the Molecular Neurobiology Laboratory. Goulding, along with co-lead authors, postdoctoral fellow Rumiko Mizuguchi, PhD., and Sonja Kriks, a graduate student at Georg-August University in Goettingen, Germany, analyzed the origins of a group of spinal cord "interneurons," neurons that bridge communications between other neurons.
Many interneurons emerging in the dorsal part of the spinal cord arise from a common progenitor cell. Since mature neurons can be either excitatory or inhibitory, the researchers asked how a single parental progenitor cell could produce both excitatory and inhibitory daughter cells, and how approximately equal numbers of each daughter cell are produced.
In a study published in the June edition of Nature Neuroscience (now available online), the team found that a receptor protein known as Notch, which was already known to regulate maturation of neurons from neural stem cells, has a reciprocal function in precursors of inhibitory and excitatory neurons: cells with high levels of activated Notch became excitatory neurons, while cells with low levels of Notch became inhibitory.
Interestingly, the researchers found that one way Notch combats an inhibitory fate is to turn off another a factor known as Ptf1a, which promotes that fate. Describing the role of Notch as an arbitrator of the choice between excitation and inhibition, Goulding says: "The degree of Notch expression on one neuron tells the sibling cell that it cannot be the same thing." If it is up-regulated in one cell, Notch will be down-regulated in its sibling. "There are thousands of different kinds of neurons in our incredibly complex nervous system, and we don't understand how this diversity comes about," Goulding explains.
Referring to the multiple roles of Notch, not only in controlling the differentiation of neurons but in determining their excitatory/inhibitory activity, he adds: "Given that we now have a detailed description of how Notch signaling provides a switch that controls the choice between two different neuronal fates, we can now look and see if it is used in similar ways elsewhere to make different kinds of neurons."
The neurons in the dorsal spinal cord analyzed by the Goulding lab form a relay station receiving and interpreting sensory signals from the environment and then sending them to the brain. In doing so these neurons evaluate the strength of sensations.
"An example of how the system works is illustrated by what happens when you cut your finger," Goulding explains. "Initially it hurts a lot, but the pain then eases. One of the reasons that this happens is because inhibitory interneurons in the dorsal spinal cord dampen down their excitatory counterparts, thus dialing down the pain."
Since interneurons play such critical roles in transmitting pain signals, it is thought that some chronic forms of pain are due to an imbalance in excitatory and inhibitory signals carried by interneurons. As such, the findings by the Goulding group are likely to be important for devising animal models to study these pain pathways.
Other authors who contributed to this work include Ralf Cordes and Achim Gossler, from the Institute for Molecular Biology at the Medizinische Hochschule Hannover, and Qiufu Ma, from the Dana Farber Cancer Institute.
The Salk Institute for Biological Studies in La Jolla, California is an independent nonprofit organization dedicated to fundamental discoveries in the life sciences, the improvement of human health, and the training of future generations of researchers. Jonas Salk, M.D., whose polio vaccine all but eradicated the crippling disease poliomyelitis in 1955, opened the Institute in 1965 with a gift of land from the City of San Diego and the financial support of the March of Dimes.