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dc.contributor.authorRibchester, Richard Rolanden
dc.date.accessioned2018-05-14T10:15:42Z
dc.date.available2018-05-14T10:15:42Z
dc.date.issued2005en
dc.identifier.urihttp://hdl.handle.net/1842/29963
dc.description.abstracten
dc.description.abstractThe thesis presents contributions to the field of neuromuscular synaptic plasticity. Synaptic remodelling brings about changes in convergence and divergence in many different parts of the nervous system during development. Neuromuscular junctions have proved to be accessible synapses in which to describe and explain the mechanims. During development, muscle fibres initially receive convergent, polyneuronal innervation (rc) by axons arising from different motor neurones. The characteristic mononeuronal innervation (jit) pattern of adult muscle is achieved by synapse elimination, a process of weakening of synaptic strength followed by withdrawal of synaptic boutons, until all but one of the motor neuron inputs to an endplate is lost. Similar hyperinnervation and elimination occur in adult muscle after nerve injury, collateral sprouting and regeneration. These processes are strongly influenced by activity, apparently in accordance with Hebbian rules of synaptic plasticity. But how decisive is activity in ultimately determining the pattern of neuromuscular connectivity? The amount of sprouting is increased and the rate of synapse elimination is decreased when muscle activity is blocked. Sprouts regress and synapse elimination resumes when muscles are stimulated, or once normal activity is restored. Selectively blocking or restoring activity in some motor neurones but not others supplying a 7t-junction gives a competitive advantage to the more active neuromuscular synapses. However, activity is not sufficient to effect synapse elimination because many muscle fibres retain 7t-junctions after activity resumes following a period of paralysis. Nor is activity strictly necessary, because - paradoxically - synapse elimination continues at some motor endplates even when muscles are completely paralysed. Competition for neurotrophic factors may play an important role in determining the outcome of synapse elimination, but factors intrinsic to the motor neurone, perhaps involving the selective trafficking of maintenance factors along specific axon collaterals, appear to be important also. In each motor neurone, synapses are eliminated or strengthened asynchronously. Though this suggests that local factors regulate the persistence or withdrawal of individual synapses, asynchronous synapse withdrawal also occurs following synchronous disruption of axonal trafficking. These latter experiments have been performed in a mouse mutant, Wlds, in which axons persist after nerve injury, but where axotomy induces synapses to withdraw, in a fashion that strongly resembles synapse elimination. The Wlds mutant - and its transgenic equivalents - offer unique opportunities to obtain insight into many aspects of the function and mechanisms of synaptic plasticity. The data thus far suggest that neurodegenerative mechanisms are compartmentalised in neurones, and that different mechanisms regulate synapse elimination and synapse degradation. The possibilities for finding other mutations, that protect synapses from degeneration in addition to the protection of axons, affords potential for intervening in neurodegenerative diseases, including - but not restricted to - neuropathies in which synaptic dysfunction and degeneration are precursors to wholesale neuronal degeneration.en
dc.publisherThe University of Edinburghen
dc.relation.isreferencedbyAlready catalogueden
dc.subjectAnnexe Thesis Digitisation Project 2018 Block 18en
dc.titleDevelopment and plasticity of neuromuscular innervationen
dc.typeThesis or Dissertationen
dc.type.qualificationlevelDoctoralen
dc.type.qualificationnameDSc Doctor of Scienceen


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