Chronically Increased Transforming Growth Factor-β1 Strongly Inhibits Hippocampal Neurogenesis in Aged Mice

Abstract

There is increasing evidence that hippocampal learning correlates strongly with neurogenesis in the adult brain. Increases in neurogenesis after brain injury also correlate with improved outcomes. With aging the capacity to generate new neurons decreases dramatically, both under normal conditions and after injury. How this decrease occurs is not fully understood, but we hypothesized that transforming growth factor (TGF)-beta1, a cell cycle regulator that rapidly increases after injury and with age, might play a role. We found that chronic overproduction of TGF-beta1 from astrocytes almost completely blocked the generation of new neurons in aged transgenic mice. Even young adult TGF-beta1 mice had 60% fewer immature, doublecortin-positive, hippocampal neurons than wild-type littermate controls. Bromodeoxyuridine labeling of dividing cells in 2-month-old TGF-beta1 mice confirmed this decrease in neuro-genesis and revealed a similar decrease in astrogenesis. Treatment of early neural progenitor cells with TGF-beta1 inhibited their proliferation. This strongly suggests that TGF-beta1 directly affects these cells before their differentiation into neurons and astrocytes. Together, these data show that TGF-beta1 is a potent inhibitor of hippocampal neural progenitor cell proliferation in adult mice and suggest that it plays a key role in limiting injury and age-related neurogenesis.

Activity Dependency and Aging in the Regulation of Adult Neurogenesis

“…Overexpression of TGF-b1 in old mice inhibited the proliferation of early precursor cells (Buckwalter et al 2006).…”

Smad3 deficiency increases cortical and hippocampal neuronal loss following traumatic brain injury

“…However, after brain injury TGF-β is also responsible for deposition of extracellular matrix proteins that contribute to glial scar formation (Logan et al, 1994(Logan et al, , 1999a which retards neuronal regeneration (McKeon et al, 1995;Windle et al, 1952) and increases the induction of traumatic epilepsy after brain injury (Hoeppner and Morrell, 1986;Tian et al, 2005). Additionally, TGF-β may suppress the early stages of neurogenesis (Buckwalter et al, 2006;Wachs et al, 2006), which may reduce the regenerative capacity of the brain. Thus, targeting TGF-β to enhance recovery from traumatic injury becomes complex because of these multiple and sometimes conflicting functions.…”

Ageing abolishes the effects of fluoxetine on neurogenesis

“…In this regard, we and others reported that intracerebroventricular infusions of TGF-b into the rat brain or overexpression of TGF-b in transgenic mice resulted in a marked downregulation of cell proliferation and neurogenesis in the hippocampus. 57,58 Moreover, levels of TGF-b are known to be increasing in the brain along with ageing. 59,60 Additional experiments targeting specifically the individual signaling systems are required to elucidate in the age-dependent loss of fluoxetine activities on neurogenesis.…”