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dc.contributor.advisorMiles, Gareth Brian
dc.contributor.authorIwagaki, Noboru
dc.coverage.spatial149en_US
dc.date.accessioned2012-07-26T08:19:23Z
dc.date.available2012-07-26T08:19:23Z
dc.date.issued2012-06-20
dc.identifieruk.bl.ethos.555592
dc.identifier.urihttps://hdl.handle.net/10023/3023
dc.description.abstractThe present study examined the role of group I metabotropic glutamate receptors (mGluRs) in mammalian spinal motor networks and investigated the potential role of mGluRs in the fatal neurodegenerative disease amyotrophic lateral sclerosis (ALS). Group I mGluR activation was found to modulate locomotor-related activity recorded from ventral roots of in vitro mouse spinal cord preparations. Activation of group I mGluRs led to an increase in the frequency of locomotor-related bursts and a decrease in their amplitude. The cellular mechanisms underlying group I mGluR-mediated modulation were investigated using whole-cell patch-clamp recordings from spinal neurons. Recordings from motoneurons revealed a wide range of effects, some of which were expected to increase motoneuron excitability, such as membrane depolarisation and hyperpolarisation of action potential thresholds. However, the net modulatory effect of group I mGluR activation was a reduction in motoneuron excitability, likely reflecting a reduction in the density of fast inactivating Na+ currents. The activation of group I mGluRs also reduced excitatory synaptic input to motoneurons, suggesting that modulation of motoneuron properties and synaptic transmission both contribute to group I mGluR-mediated reductions in locomotor motoneuron output. Recordings from spinal interneurons revealed a smaller range of modulatory effects for group I mGluRs. The clearest effect on interneurons, membrane depolarisation, may underlie group I mGluR-mediated increases in the frequency of locomotor activity. Finally, the potential role of group I mGluRs in the pathogenesis of ALS was investigated using a mouse model of the disease. Although no major perturbations in group I mGluR-mediated modulation were demonstrated in ALS affected spinal cords, there appeared to be a difference in the intrinsic excitability of spinal interneurons between wild type and ALS affected animals. Together these data highlight group I mGluRs as important sources of neuromodulation within the spinal cord and potential targets for the treatment of ALS.en_US
dc.language.isoenen_US
dc.publisherUniversity of St Andrews
dc.subjectMGluRsen_US
dc.subjectSpinal corden_US
dc.subjectMotoneuronsen_US
dc.subjectALSen_US
dc.subject.lccQP367.I8
dc.subject.lcshGlutamic acid--Receptorsen_US
dc.subject.lcshMotor neuronsen_US
dc.subject.lcshLocomotion--Regulationen_US
dc.subject.lcshAmyotrophic lateral sclerosisen_US
dc.titleModulation of mammalian spinal motor networks by group I metabotropic glutamate receptors : implications for locomotor control and the motor neuron disease amyotrophic lateral sclerosisen_US
dc.typeThesisen_US
dc.contributor.sponsorMotor Neurone Disease Scotlanden_US
dc.type.qualificationlevelDoctoralen_US
dc.type.qualificationnamePhD Doctor of Philosophyen_US
dc.publisher.institutionThe University of St Andrewsen_US


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