Activity-dependent BDNF release via endocytic pathways is regulated by synaptotagmin-6 and complexin

Wong, Yu Hui; Lee, Chia Ming; Xie, Wenjun; Cui, Bianxiao; Poo, Mu Ming

doi:10.1073/pnas.1511830112

Cited by 76 publications

(85 citation statements)

References 48 publications

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“…We used both a BDNF blocking antibody (anti-BDNF, 20 μg ml −1 )36 and a chimeric BDNF scavenger (TrkB-Fc, 20 μg ml −1 )3738 to remove the endogenous BDNF secreted during stimulation, for 30 min before the pulse-chase (Fig. 9a).…”

Section: Resultsmentioning

confidence: 99%

Flux of signalling endosomes undergoing axonal retrograde transport is encoded by presynaptic activity and TrkB

et al. 2016

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Axonal retrograde transport of signalling endosomes from the nerve terminal to the soma underpins survival. As each signalling endosome carries a quantal amount of activated receptors, we hypothesized that it is the frequency of endosomes reaching the soma that determines the scale of the trophic signal. Here we show that upregulating synaptic activity markedly increased the flux of plasma membrane-derived retrograde endosomes (labelled using cholera toxin subunit-B: CTB) in hippocampal neurons cultured in microfluidic devices, and live Drosophila larval motor neurons. Electron and super-resolution microscopy analyses revealed that the fast-moving sub-diffraction-limited CTB carriers contained the TrkB neurotrophin receptor, transiently activated by synaptic activity in a BDNF-independent manner. Pharmacological and genetic inhibition of TrkB activation selectively prevented the coupling between synaptic activity and the retrograde flux of signalling endosomes. TrkB activity therefore controls the encoding of synaptic activity experienced by nerve terminals, digitalized as the flux of retrogradely transported signalling endosomes.

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Section: Resultsmentioning

confidence: 99%

Flux of signalling endosomes undergoing axonal retrograde transport is encoded by presynaptic activity and TrkB

et al. 2016

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“…In addition, DNE reduces the number of excitatory synaptic events recorded in neonatal hypoglossal motoneurons (Pilarski et al ., 2011). Both would alter the activity of the motoneuron and could influence dendritic growth through mechanisms mediated by contact or the release of diffusible morphogens and growth factors (Kuczewski et al ., 2009; Wong et al ., 2015). Furthermore, it is clear that early cholinergic transmission is essential for the normal development of the cortex, among other brain regions (Slotkin, 2008; Dwyer et al ., 2009; Muhammad et al ., 2012).…”

Section: Discussionmentioning

confidence: 99%

Developmental nicotine exposure disrupts dendritic arborization patterns of hypoglossal motoneurons in the neonatal rat

Powell

Gaddy

Xu³

et al. 2016

Developmental Neurobiology

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Maternal smoking or use of other products containing nicotine during pregnancy can have significant adverse consequences for respiratory function in neonates. We have shown, in previous studies, that developmental nicotine exposure (DNE) in a model system compromises the normal function of respiratory circuits within the brainstem. The effects of DNE include alterations in the excitability and synaptic interactions of the hypoglossal motoneurons, which innervate muscles of the tongue. This study was undertaken to test the hypothesis that these functional consequences of DNE are accompanied by changes in the dendritic morphology of hypoglossal motoneurons. Hypoglossal motoneurons in brain stem slices were filled with neurobiotin during whole-cell patch clamp recordings and subjected to histological processing to reveal dendrites. Morphometric analysis, including the Sholl method, revealed significant effects of DNE on dendritic branching patterns. In particular, whereas within the first 5 postnatal days there was significant growth of the higher-order dendritic branches of motoneurons from control animals, the growth was compromised in motoneurons from neonates that were subjected to DNE.

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“…Under these conditions, control of the membrane potential is limited to somatic and perisomatic regions (Williams and Mitchell, 2008). However, dendritic Ca 2+ influx via these channels is likely responsible for the retrograde release of BDNF that mediates LTP-GABA A R (Dean et al, 2009; Kuczewski et al, 2008; Magby et al, 2006; Wong et al, 2015). Consequently, we further characterized the acute effect of ethanol using Ca 2+ imaging techniques, which allowed visualization of voltage-gated Ca 2+ channel function at dendritic sites.…”

Section: Discussionmentioning

confidence: 99%

Further characterization of the effect of ethanol on voltage-gated Ca2+ channel function in developing CA3 hippocampal pyramidal neurons

Morton

Valenzuela

2016

Brain Research

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Developmental ethanol exposure damages the hippocampus, a brain region involved in learning and memory. Alterations in synaptic transmission and plasticity may play a role in this effect of ethanol. We previously reported that acute and repeated exposure to ethanol during the 3rd trimester-equivalent inhibits long-term potentiation of GABAA receptor-dependent synaptic currents in CA3 pyramidal neurons through a mechanism that depends on retrograde release of brain-derived neurotrophic factor driven by activation of voltage-gated Ca2+ channels (Zucca and Valenzuela, 2010). We found evidence indicating that voltage-gated Ca2+ channels are inhibited in the presence of ethanol, an effect that may play a role in its mechanism of action. Here, we further investigated the acute effect of ethanol on the function of voltage-gated Ca2+ channels in CA3 pyramidal neurons using Ca2+ imaging techniques. These experiments revealed that acute ethanol exposure inhibits voltage-gated Ca2+ channels both in somatic and proximal dendritic compartments. To investigate the long-term consequences of ethanol on voltage-gated Ca2+ channels, we used patch-clamp electrophysiological techniques to assess the function of L-type voltage-gated Ca2+ channels during and following ten days of vapor ethanol exposure. During ethanol withdrawal periods, the function of these channels was not significantly affected by vapor chamber exposure. Taken together with our previous findings, our results suggest that 3rd trimester-equivalent ethanol exposure transiently inhibits L-type voltage-gated Ca2+ channel function in CA3 pyramidal neurons and that compensatory mechanisms restore their function during ethanol withdrawal. Transient inhibition of these channels by ethanol may be, in part, responsible for the hippocampal abnormalities associated with developmental exposure to this agent.

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Activity-dependent BDNF release via endocytic pathways is regulated by synaptotagmin-6 and complexin

Cited by 76 publications

References 48 publications

Flux of signalling endosomes undergoing axonal retrograde transport is encoded by presynaptic activity and TrkB

Flux of signalling endosomes undergoing axonal retrograde transport is encoded by presynaptic activity and TrkB

Developmental nicotine exposure disrupts dendritic arborization patterns of hypoglossal motoneurons in the neonatal rat

Further characterization of the effect of ethanol on voltage-gated Ca2+ channel function in developing CA3 hippocampal pyramidal neurons

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