Increasing neurogenesis in the adult mammalian brain

The conventional wisdom is that we are born with all the brain cells we’re ever going to have, and it’s all downhill from there—as we age, we lose brain cells, never to replace them. This, of course, explains why teenagers are so much smarter than their parents. Unfortunately for the conventional wisdom, it’s wrong. Within the adult central nervous system (CNS) of mammals there are small populations of cells involved in neurogenesis, or the birth of new neurons. A major goal in therapeutic intervention for neurodegenerative diseases (e.g., Alzheimer’s, Huntington’s) and spinal cord injuries is to find ways to kickstart the relatively modest ability of the nervous system to produce new cells into a really robust regenerative response.

A paper from June in PNAS suggests that the neuronal stem cells responsible for neurogenesis are distributed broadly throughout the CNS, rather than limited to a small number of regions. It also identifies ephrins as potential target molecules for therapeutic strategies. Ephrins are a family of molecules involved in directing the migration of neurons, often acting as repulsive cues that cause neurons to turn away from cells and tissues producing ephrins.

To begin, the researchers took cells from regions of the adult mouse CNS not known to possess stem cells (including the cerebellum, spinal cord, and parts of the cerebral cortex), dissociated them from one another, and grew them in culture dishes together with non-neuronal support cells, called astrocytes, from the brains of neonatal mice. Even after several days of co-growth, they could tell the two types of cells apart because the adult mouse cells were labeled green with GFP. So they could see that the green cells could form neurospheres, clusters formed by neural stem cells, when co-cultured with astrocytes, but not when grown on their own or in the presence of fibroblast cells. However, when cultured with adult astrocytes rather than neonatal astrocytes, fewer neurospheres would grow—even fewer than without any co-cultured cells. This result indicates that the adult astrocytes produce a factor (absent in the neonatal astrocytes) that prevents growth.

Two candidates they identified for these factors were ephrin-A2 and ephrin-A3, which are present in higher levels in the adult astrocytes than the neonatal astrocytes. The researchers generated mice lacking both of these factors, and looked in the adult brain for signs of neurogenesis. They found greater numbers of neural precursor cells (as determined by looking for expression of specific genetic markers) throughout the CNS, including the typically non-neurogenic regions of the midbrain, hindbrain, cerebellum, and spinal cord. In addition, these precursor cells were developing into neurons, as increased levels of early and late neuronal differentiation genes were also observed throughout the CNS.

The increased amount of neurogenesis in the brains of mice that lack these two factors indicates that they are normally important for reducing neurogenesis in adult brains. So, in addition to their previously known role in directing neurons where to go, these ephrins also are involved in keeping neuronal stem cells from proliferating (the researchers also tested to exclude the possibility that ephrins increased cell death rather prevented cell growth). Therefore, if the action of these two ephrin family members could be selectively blocked, it may be possible to stimulate the production of more nerve cells in the CNS to replace those lost to neurodegenerative disease or spinal cord injury.

Jiao, J., Feldheim, D.A., Chen, D.F. (2008). Ephrins as negative regulators of adult neurogenesis in diverse regions of the central nervous system. Proceedings of the National Academy of Sciences, 105(25), 8778-8783. DOI: 10.1073/pnas.0708861105