THESIS
2013
xii, 103 pages : illustrations ; 30 cm
Abstract
The neuromuscular junctions (NMJs) undergo maturation process after the initiation
of nerve-muscle interaction. The morphological changes of NMJs during the process
were meticulously studied. At the presynaptic side, SV clusters formed before the
establishment of NMJ was enhanced at the nerve-muscle contact site. At the
postsynaptic side, small puncta of nerve-induced AChR clusters consolidated into large
patches. In addition, the apposition of pre- and postsynaptic specializations was also
strengthened during the maturation process. Interestingly, chronic application of
brain-derived neurotrophic factors (BDNF) or elevation of intracellular cyclic AMP
(cAMP) level caused inhibitory effects on the NMJ maturation process. The density of
nerve-induced AChR clusters as well as the...[
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The neuromuscular junctions (NMJs) undergo maturation process after the initiation
of nerve-muscle interaction. The morphological changes of NMJs during the process
were meticulously studied. At the presynaptic side, SV clusters formed before the
establishment of NMJ was enhanced at the nerve-muscle contact site. At the
postsynaptic side, small puncta of nerve-induced AChR clusters consolidated into large
patches. In addition, the apposition of pre- and postsynaptic specializations was also
strengthened during the maturation process. Interestingly, chronic application of
brain-derived neurotrophic factors (BDNF) or elevation of intracellular cyclic AMP
(cAMP) level caused inhibitory effects on the NMJ maturation process. The density of
nerve-induced AChR clusters as well as the apposition of SV and AChR clusters were
significantly suppressed. However, the inhibitory effects of BDNF and cAMP were
strongly reversed by TrkB and PKA inhibitors. It turns out that the TrkB signaling
activated by BDNF plays an important role in the process through the mediation of
PKA. FRET measurement of cAMP level in spinal cord neurons revealed that TrkB
activation by BDNF raises intracellular cAMP level through the mediation of the MAPK
pathway, which in turn leads to PKA activation. In addition, the PI3k-Akt pathway
downstream of TrkB was also found to inhibit NMJ development. When the Akt
activity was increased by PTEN inhibition, NMJ formation was compromised. This process was partially rescued by rapamycin, which means that the target of rapamycin
(TOR) mediates the inhibitory effects of the PI3k-Akt pathway on NMJ formation. As a
result, the downstream effector molecules of PKA and TOR may together regulate the
inhibitory effects of TrkB signaling on NMJ development. These results suggest that
the TrkB signaling, though essential for neuronal survival and growth, needs to be
turned down for NMJ formation and maturation.
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