Anterograde transport of brain-derived neurotrophic factor and its role in the brain

In addition to well established trophic functions, neurotrophins acutely affect neurotransmitter secretion from the presynaptic nerve terminal, inf luence synaptic development, and may serve as selective retrograde messengers that regulate synaptic efficacy. The crucial question related to the mechanisms of neurotrophin-mediated signaling is whether acute effects of neurotrophins are spatially restricted to the activated synapses. Here we have used a local perfusion technique for local delivery of neurotrophin-3 (NT-3) to various regions of developing Xenopus embryo neurons in culture. Within minutes after a focal exposure of a soma or a small (Ϸ30 m in length) axonal segment to NT-3, we observed an increase in the spontaneous neurotransmitter secretion from the presynaptic nerve terminals located Ϸ300-400 m away from the site of NT-3 application. Secretory activity along the axonal shaft was not affected. Our findings suggest that the NT-3-mediated signal may rapidly travel through neuronal cytoplasm over unexpectedly long distances and modulate neurotransmitter release specifically at the presynaptic nerve terminals.The neurotrophin hypothesis holds that proliferation, survival, and differentiation of various neuronal populations are determined by the competition between neurons for a limited amount of trophic factors produced primarily by target tissues (1-3). In addition to these classic long-lasting trophic activities, neurotrophins mediate neurotransmitter secretion from the presynaptic neurons, both in cell culture (4) and in hippocampal slices (5). Neurotrophin synthesis in the central nervous system is rapidly regulated by neuronal activity (6, 7), and neurotrophin release from the postsynaptic targets is activity dependent (8). Taken together, these results support a positive feedback model, in which presynaptic activity enhances neurotrophin synthesis and release from the postsynaptic cells, leading to potentiation of synaptic efficacy (9-12). Thus, neurotrophins may serve as selective retrograde messengers involved in the processes of synaptic maturation and synaptic competition (13).In the past, neurotrophin effects were thought to be primarily mediated by long-range retrograde signaling to the soma, where changes in gene transcription are induced (14,15). The signaling requires autophosphorylation of specific tyrosine residues on neurotrophin receptors (Trks), followed by receptor endocytosis and retrograde transport to the cell body (15). However, there are neurotrophin-mediated effects that occur on the time scale of minutes; these do not require protein synthesis or signaling to the cell body (4,11,16). Although the signal transduction pathways involved in such acute effects have yet to be firmly established, it is generally believed that the neurotrophin-mediated acute effects are spatially restricted to the site of neurotrophin secretion (11, 17).Xenopus nerve-muscle coculture is a well established model for synaptic plasticity. In these developing neuromuscular synapses, spontaneous s...

Section: Discussionmentioning

confidence: 77%

Long-range signaling within growing neurites mediated by neurotrophin-3

Chang

Popov

1999

“…It is known that BDNF strengthens connections (20)(21)(22), and this may be the primary phenomenon behind the survival effect we saw. New neurons recruited into HVC can be first back-filled from one of their targets, nucleus Robustus of the Archistriatum, Ϸ15 days after they are born.…”

Section: Discussionmentioning

confidence: 81%

Timing of brain-derived neurotrophic factor exposure affects life expectancy of new neurons

Alvarez-Borda

Haripal

Nottebohm

2004

The high vocal center (HVC) of adult male canaries, Serinus canaria, is necessary for the production of learned song. New neurons are added to HVC every day, where they replace older neurons that have died, but the length of their survival depends on the time of year when they are born. A great number of HVC neurons born in the fall, when adult canaries learn a new song, are still present 8 mo later, when this song is used during the breeding season. By contrast, most of the neurons born in HVC in the spring, when little song learning takes place, disappear much sooner. Here we show that infusion of brain-derived neurotrophic factor into HVC during days 14 -20 after new HVC neurons are born in the spring confers on them a life expectancy comparable to that of fall-born neurons; this extension on life is not seen when infusion occurs 10 days earlier or later. We suggest that there is, in the adult HVC, a subset of neurons whose life expectancy is determined by brain-derived neurotrophic factor during a sensitive period soon after these neurons reach destination and start forming connections.N ew neurons are born in the adult canary brain in the ventricular zone lining the wall of the lateral ventricles (1, 2). They migrate into the high vocal center (HVC) and assume a sedentary phenotype 8-15 days after their birth. The number of these new neurons is much reduced during their third week of life (3). By day 30, the axons of many of the surviving new HVC neurons have reached their target, and many of the new cells have become a functional part of existing circuits (3-5). Thereafter, the life expectancy of the neurons depends on the time of year when they are born. Whereas the number of fall-born neurons is virtually the same 30 and 120 days after their birth, this number drops by one-half at the later survival time in spring-born neurons (6). However, the mechanism that regulates this season-dependent survival͞attrition has not been worked out in detail.In addition to season, the presence of new neurons in HVC has been shown to depend on variables such as amount of singing (7,8), auditory experience (9), blood testosterone levels (8, 10), and the presence of brain-derived neurotrophic factor (BDNF) in HVC (11). Some of these factors are related. For example, both amount of singing and blood testosterone levels change seasonally (12) and both influence the amount of BDNF present in HVC (8). There are at least two major sources of BDNF in HVC: neurons that project to the robust nucleus of the archistriatum (7) and endothelial cells lining HVC capillaries (13); in addition, a small percentage of HVC neurons that project to area X also express BDNF (7). Knowing that BDNF can influence neuron survival and that there is a dramatic decline in new neuron numbers 15-22 days after their birth (3), we decided to test whether BDNF infusion during this period could enhance the survival of new neurons born in the spring. We found that, whereas BDNF infusion into HVC during days 14-20 after new neurons are born markedly extends t...

“…We do not know whether BDNF protein produced during previous days contributed to the basal level seen in our nonsinging birds. Finally, and perhaps most importantly, it is known that much of the BDNF protein produced in one site can be carried away by anterograde transport (47,48). If part of the BDNF protein produced in HVC was transported to RA or Area X, then the amount left in HVC would grossly underestimate the amount produced.…”

Section: Discussionmentioning

confidence: 99%

A relationship between behavior, neurotrophin expression, and new neuron survival

Jarvis

Alvarez-Borda

et al. 2000

187

149

The high vocal center (HVC) controls song production in songbirds and sends a projection to the robust nucleus of the archistriatum (RA) of the descending vocal pathway. HVC receives new neurons in adulthood. Most of the new neurons project to RA and replace other neurons of the same kind. We show here that singing enhances mRNA and protein expression of brain-derived neurotrophic factor (BDNF) in the HVC of adult male canaries, Serinus canaria. The increased BDNF expression is proportional to the number of songs produced per unit time. Singing-induced BDNF expression in HVC occurs mainly in the RA-projecting neurons. Neuronal survival was compared among birds that did or did not sing during days 31-38 after BrdUrd injection. Survival of new HVC neurons is greater in the singing birds than in the nonsinging birds. A positive causal link between pathway use, neurotrophin expression, and new neuron survival may be common among systems that recruit new neurons in adulthood.A set of interconnected brain nuclei referred to as the song system is responsible for song acquisition and production in songbirds. This system includes the high vocal center (HVC), which sends projections to two nuclei, the robust nucleus of the archistriatum (RA), and Area X (Fig. 1). The main motor pathway for song production runs from HVC to RA; RA in turn innervates mesencephalic and medullary nuclei that control respiratory muscles and the bird's vocal organ, the syrinx (1, 2). The projection from HVC to Area X is part of a separate forebrain circuit that is necessary for song learning but not for the production of learned song (3-6).HVC continues to receive new neurons in adulthood, and a majority of these cells project to RA (7-10). The recruitment of new HVC neurons is part of a replacement process, with peaks in cell death in August (midsummer) and January (midwinter), when blood testosterone levels of adult male canaries are low. These peaks in cell death are followed by peaks in new neuron incorporation in October and March, when blood testosterone levels are high (11). Male canaries modify their song in adulthood by adding, dropping, and altering song syllables. Most of these changes occur during the summer and fall, with a secondary wave of change in winter. Song stability is maximal in the spring, when canaries breed and recruitment of new HVC neurons is at its lowest (12). It has been hypothesized that neuronal replacement in HVC provides a cellular basis for the song plasticity observed in adult canaries (11,13).The mechanism that regulates neuronal survival and turnover in HVC has been the focus of two previous studies. These studies suggested that the survival of new HVC neurons can be regulated by testosterone or a testosterone metabolite (14), and the testosterone effect is mediated by the brain-derived neurotrophic factor (BDNF) (15). Specifically, the increase in the recruitment of new HVC neurons after systemic testosterone treatment is blocked by infusing an antibody against BDNF into HVC. Moreover, the effect of testost...