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1

Persistent TrkB signaling to MNK activates a two-stage translational switch underlying in vivo LTP maintenance

100%
Bramham C. R.
Acta Neurobiologiae Experimentalis
|
2013
|
tom 73
|
nr Suppl.1
Long-term synaptic plasticity requires stimulus-evoked changes in protein translation. However, the dynamics of translational control post-stimulus are little understood. We report that LTP maintenance at excitatory synapses in live rats requires repetitive BDNF activation of TrkB over hours. TrkB signalling to the MAP kinase-interacting kinases (MNKs) mediates sustained eIF4F translation initiation complex formation through a two-stage mechanism. In early LTP maintenance, MNK triggers release of the CYFIP1/FMRP repressor complex from the 5’- mRNA cap, coupled to translation of FMRP-regulated mRNAs. In late LTP maintenance, MNK switches to regulate the canonical translational repressor 4E-BP2 specifically within the synaptic compartment. This delayed release of 4E-BP2 is associated with synapse-specific polyribosome formation and enhanced dendritic mRNA translation. In MNK knockout mice, both CYFIP1 and 4E-BP2 repressor complexes are disrupted. Hence, sustained TrkB-MNK signalling drives the sequential activation of distinct forms of cap-dependent translation, culminating in synapse-specific translation and LTP maintenance.
2

Chronic morphine treatment enhances sciatic nerve stimulation-induced immediate early gene expression in the rat dorsal horn

51%
Bojovic O., Bramham C. R., Tjolsen A.
Acta Neurobiologiae Experimentalis
|
2015
|
tom 75
|
nr 3
Synaptic plasticity is a property of neurons that can be induced by conditioning electrical stimulation (CS) of afferent fibers in the spinal cord. This is a widely studied property of spinal cord and hippocampal neurons. CS has been shown to trigger enhanced expression of immediate early gene proteins (IEGPs), with peak increases observed 2 hour post stimulation. Chronic morphine treatment has been shown to promoteinduce opioid-induced hyperalgesia, and also to increase CS-induced central sensitization in the dorsal horn. As IEGP expression may contribute to development of chronic pain states, we aimed to determine whether chronic morphine treatment affects the expression of IEGPs following sciatic nerve CS. Changes in expression of the IEGPs Arc, c-Fos or Zif268 were determined in cells of the lumbar dorsal horn of the spinal cord. Chronic Morphine pretreatment over 7 days led to a significant increase in the number of IEGP positive cells observed at both 2 h and 6 h after CS. The same pattern of immunoreactivity was obtained for all IEGPs, with peak increases occurring at 2 h post CS. In contrast, morphine treatment alone in sham operated animals had no effect on IEGP expression. We conclude that chronic morphine treatment enhances stimulus-induced expression of IEGPs in the lumbar dorsal horn. These data support the notion that morphine alters gene expression responses linked to nociceptive stimulation and plasticity.
3

Arc functional neighbourhood in the neuronal cell nucleus

39%
Parobczak K., Rutkowska-Wlodarczyk L., Szczepankiewicz A. A., Khanema-Jakobsen T., Schubert M., Bramham C. R., Wilczynski G. M.
Acta Neurobiologiae Experimentalis
|
2013
|
tom 73
|
nr Suppl.1
Arc protein is a versatile factor connecting memory formation, plasticity changes and neuronal activity. Through regulation of actin polymerization, Arc contributes to synapse expansion and may furthermore influence synapse strength via management of AMPA receptor turnover. The function of Arc in the neuronal cell nucleus is poorly understood. In this work we performed structural, functional and biochemical analysis to identify Arc`s nuclear interactome. Using confocal microscopy we investigated Arc`s functional neighborhood and found that it occupied internal parts of the nucleus, closely to hnRNPs. This observation were confirmed with electron microscopy, which demonstrated that Arc localizes mainly at the peripheral areas of chromatin. Furthermore, pull-down-based biochemical experiments suggested that Arc interacts with splicing machinery. Collectively, our data suggest that nuclear Arc is involved in the gene expression phenomena.
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