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BDNF and Synaptic Plasticity: The Recent Cell Biology for Understanding of Brain Disorders | OMICS International
ISSN: 2167-065X
Clinical Pharmacology & Biopharmaceutics
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BDNF and Synaptic Plasticity: The Recent Cell Biology for Understanding of Brain Disorders

Toshiyuki Mizui1,2* and Masami Kojima1,2
1Bio-interface Research Group, Health Research Inst., National Institute of Advanced Industrial Science and Technology (AIST), Osaka, Japan
2Core Research for Evolutional Science and Technology (CREST), Japan Science and Technology Agency (JST), Kawaguchi, Japan
Corresponding Author : Mizui T
Bio-interface Research Group
Health Research Inst.
National Institute of Advanced
Industrial Science and Technology (AIST)
1-8-31 Midorioka, Ikeda, Osaka
563-8577, Japan
E-mail: [email protected]
Received November 27, 2012; Accepted March 20, 2013; Published March 26, 2013
Citation: Mizui T, Kojima M (2013) BDNF and Synaptic Plasticity: The Recent Cell Biology for Understanding of Brain Disorders. Clin Pharmacol Biopharm S1:004. doi:10.4172/2167-065X.S1-004
Copyright: © 2013 Mizui T, et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

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Abstract

The cell biology of synaptic plasticity and neurotrophic factor has been extending to the understanding of pathological mechanisms of brain disorders. This knowledge could prove beneficial for the development of new therapies against brain diseases. Dendritic spines are actin-rich structures, which are part of most excitatory synapses in the central nervous systems. Recent studies have shown that the morphological plasticity of the spine plays a crucial role in higher brain functions, such as learning and memory. How neuronal activity modifies the morphology of the spines is an exactly prominent issue. Brain-derived Neurotrophic Dactor (BDNF) is a traditional, yet fully characterized neurotrophic factor, and the key role in the adult brain is to modulate synaptic plasticity. This review focuses on recent advances in the research of dendrite spines, synaptic plasticity, and BDNF. Lastly, the recent research of BDNF for the development of new therapies, in particular, against depression is discussed.

Keywords
BDNF; TrkB; Synaptic plasticity; Spine; Morphology; Depression
Introduction
The brain exerts considerable structural and functional plasticity [1-3]. As an important interface between neurons, synapses are required for computation of circuits and information processing. Accumulating evidence indicates that once formed, synapses and dendrites can be maintained for long periods of time. However, they are eliminated or rewired to respond to environmental changes, as reported by Walsh and Lichtman [4]. The cell biology of neurons has been developed to the understanding of pathological mechanisms of brain disorders (review paper). This review article will pay an attention to the biological and pathological role of BDNF, which modulate synaptic plasticity in adult brain because this knowledge could prove beneficial for the development of new therapies against brain diseases. Dendritic spines are actin-rich structures, which are part of most excitatory synapses in the central nervous systems. Recent studies have shown that the morphological plasticity of the spine plays a crucial role in higher brain functions, such as learning and memory. This review focuses on recent advances in the research of dendrite spines, synaptic plasticity, and BDNF. Lastly, we will introduce recent reports demonstrating the role of BDNF in depression.
Dendrite Spines
The majority of excitatory synapses develop small protrusions on dendrites, called dendrite spines, which form the main platforms of synaptic input for neurons. Neurotransmitter receptors are largely localized at the surface of spines to counteract the presynaptic structure, axon terminals. Previously, consensus was that spine morphology is controlled for higher brain functions, such as learning and memory. Indeed, this notion has been supported by a significant number of studies. The strength of synaptic activity is controlled by the size and number of dendritic spines [5-7]. Activity-dependent remodeling and stability of spine structures is an important cellular mechanism for the maintenance and refinement of neuronal circuits [8,9]. Developing brain spines are structurally dynamic. Conversely, stable spines predominate during adult stages [2]. Interestingly, imaging studies demonstrate experience-dependent structural alterations of spines in animals [8,10], and spin genesis has a salient association with human cognitive function [11]. Moreover, autopsy studies of patients with dementia indicated a correlation between brain dysfunction and abnormal spine morphology [12,13]. Although synaptic function cannot be assessed from spine morphology, the regulatory mechanisms of spine morphogenesis, and the dynamics of spine morphology would provide insight into higher brain functions and their disorders.
Dendritic spines are actin-rich protrusions [14,15] and highly dynamic [16]. The dynamics are controlled by the architecture of their actin cytoskeleton [17]. The formation, maturation, and plasticity of spines depend on actin cytoskeleton remodeling [18,19]. Many of the key molecules controlling this process are members of the Rhofamily of small GTPases [20-22], and several actin-binding proteins [23]. Most extracellular signals, affecting the organization of actin cytoskeleton in cells, converge inside the cells on Rho GTPases, such as RhoA, Rac1, and cdc42 [24,25]. The activation of RhoA-GTPase signaling, through the stimulation of glutamate receptors, could control actin cytoskeleton reorganization and spine morphology [26]. Rac activity also controls actin dynamics. The small GTPase activity itself is under the control of GEFs, which serve as activators of small GTPases [27]. Inhibition of the expression or function of upstream regulators of the actin cytoskeleton, including Rac-GEFs, Rac, and Rac targets such as PAK, cause the loss of spines [28-31]. The activation of these GTPase molecules leads to the assembly and organization of actin filaments in spines by controlling the activity of a variety of actin binding proteins. Many actin-binding proteins have been identified, such as Arp2/3, cortactin, ADF/cofilin, profilin, gelsolin, drebrin and neurabin [18,23]. Some actin-binding proteins inhibit the growth of actin filaments in spines by capping the growing ends of actins, whereas others exhibit opposite roles in the capping mechanism, or promote filament polymerization by the nucleation of new filaments [32]. This balancing mechanism is crucial for rapid control of actin dynamics within the spines.
The morphological changes in spines were shown in two electrophysiological models of synaptic plasticity, namely long-term potentiation (LTP) and long-term depression (LTD). LTP stimulation increased the density of spines [7,33], and enlarged existing spines [20]. LTD, which induces a long-lasting reduction in synaptic transmission by low-frequent stimulation, decreases spine density [34,35], and promotes spine shrinkage [36]. Previous studies indicate a correlation between the actin cytoskeleton, spine morphology, and synaptic strength [14,37-39]. Hippocampal pyramidal neurons increase and decrease the volume of dendritic spines during LTP and LTD, respectively [20,21,36]. Such activity-dependent spine morphology alterations, likely caused by the reorganization of the actin cytoskeleton, may contribute to the change in synaptic strength.
The Role of Brain-derived Neurotrophic Factor (BDNF) in Synaptic Plasticity
The morphology of dendritic spines is regulated by several molecular and cellular mechanisms [23,39]. In the central nervous system (CNS), BDNF plays a crucial role on the regulation of functional and structural plasticity. This paragraph focuses on this important aspect, and the reports are plenty. For more understating this part, the fantastic figures of several excellent reviews [9,40] could help the readers to understand these progresses.
In 1982, the group of Professor Barde et al. reported the isolation of a new neurotrophic factor BDNF [41]. Since this discovery, the biological role of BDNF for developing neurons has been shown extensively: BDNF promotes the differentiation and survival of developing neurons in vivo and in vitro [42]. In 1986, the group of Professor Chao reported on the first neurotrophin receptor p75NTR, which binds the neurotrophins with relatively low affinity [43]. In 1991, tropomyosin sensitive receptor kinases (Trks), were identified as the high-affinity receptors for the neurotrophin family of growth factors Reichardt [44]. Since these discoveries, Trk signaling, and BDNF-TrkB signaling has been characterized in plenty of brain functions: neuronal cell survival, neurite growth, cell migration, glutamate dependent spine, dendritic growth, synapse formation, stabilization, and potentiation. The Trk receptor tyrosine kinase family contains TrkA and TrkC, receptors for nerve growth factor (NGF) and neurotrophic factor 3 (NT-3), and TrkB, for BDNF and neurotrophic factor 4 (NT-4). The molecular properties of BDNF-TrkB signaling are beyond the scope of this article and are reviewed elsewhere [45]. There are several BDNF receptors (TrkB isoforms) in the mammalian CNS [44]. The full-length TrkB isoform causes tyrosine phosphorylation in the intracellular Trk domains, thereby exerting transduction of the BDNF/TrkB signaling. These events trigger the activation of mitogen-activated protein kinase (MAPK), phosphatidylinositol 3-kinase (PI3K), or phospholipase C gamma (PLCγ).
Electrophysiological studies have demonstrated that BDNF have a key role in synaptic plasticity [40,46]. BDNF far surpasses all other neurotrophins in its role in regulating long-term potentiation (LTP). Application of mature form of BDNF facilitates the early phase of LTP (E-LTP) in the hippocampus [47-49]. Inhibition of BDNF activity, by gene knockout or functional blocking using BDNF antibody or TrkB-immunoglobulin G, attenuates hippocampal E-LTP [47-50]. Impairment in BDNF knockout mice was rescued by acute application of recombinant BDNF [48,49]. Further evidence for the role of BDNF in LTP was illuminated [48,51]. Moreover, application of BDNF indicates the rapid enhancement of neurotransmitter release [52,53]. This effect is caused primarily by a presynaptic mechanism [50,54]. Postsynaptic effects of BDNF on dentate LTP in slice cultures and on NMDA (N-methyld-aspartate) receptors in cultured hippocampal neurons have been reported [55,56].
Like BDNF-TrkB signaling, L-LTP is known to induce gene expression through PI3K-Akt-mTOR and MAPK/Erk pathways [57]. Synaptic activity drives these signaling pathways that regulate the assembling of TrkB with synaptic proteins [58], gene transcription [26,32], protein translation [59], and trafficking of TrkB into synapses [58]. PI3K signaling regulates trafficking a postsynaptic density protein, PSD-95 to a synapse and cAMP regulates formation of synaptic PSD-95-TrkB complex [47,58]. BDNF-TrkB signaling regulates protein translation through both MAPK/Erk and PI3K-Akt-mTOR pathways [59].
Neuronal activity leads to the expression of over 300 genes [48], including brain-derived neurotrophic factor (BDNF), one of the major mediators of activity-dependent functions [40]. Regulation of BDNF has been studied in rodents thoroughly. Rat BDNF (rBDNF) gene was first described to have four promoters driving expression of transcripts containing different 5′ exons spliced to a single coding exon [49]. To date, it has been reported that rodent BDNF contains nine exons [50]. Cytoplasmic Ca2+ plays an important role, because it activates BDNF transcription through protein kinase cascades that lead to the activation of several transcription factors, including cyclic AMP response element binding protein (CREB) [57]. These reports support the important theory concerning the adult brain: the modulation of synaptic plasticity by BDNF.
Compared to that of LTP, few studies support the hypothesis that BDNF modulates long-term depression (LTD) Lu et al. [9]). In the visual cortex, BDNF attenuates LTD in layer II/III synapses of young adult rats [60]. However, it was reported that pro- and mature neurotrophins activate different receptor/signaling to have opposing effects on neuronal survival [61]. proBDNF is a precursor form of BDNF. It was reported that the signaling of BDNF/TrkB and proBDNF/p75NTR promote neuronal survival and death, respectively [51,53]. There are reports showing that proBDNF may play a role in synaptic depression through p75NTR. The p75NTR mutant mice exhibit impairment in the behavioral tests of memory [62] and habituation [4]. Recently, it was demonstrated that proBDNF modulated hippocampal LTD through the activation of p75NTR [63]. The NMDA receptor-dependent LTD was pronounced at hippocampal synapses, but conversely and severely deficient in p75NTR-knockout animals [63,64].
The Possible Role of BDNF in the Regulation of Structural Plasticity
Given that the long-term changes in synaptic efficacy (LTP and LTD) lead to structural alterations of synapses, the bi-directional structural changes of synaptic structures may be controlled by the growth activity of BDNF. In line with this notion, it was shown that the exposure to BDNF led to axonal branching [65,66], dendritic growth [67,68], and refinement of synapses in an activity-dependent manner [69]. It was shown that long-term treatment of hippocampal slice with BDNF increases synapse number and spine density in apical dendrites of pyramidal neurons in the hippocampus [70], suggesting that BDNF acts on different types of spine, depending on spontaneous synaptic transmission. Moreover, BDNF regulation of spine formation in the dendrites of hippocampal neurons is controlled by cyclic AMP (cAMP), a signaling molecule involved in L-LTP [58]. Thus, spontaneous neuronal activity and the consequent rise in the intracellular concentration of cAMP might be important for the spino-genesis exerted by BDNF.
The study of pro-neurotrophins has generated new focus into neurotrophin researches and disorders in the nervous system [71]. Using cultured hippocampal neurons, we demonstrated that proBDNF reduced the density of dendritic spines [53]. Then, the amplitude, but not the frequency, of spontaneous activity was significantly low in proBDNF-treated cultures [53]. While cultured neurons were used, this report suggests the role of BDNF processing in structural plasticity. There was more physiological study using slice cultures. Zagrebelsky et al. [60] demonstrated that the p75NTR negatively modulates dendrite complexity and spine density in hippocampal neurons.
Advance of BDNF Biology for the Development of New Therapies against Depression
Cell biology of BDNF has been developing, and is now aimed at the understanding of pathological mechanisms of brain disorders [72,73]. In particular, there are several studies indicating that BDNF is involved in depression. The initial reports showed that the expression of BDNF was decreased [74,75], and that antidepressant treatment rescued the expression of BDNF and led to the proposal of the “neurotrophin hypothesis of depression” [76]. Another important hypothesis is that the structure and function of synapses may be significantly impaired in depressed brain [76,77]. Thus, a bidirectional role of BDNF and proBDNF in structural and functional plasticity is also thought to be a tempting model [73] because it has been shown that proBDNF promotes synaptic depression and spine retraction [53,63].
A single sub-psychomimetic dose of ketamine, an ionotropic glutamatergic NMDAR (NMDA receptor) antagonist, produces fast-acting antidepressant responses in patients suffering from major depression [78-80]. Depressed patients report the alleviation of major depressive disorder symptoms within two hours of a single, low-dose intravenous infusion of ketamine, with effects lasting up to two weeks [78-80], while traditional antidepressants (serotonin re-uptake inhibitors) take weeks to reach efficacy. This delay is a major drawback to current therapies for major depressive disorder, and faster-acting antidepressants are needed, particularly for patients at risk of suicide [80]. Ketamine has the ability to produce rapid and long-lasting antidepressant responses in depressed patients.
Very recently, Autry et al. [81] demonstrated that ketamine and other NMDAR antagonists produce fast-acting antidepressant-like effects in mouse models, and, interestingly, these effects depended on the rapid synthesis of BDNF. The ketamine-mediated blockade of NMDAR deactivated eukaryotic elongation factor 2 (eEF2) kinase, resulting in the reduction in the phosphorylation levels of eEF2 and de-suppression of the translation of BDNF, indicating that the regulation of protein synthesis by spontaneous neurotransmission. The ketamine administration produced antidepressant-like effects in the forced swim test in mice [82,83]. These cellular and molecular findings would be a viable therapeutic mechanism approach for the development of fast-acting antidepressants.
As we described in this review, the cell biology of synaptic plasticity and BDNF has now fully developed and extended to the understanding of pathological mechanisms of brain disorders. This knowledge could prove beneficial for the development of new therapies against brain diseases.
Acknowledgements
The authors thank members of Kojima laboratory for helpful comments. T.M. and M.K. are supported by fellowship from CREST, JST. The funding organization had no role in the study design, data collection and analysis, the decision to publish, or the preparation of the manuscript.
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