Cellular and molecular mechanisms regulating neuronal growth by brain‐derived neurotrophic factor

Abstract

Brain-derived neurotrophic factor (BDNF) and its receptors TrkB and p75 regulate dendritic and axonal growth during development and maintenance of the mature nervous system; however, the cellular and molecular mechanisms underlying this process are not fully understood. In recent years, several advances have shed new light on the processes behind the regulation of BDNF-mediated structural plasticity including control of neuronal transcription, local translation of proteins, and regulation of cytoskeleton and membrane dynamics. In this review, we summarize recent advances in the field of BDNF signaling in neurons to induce neuronal growth. V C 2016 Wiley Periodicals, Inc.Key Words: BDNF; dendritic growth; signaling; cytoskeleton dynamics; membrane trafficking Introduction T he functionality of the nervous system (NS) depends on the extent of connectivity achieved by neurons. Although there is wide range of neuronal morphologies, neurons are specialized to form part of a given neuronal circuit and thus their morphology must adjust to this task [Gao, 2007]. In this regard, neurons are highly polarized cells composed of two main domains: the somato-dendritic compartment where neurons receive and integrate information from several axonal inputs and axons that are responsible for transmitting the action potential and conveying the information to the next relay in the network. A close relationship between the appropriate development of dendrites and axons and the functionality of the NS has been described. For example, alterations in dendrites, axonal inputs and dendritic spines are linked to neurodevelopmental and neuropathological conditions. Thus, the study of the mechanisms implicated in the regulation of neuronal morphology during development and maintenance of the adult NS is a focus of intense research [Armstrong et al., 1998;Wood et al., 2004;Bronfman et al., 2007;Dickstein et al., 2010;Cabeza et al., 2012;Eiland and McEwen, 2012;Kulkarni and Firestein, 2012].Neuronal morphology is regulated by both intrinsic and extrinsic factors, whose actions are overlapping. The intrinsic factors are described as the action of the genetic program of neurons that leads to a basic pattern of branching. In addition to this, there is an extensive list of molecules grouped as extrinsic factors that shape axonal and dendritic morphology throughout development and in response to sensory experience. These include bone morphogenetic family proteins (BMPs), semaphorins, Reelin, neurotrophins, and neuronal activity, among others [Jan and Jan, 2010]. The mechanisms underlying the effects of external cues to induce dendritic and axonal branching have only begun to be understood, and several steps including stimulation of intracellular signaling pathways to activate specific transcription factors, local synthesis of proteins and cellular membrane addition and turnover are involved. An interesting point of convergence is the effect of these external signals on the stability and dynamics of the cytoskeleton and the activity of molecular mo...

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“…In the adult brain, this neurotrophic factor regulates synaptic transmission and plasticity (Gonzalez et al, 2016; Poo, 2001; Tao et al, 1998). BDNF induces an increase in the cytosolic content of calcium (Berninger et al, 1993; Stoop, & Poo, 1996) that can affect the vesicle exocytosis of several neurotransmitters in the synaptic space (Pozzo-Miller et al, 1999).…”

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“…However, it also appears to have a larger, neuroprotective role. Acting through the tropomyosin‐related kinase B (TrkB) receptor, BDNF seems to preserve neural progenitor cells, prevent the degeneration of cortical neurons, promote the formation, maintenance, and plasticity of synapses, and support the consolidation of memory from short‐term to long‐term stores …”

“…However, it also appears to have a larger, neuroprotective role. Acting through the tropomyosin-related kinase B (TrkB) receptor, BDNF seems to preserve neural progenitor cells, prevent the degeneration of cortical neurons, 87,88 promote the formation, maintenance, and plasticity of synapses, 88 and support the consolidation of memory from short-term to longterm stores. 87 At least in rats, BDNF is also involved in neural repair, promoting recovery from spinal cord injury and, in the brain, rescuing synapses and cognition after experimental transient ischemia [89][90][91][92] and psychosocial stress.…”

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“…Neuronal polarization events are controlled by intrinsic and extrinsic mechanisms that are dependent on multiple families of molecules, ranging from extracellular cues, membrane receptors, signalling molecules, cytoskeleton elements and transcription factors (Tahirovic and Bradke, ; Villarroel‐Campos, Bronfman, & Gonzalez‐Billault, ). The extracellular cues involved in neuronal differentiation, include neurotrophins such as brain‐derived neurotrophic factor and neurotrophin‐3, which play a major role (Cheng, Lu, Shelly, Gao, & Poo, ; Cheng, Song, Wong, Wang, Zhang, & Poo, ; Gonzalez, Moya‐Alvarado, Gonzalez‐Billaut, & Bronfman, ; Nakamuta, Funahashi, Namba, Arimura, Picciotto, Tokumitsu, … Kaibuchi, ). At the intracellular level, neurotrophin signalling is relayed by cAMP‐dependent signalling pathways, amongst others (Cheng and Poo, ).…”

“…such as brain-derived neurotrophic factor and neurotrophin-3, which play a major role (Cheng, Lu, Shelly, Gao, & Poo, 2011a;Cheng, Song, Wong, Wang, Zhang, & Poo, 2011b;Gonzalez, Moya-Alvarado, Gonzalez-Billaut, & Bronfman, 2016;Nakamuta, Funahashi, Namba, Arimura, Picciotto, Tokumitsu, . .…”