Brain-derived neurotrophic factor and the development of structural neuronal connectivity

Abstract

During development, neural networks are established in a highly organized manner, which persists throughout life. Neurotrophins play crucial roles in the developing nervous system. Among the neurotrophins, brain-derived neurotrophic factor (BDNF) is highly conserved in gene structure and function during vertebrate evolution, and serves an important role during brain development and in synaptic plasticity. BDNF participates in the formation of appropriate synaptic connections in the brain, and disruptions in this process contribute to disorders of cognitive function. In this review, we first briefly highlight current knowledge on the expression, regulation, and secretion of BDNF. Further, we provide an overview of the possible actions of BDNF in the development of neural circuits, with an emphasis on presynaptic actions of BDNF during the structural development of central neurons.

Figure 1

Synthesis and release of BDNF, and molecular cascades that influence presynaptic structure. A simplified schematic view of BDNF action at sites of pre- and postsynaptic contact (yellow dots). Presynaptic activity induces glutamate release leading to the activation of postsynaptic NMDA (N-methyl-D-aspartate) and AMPA (α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid) receptors. Local BDNF mRNA, selectively transported into the spine, is translated and released in an activity dependent manner from the postsynaptic site. BDNF binds to presynaptic TrkB receptors and activates intracellular signal transduction pathways, influencing among many downstream signals the activity of the RhoGTPases, RhoA, Rac and Cdc42 which affect the actin cytoskeleton. Rac and Cdc42 are positive regulators that promote growth and branching, whereas RhoA is a negative regulator that causes the collapse of the growth cone. BDNF can also act in an autocrine fashion through postsynaptic TrkB. PSD-95, postsynaptic density protein 95; PI3K, Phosphatidylinositol 3-kinase.

Figure 2

The visual system of Xenopus laevis as a model to understand roles for BDNF during synaptic circuit formation in the living brain (A) Dynamic interactions between axon and dendritic terminals during retinotectal circuit development. A series of time-lapse confocal microscopy images of the optic tectum of a live, developing tadpole show the growth and arborization of a tectal neuron (top) and a retinal axon (bottom) both expressing GFP. Over time, the tectal neuron dendrites and the retinal axon actively and coordinately, branch and grow toward one another, as formation of the retinotectal circuit proceeds. This image series exemplifies the dynamic structural rearrangements occurring in presynaptic as well as postsynaptic neurons, a process that is modulated by BDNF (see Fig. 1 and also Alsina et al., 2001; Hu et al., 2005; Sanchez et al., 2006). The small white arrows point to the tectal neuron's axon. Scale bar = 20 μm. (B) TrkB signaling influences retinal axon growth cone morphology and branch initiation at the target. Representative retinal axons expressing GFP (top), or dominant negative TrkB tagged with GFP (GFP-TrkB.T1; bottom), illustrate the dynamic changes in axon growth cones as they begin to branch in the target optic tectum. Axons expressing dominant negative TrkB display dynamic behavior and growth cone morphologies that differ from the GFP expressing control axons. The two retinal axons expressing GFP-TrkB.T1 in this tadpole brain illustrate the variability in growth cone dynamics and structure. Axons may possess growth cones with uncharacteristically long filopodia and large lamellipodia (red arrows), or show dynamic growth cone behavior but fail to branch (asterisks). Axons that express dominant negative TrkB, and eventually branch, continue to bear multiple abnormal growth cone-like structures (red arrows; 24 hr). Interfering with TrkB signaling also results in axons with decreased density of presynaptic specializations and higher axon degeneration rate (for details see Marshak et al., 2007). Scale bar = 20 μm.

Figure 3. Neurotrophins and classical axon guidance cues are capable of inducing axonal differentiation in similar, yet distinct ways

BDNF and netrin-1 have a common, but unique ability to modulate retinal ganglion cell axon arbor complexity. This cartoon represents the change in arbor structure over time of retinal ganglion cell axons branching at their target, acutely treated with BDNF or netrin-1 (see Alsina et al., 2001 and Manitt et al., 2009). Red dots represent presynaptic specializations present before treatment, yellow represent newly added specializations and purple represents specializations added and stabilized over time. Both BDNF and netrin treated retinal axons significantly increase the complexity of their arbors by 24 hours following treatment. BDNF rapidly increases axon branch and presynaptic site formation and stabilization in the same time scale, while netrin increases presynaptic site addition and subsequent branching.