ProBDNF and Mature BDNF as Punishment and Reward Signals for Synapse Elimination at Mouse Neuromuscular Junctions

Je, Heinrich; Yang, Feng; Ji, Youngmi; Potluri, S.; Fu, Xiu-Qing; Luo, Zhen-Ge; Nagappan, Guhan; Chan, Jason P.; Hempstead, Barbara L.; Son, Young–Jin; Lu, Bai

doi:10.1523/jneurosci.0163-13.2013

Cited by 107 publications

(85 citation statements)

References 30 publications

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“…The present work aims to provide more insights into the neurotoxic mechanisms of morphine withdrawal, by looking at its effect on proBDNF. proBDNF is a secreted protein that binds to p75NTR and induces neurotoxic events such as apoptosis (Teng et al 2005), growth cone collapse (Sun et al 2012), presynaptic terminal retraction (Je et al 2013), and axonal degeneration (Bachis et al 2012). Our study shows that mBDNF is increased by both chronic morphine treatment and withdrawal but withdrawal augments proBDNF so that it significantly decreases the ratio mBDNF/proBDNF.…”

Section: Discussionmentioning

confidence: 99%

Morphine Withdrawal Increases Brain-Derived Neurotrophic Factor Precursor

et al. 2017

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Morphine has been shown to increase the expression of brain-derived neurotrophic factor (BDNF) in the brain. However, little is known about the effect of morphine withdrawal on BDNF and its precursor protein, or proBDNF, which induces neuronal apoptosis. In this work, we examined whether BDNF and proBDNF levels change in rats chronically injected with escalating doses of morphine and those who undergo spontaneous withdrawal for 60 hr. We observed, in the frontal cortex and striatum, that the ratio of BDNF to proBDNF changed depending upon the experimental paradigm. Morphine treatment and morphine withdrawal increased both BDNF and proBDNF levels. However, the increase in proBDNF immunoreactivity in withdrawal rats was more robust than that observed in morphine-treated rats. proBDNF is processed either intracellularly by furin or extracellularly by the tissue plasminogen activator (tPA)/plasminogen system or matrix metalloproteases (MMPs). To examine the mechanisms whereby chronic morphine treatment and morphine withdrawal differentially affects BDNF/proBDNF, the levels MMP-3 and -7, furin, and tPA were analyzed. We found that morphine increases tPA levels whereas withdrawal causes a decrease. To confirm the involvement of tPA in the morphine-mediated effect on BDNF/proBDNF, we exposed cortical neurons to morphine in the presence of the tPA inhibitor PAI-1. This inhibitor reversed the morphine-mediated decrease in proBDNF, supporting the hypothesis that morphine increases the availability of BDNF by promoting the extracellular processing of proBDNF by tPA. Because proBDNF could negatively influence synaptic repair, preventing withdrawal is crucial for reducing neurotoxic mechanisms associated with opioid abuse.

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Section: Discussionmentioning

confidence: 99%

Morphine Withdrawal Increases Brain-Derived Neurotrophic Factor Precursor

et al. 2017

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“…Since a number of manipulations in addition to expression of NRG1-III can be shown to influence the rate of synapse elimination, control of synapse elimination is clearly multifactorial. Neuronal activity, as mentioned above, is clearly important [32–35]. There is evidence that NRG1 expression is itself influenced by the level of activity of neurons [36,37], suggesting a mechanism by which activity may lie upstream of NRG1-III regulation of tSCs.…”

Section: Control Of Tsc Activitiesmentioning

confidence: 99%

Schwann cells participate in synapse elimination at the developing neuromuscular junction

Lee

Thompson

Harlow

2017

Current Opinion in Neurobiology

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During the initial stages of innervation of developing skeletal muscles, the terminal branches of axons from multiple motor neurons form neuromuscular junctions (NMJs) on a small region of each muscle fiber, the motor endplate. Subsequently, the number of axonal inputs at the endplate region is reduced so that, at maturity, each muscle fiber is innervated by the terminals of a single motor neuron. The Schwann cells associated with the axon terminals are involved in the removal of these synapses but do not select the axon that is ultimately retained on each fiber. Schwann cells perform this function by disconnecting terminal branches from the myofiber surface and by attacking them phagocytically. Here we discuss how this behavior is regulated and argue that such regulation is not unique to development of neuromuscular innervation but is also expressed in the response of the mature NMJ to various manipulations and pathologies.

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“…Several experimental conditions delay synapse elimination at the NMJ, including changes in synaptic activity (Misgeld et al, 2002; Thompson et al, 1979), NMDAR activation (Personius et al, 2008), GDNF (Nguyen et al, 1998), BDNF or its receptor TrkB (Je et al, 2013), NCAM (Rafuse et al, 2000), glial neurofascin (Roche et al, 2014), or PKC theta (Li et al, 2004). Synapse elimination is also disrupted in mice which bear a dominant-negative mutation in the GARS gene, a mouse model of Charcot-Marie-Tooth type 2D which includes apparent developmental arrest of NMJ maturation (Sleigh et al, 2014).…”

Section: 3 Discussionmentioning

confidence: 99%

“…Several manipulations either delay (Je et al, 2013; Lee et al, 2011; Li et al, 2004; Misgeld et al, 2002; Nguyen et al, 1998; Personius et al, 2008; Rafuse et al, 2000; Roche et al, 2014; Sleigh et al, 2014; Thompson et al, 1979) or accelerate (Bogdanik et al, 2012; O'Brien et al, 1978; Personius et al, 2007; Thompson, 1983) synapse elimination at the developing NMJ. However, in most cases, uniform monoinnervation is still established within the first few postnatal weeks.…”

Section: 1 Introductionmentioning

confidence: 99%

MHCI promotes developmental synapse elimination and aging-related synapse loss at the vertebrate neuromuscular junction

Tetruashvily

McDonald

Frietze

et al. 2016

Brain, Behavior, and Immunity

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Synapse elimination at the developing neuromuscular junction (NMJ) sculpts motor circuits, and synapse loss at the aging NMJ drives motor impairments that are a major cause of loss of independence in the elderly. Here we provide evidence that at the NMJ, both developmental synapse elimination and aging-related synapse loss are promoted by specific immune proteins, members of the major histocompatibility complex class I (MHCI). MHCI is expressed at the developing NMJ, and three different methods of reducing MHCI function all disrupt synapse elimination during the second postnatal week, leaving some muscle fibers multiply-innervated, despite otherwise outwardly normal synapse formation and maturation. Conversely, overexpressing MHCI modestly accelerates developmental synapse elimination. MHCI levels at the NMJ rise with aging, and reducing MHCI levels ameliorates muscle denervation in aged mice. These findings identify an unexpected role for MHCI in the elimination of neuromuscular synapses during development, and indicate that reducing MHCI function can preserve youthful innervation of aging muscle.

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ProBDNF and Mature BDNF as Punishment and Reward Signals for Synapse Elimination at Mouse Neuromuscular Junctions

Cited by 107 publications

References 30 publications

Morphine Withdrawal Increases Brain-Derived Neurotrophic Factor Precursor

Morphine Withdrawal Increases Brain-Derived Neurotrophic Factor Precursor

Schwann cells participate in synapse elimination at the developing neuromuscular junction

MHCI promotes developmental synapse elimination and aging-related synapse loss at the vertebrate neuromuscular junction

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