Actions of Brain-Derived Neurotrophic Factor and Glucocorticoid Stress in Neurogenesis

Abstract

Altered neurogenesis is suggested to be involved in the onset of brain diseases, including mental disorders and neurodegenerative diseases. Neurotrophic factors are well known for their positive effects on the proliferation/differentiation of both embryonic and adult neural stem/progenitor cells (NSCs/NPCs). Especially, brain-derived neurotrophic factor (BDNF) has been extensively investigated because of its roles in the differentiation/maturation of NSCs/NPCs. On the other hand, recent evidence indicates a negative impact of the stress hormone glucocorticoids (GCs) on the cell fate of NSCs/NPCs, which is also related to the pathophysiology of brain diseases, such as depression and autism spectrum disorder. Furthermore, studies including ours have demonstrated functional interactions between neurotrophic factors and GCs in neural events, including neurogenesis. In this review, we show and discuss relationships among the behaviors of NSCs/NPCs, BDNF, and GCs.

Keywords: BDNF; glucocorticoids; intracellular signaling; neural stem cells; neurogenesis.

Figure 1

A proposed model for microtubule-dependent vesicular transport of brain-derived neurotrophic factor (BDNF) protein. Huntingtin (htt) and htt-associated protein 1 (HAP1) stabilize the linkage between dynein and dynactin complex. Dynein functions as a motor protein and dynactin complex attaches BDNF-containing vesicles to the motor protein complex with p150^Glued protein.

Figure 2

(A) Vesicular distribution of BDNF-GFP expressed in cultured cortical neuron obtained from rat brain (12 days in vitro). BDNF-containing vesicles are transported both in dendrites (MAP2-positive neurites) and axon (MAP2-negative one); (B) A magnified image of the white square region of A; (C) The effect of GCs on the proportion of the state of BDNF-vesicle transport. Time-laps imaging of BDNF-GFP revealed that more than 50% of BDNF-containing vesicles were not transported (stationary) in dendrites in the normal condition while DEX (an agonist for GR, 1 µM) increased and decreased the proportion of transported (>10 µm) and stationary vesicles, respectively. Data represent mean ± SE. Data was obtained from 7 (control) to 6 (DEX) neurons in four independent culture preparations including 388 and 302 vesicles, respectively. Statistical significance was evaluated by student’s t-test. Please see details in [78].

Figure 3

Chronic glucocorticoids (GCs) stress, which stimulates glucocorticoid receptor (GR) activation, causes downregulation of expression/function of BDNF. Because BDNF has pivotal roles in supporting neurogenesis and preventing neurodegeneration, it is possible that excess GCs functions as a negative factor in neurogenesis and a risk factor for the development/progression of neurodegenerative pathologies.