Activity-Dependent Dendritic Release of BDNF and Biological Consequences

Kuczewski, Nicola; Porcher, Christophe; Leßmann, Volkmar; Medina, Igor; Gaı̈arsa, Jean-Luc

doi:10.1007/s12035-009-8050-7

Cited by 138 publications

(106 citation statements)

References 99 publications

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“…The fact that BDNF is necessary for the maturation of GABAergic synapses has been clearly established, but the source and mechanism of its activity-dependent release have remained unexplored. So far, at least three distinct signals regulating dendritic BDNF secretion have been directly identified in neuronal cultures (Kuczewski et al, 2009): (1) tetanic stimulation of presynaptic glutamatergic fibers (Hartmann et al, 2001), (2) action potentials that propagate backwards into the dendrites (Kuczewski et al, 2008b), and (3) prolonged depolarization of the postsynaptic neuron (Magby et al, 2006). Our study provides a novel and unexpected mechanism by which synaptic activity can trigger a Ca 2ϩ -dependent dendritic release of BDNF.…”

mentioning

confidence: 72%

GABA_BReceptor Activation Triggers BDNF Release and Promotes the Maturation of GABAergic Synapses

Fiorentino¹,

Kuczewski²,

Diabira³

et al. 2009

J. Neurosci.

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GABA, the main inhibitory neurotransmitter in the adult brain, has recently emerged as an important signal in network development. Most of the trophic functions of GABA have been attributed to depolarization of the embryonic and neonatal neurons via the activation of ionotropic GABAAreceptors. Here we demonstrate a novel mechanism by which endogenous GABA selectively regulates the development of GABAergic synapses in the developing brain. Using whole-cell patch-clamp recordings on newborn mouse hippocampi lacking functional GABABreceptors (GABAB-Rs) and time-lapse fluorescence imaging on cultured hippocampal neurons expressing GFP-tagged brain-derived neurotrophic factor (BDNF), we found that activation of metabotropic GABABreceptors (GABAB-Rs) triggers secretion of BDNF and promotes the development of perisomatic GABAergic synapses in the newborn mouse hippocampus. Because activation of GABAB-Rs occurs during the characteristic ongoing physiological network-driven synaptic activity present in the developing hippocampus, our results reveal a new mechanism by which synaptic activity can modulate the development of local GABAergic synaptic connections in the developing brain.

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mentioning

confidence: 72%

GABA_BReceptor Activation Triggers BDNF Release and Promotes the Maturation of GABAergic Synapses

Fiorentino¹,

Kuczewski²,

Diabira³

et al. 2009

J. Neurosci.

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“…We report here a unique additional mechanism by which the cAMP-mediated pathway controls the level of BDNF via RACK1. BDNF is a major contributor to synaptic plasticity, learning, and memory, as well as neuronal morphology (23,25,26), and the cAMP pathway has been linked to various forms of learning (60). BDNF and the cAMP pathways are also tightly associated with various psychiatric disorders and addiction (61)(62)(63).…”

Section: Discussionmentioning

confidence: 99%

“…Through its receptor tyrosine kinase, TrkB, BDNF activates several signaling pathways such as the MAPK, phosphatidylinositol-3-OH kinase, and phospholipase C␥ cascades (24). BDNF plays an important role in neuronal proliferation, differentiation, and survival, as well as synaptic plasticity, learning, and memory (23,25,26). The genomic structure of the BDNF gene consists of eight 5Ј-non-coding exons and one 3Ј-coding exon (27,28) and is very similar between human and rodents (27)(28)(29)(30).…”

mentioning

confidence: 99%

Epigenetic Regulation of BDNF Expression via the Scaffolding Protein RACK1

Neasta

Ron

2010

Journal of Biological Chemistry

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Scaffolding proteins are major contributors to the spatial and temporal orchestration of signaling cascades and hence cellular functions. RACK1 is a scaffolding protein that plays an important role in the regulation of, and cross-talk between, various signaling pathways. Here we report that RACK1 is a mediator of chromatin remodeling, resulting in an exon-specific expression of the brain-derived neurotrophic factor (BDNF) gene. Specifically, we found that following the activation of the cAMP pathway, nuclear RACK1 localizes at the promoter IV region of the BDNF gene by its association with histones H3 and H4, leading to the dissociation of the transcription repressor methyl-CpGbinding protein 2 (MeCP2) from the promoter, resulting in the acetylation of histone H4. These chromatin modifications lead to the activation of the promoter and to the subsequent promoter-controlled transcription of BDNF exon IV. Our findings expand our knowledge regarding the function of scaffolding proteins such as RACK1. Furthermore, this novel mechanism for the regulation of exon-specific expression of the BDNF gene by RACK1 could have implications on the neuronal functions of the growth factor including synaptic plasticity, learning, and memory.Signal transduction cascades are tightly regulated events. Scaffolding proteins play an essential role in the spatial and temporal regulation of individual enzymes and provide the link between extracellular events and intracellular compartments including the nucleus (1). Scaffolding proteins, by means of protein-protein interactions, provide platforms for protein assembly. The scaffolding protein RACK1, which was originally identified as an anchoring protein of protein kinase C ␤II (2), belongs to the WD40 family of proteins characterized by seven WD40 repeats forming a seven-blade ␤-propeller structure (3, 4). This particular structure allows RACK1 to interact with various enzymes including Fyn kinase (5), focal adhesion kinase (6), receptor protein tyrosine phosphatase (7), the cyclic AMP-specific phosphodiesterase (PDE4) isoform PDE4D5 (8), as well as the intracellular tails of receptors such as the insulin-like growth factor 1 receptor (IGF-1R) (9, 10), the inositol 1,4,5-triphosphate receptor (11), and ion channels such as the NR2B subunit of the N-methyl D-aspartate receptors (5). These interactions, and others, put RACK1 at a focal point for spatial and temporal regulation of various signaling cascades. For example, in transformed cultured cancer cells, RACK1 was shown to form a scaffolding complex that includes the IGF-1R, ␤1 integrin, and focal adhesion kinase (6,9,10,12). In addition, RACK1 is also found at the 40 S ribosomal subunit (3,13,14) and was shown to bridge protein kinase C-mediated signaling to the ribosomal translation machinery (15). RACK1 plays an important role in the central nervous system (16). For example, RACK1 links Fyn kinase to its substrate, the NR2B subunit of the N-methyl D-aspartate receptor (5, 17), and contributes to the regulation of channel activity (18)...

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“…Following the initial stages of synaptogenesis, neurons enlist additional activity-dependent processes to finetune the maturation and pattern of synaptic connections (Katz and Shatz, 1996;Cline and Haas, 2008;Kerschensteiner et al, 2009). Several proteins, including the growth factor BDNF (Kuczewski et al, 2009), are implicated in these processes, but in general, the molecular cues that govern this phase of synapse development remain unclear.…”

Section: Introductionmentioning

confidence: 99%

Astrocytes Control Glutamate Receptor Levels at Developing Synapses through SPARC–β-Integrin Interactions

Jones¹,

Bernardinelli²,

Tse³

et al. 2011

J. Neurosci.

120

112

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Neurons recruit numerous mechanisms to facilitate the development of synaptic connections. However, little is known about activitydependent mechanisms that control the timing and fidelity of this process. Here we describe a novel pathway used by neurons to regulate glutamate receptors at maturing central synapses. This pathway relies on communication between neurons and astrocytes and the ability of astrocytes to release the factor SPARC (secreted protein, acidic and rich in cysteine). SPARC expression is dynamically regulated and plays a critical role in determining the level of synaptic AMPARs. SPARC ablation in mice increases excitatory synapse function, causes an abnormal accumulation of surface AMPARs at synapses, and impairs synaptic plasticity during development. We further demonstrate that SPARC inhibits the properties of neuronal ␤3-integrin complexes, which are intimately coupled to AMPAR stabilization at synapses. Thus neuron-glial signals control glutamate receptor levels at developing synapses to enable activity-driven modifications of synaptic strength.

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Activity-Dependent Dendritic Release of BDNF and Biological Consequences

Cited by 138 publications

References 99 publications

GABA_BReceptor Activation Triggers BDNF Release and Promotes the Maturation of GABAergic Synapses

GABA_BReceptor Activation Triggers BDNF Release and Promotes the Maturation of GABAergic Synapses

Epigenetic Regulation of BDNF Expression via the Scaffolding Protein RACK1

Astrocytes Control Glutamate Receptor Levels at Developing Synapses through SPARC–β-Integrin Interactions

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Activity-Dependent Dendritic Release of BDNF and Biological Consequences

Cited by 138 publications

References 99 publications

GABABReceptor Activation Triggers BDNF Release and Promotes the Maturation of GABAergic Synapses

GABABReceptor Activation Triggers BDNF Release and Promotes the Maturation of GABAergic Synapses

Epigenetic Regulation of BDNF Expression via the Scaffolding Protein RACK1

Astrocytes Control Glutamate Receptor Levels at Developing Synapses through SPARC–β-Integrin Interactions

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GABA_BReceptor Activation Triggers BDNF Release and Promotes the Maturation of GABAergic Synapses

GABA_BReceptor Activation Triggers BDNF Release and Promotes the Maturation of GABAergic Synapses