The repair of complex neuronal circuitry by transplanted and endogenous precursors

Abstract

During the past three decades, research exploring potential neuronal replacement therapies has focused on replacing lost neurons by transplanting cells or grafting tissue into diseased regions of the brain. However, in the last decade, the development of novel approaches has resulted in an explosion of new research showing that neurogenesis, the birth of new neurons, normally occurs in two limited and specific regions of the adult mammalian brain, and that there are significant numbers of multipotent neural precursors in many parts of the adult mammalian brain. Recent advances in our understanding of related events of neural development and plasticity, including the role of radial glia in developmental neurogenesis, and the ability of endogenous precursors present in the adult brain to be induced to produce neurons and partially repopulate brain regions affected by neurodegenerative processes, have led to fundamental changes in the views about how the brain develops, as well as to approaches by which transplanted or endogenous precursors might be used to repair the adult brain. For example, recruitment of new neurons can be induced in a region-specific, layer-specific, and neuronal type-specific manner, and, in some cases, newly recruited neurons can form long-distance connections to appropriate targets. Elucidation of the relevant molecular controls may both allow control over transplanted precursor cells and potentially allow for the development of neuronal replacement therapies for neurodegenerative disease and other CNS injuries that might not require transplantation of exogenous cells.

FIG. 1.

Induction of neurogenesis in the neocortex of adult mice. Cartoon showing targeted apoptosis of corticothalamic projection neurons and subsequent recruitment of new neurons from endogenous neural precursors, without transplantation, in adult mouse neocortex. A: In intact adult mouse neocortex, endogenous precursors exist in the cortex itself, and in the underlying SVZ. Normally, these precursors produce only glia in cortex. Neurons produced in the anterior SVZ migrate along the rostral migratory stream to the olfactory bulb (not shown). B: When corticothalamic projection neurons are induced to undergo synchronous targeted apoptosis, new migratory neuroblasts are born from endogenous precursors. These cells migrate into cortex, differentiate progressively into fully mature neurons, and a subset send long-distance projections to the thalamus, the appropriate original target of the neurons being replaced. The new neurons appeared to be recruited from SVZ precursors and potentially also from precursors resident in cortex itself. Adapted from Björklund and Lindvall, Nature 405:892-894, 2000, re: Magavi et al., ibid, 405:951-955, 2000. Reprinted with permission from Nature © 2000, Macmillan Magazines Ltd.