Pasadena--Like a commuter trying to get to work during rush hour, a growing axon must thread its way through a throng of other axons that are headed in many different directions in the developing brain. Axons are the wire like extensions of nerve cells that carry electrical signals from one place to another in the brain, and during development they must navigate across long distances (many centimeters) to reach their correct address within the brain. If the axon gets lost, brain circuits cannot form normally, and, like the commuter showing up at the wrong office, the axon may not be able to do its job. So how do axons find their way? A report published in the July 24 issue of the journal Science. by Drs. Susan Catalano and Carla Shatz of the University of California at Berkeley, sheds light on how axons home in on their correct targets.
Traditionally, scientists studying the mechanisms of axon navigation thought in terms of molecular guidance cues. Molecules located in specific places in the brain can tell a growing axon "grow here," "don't grow there," or "make a left turn here." The collective distribution of these molecules in the developing brain forms a pathway that the axon can follow to get to the right place. But Catalano and Shatz suspected that the situation might be more complicated than that. The brain is too complicated, and the genome too small, for there to be a molecular address at every possible target location in the brain. They suspected that there might be another potential source of guidance cues for the growing axons: electrical activity itself. They decided to block electrical activity within the developing brain with a neurotoxin made by the Japanese puffer fish, and their suspicions were confirmed: in the absence of activity many axons fail to find their way to the correct address. Instead they become confused and wander into other regions they normally bypass. Dr. Susan Catalano, now at the California Institute of Technology, offers this analogy: "If the growing axon is like a car, then the highway pavement and traffic signals would be like the guidance molecules. Demonstrating that neural activity is critical for axon navigation is like adding a Global Positioning System into the mix; its a whole new level of information that the axon can potentially use to guide its way toward the appropriate target."
Catalano and Shatz studied axons that grow out from nerve cells located in a brain structure called the thalamus. During development these axons must navigate toward their correct target, the neocortex. The thalamus is a vital way station within the brain; all of the information coming from the sensory organs (such as the eyes, ears, and skin surface) passes through the thalamus on its way to the neocortex. The neocortex is the highly folded layer of neurons on the surface of the brain that is responsible for such functions as language processing; in other words, it is the brain structure that makes us uniquely human. The connections from the thalamus to the cortex are not randomly organized: specific groups of nerve cells within the thalamus (called nuclei) connect up to specific areas of the neocortex. This precise organization, or "map", is critical for proper brain function. In order to form this circuit correctly during development, groups of axons coming from specific places within the thalamus must navigate across the vast expanse of neocortex. They must bypass incorrect areas of the neocortex and choose just the right area to connect with, but without electrical activity, the axons become lost.
How might electrical activity produce this effect? While that is not currently known, clues can be found in studies of other regions in the brain. Previous work from Dr. Shatz's lab has shown that very early in development when the axons from the eye are still navigating toward their targets in the brain, waves of electrical activity sweep across the retina. This means that axons that are nearest neighbors are electrically active at the same time. Simultaneous activity could alter the molecular environment of the pathway through which the axons grow and allow cohorts of axons to keep together during navigation.
Ever since the pioneering work of Nobel laureates David Hubel and Torsten Wiesel, it has been known that the pattern of electrical activity carried by different sets of axons can influence the physical shape of the axons themselves. During the last phases of development, axons from the thalamus form many branches as they spread out through the neocortex to make their final sets of connections. These branches are literally shaped like the branches of a tree, and hence are called the "terminal arbor." Changes in the axon's pattern of electrical activity can change the shape of the tree that forms; less activity results in a shrunken, knarled axon tree. Surrounding axons with normal levels of activity form many more branches that grow into the shrunken tree's territory, just like their counterparts in nature that grow into the sunlit space created when a neighbor falls.
While the role of electrical activity in the final stages of thalamic axon branch formation had been well established, the possibility that the same process might be crucial in early development during axon navigation remained uninvestigated until now. The clinical implications of this are potentially alarming: drugs such as nicotine, which can affect electrical activity within the brain, have the potential to disrupt circuit formation in a developing infant's brain at very early stages, when the major circuits of the brain are being formed. The possibility that developing brains are vulnerable to disruption by activity-altering agents at such early times suggests important areas for future research.
