Use this URL to cite or link to this record in EThOS: http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.558790
Title: Effects of the antiepileptic drug levetiracetam on synaptic transmission and presynaptic voltage-dependent Ca²+ channel activity in superior cervical ganglion neurones
Author: Vogl, Christian
Awarding Body: University of Reading
Current Institution: University of Reading
Date of Award: 2011
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Abstract:
Levetiracetam (LEV) is a prominent antiepileptic drug (AED) with an unknown mechanism of action. Within this thesis, electrophysiological, biochemical and imaging approaches were combined to investigate potential effects of LEV on action potential (AP) -dependent synaptic transmission and presynaptic voltage-dependent Ca2+ channel (VDCC) activity in superior cervical ganglion neurons (SCGNs). The putative role of LEV's molecular target, synaptic vesicle protein 2A (SV2A) in mediating LEV effects was investigated using the R-enantiomer, UCB L060, which exerts a lOOO-fold lower SV2A binding affinity than LEV. In these experiments, LEV inhibited synaptic transmission in SCG model synapses in a time-dependent manner, significantly reducing excitatory postsynaptic potential (EPSP) amplitudes and surface areas when applied for 2:30 min in comparison to UCB L060. In isolated SCGNs and recombinantly expressed Cav2.2 channels in HEK293 cells, LEV pretreatment (2:1 h), but not acute external application, significantly inhibited whole-cell IBa- Antibody labelling of SV2A in SCGNs revealed that the protein was predominantly expressed in close proximity to the plasma membrane and did not appear to redistribute or change its total expression in response to LEV pretreatment. Intracellular LEV application significantly inhibited IBa rapidly after establishing the whole-cell configuration to an extent comparable to that following LEV pretreatment; however, neither pretreatment nor intracellular application of UCB L060 produced any inhibitory effects in these experiments, which indicates an intracellular site of action. Under physiological conditions, LEV reduced both, fast and slow AP after- hyperpolarisations in a Ca2+ -dependent manner but did not affect the AP waveform or resting membrane potential. Additionally, LEV increased AP latency and slowed the repolarisation rates in a Ca2+-independent manner, suggesting further mechanisms associated with reduced excitability . Taken together, the presented results identify presynaptic VDCCs as targets for the archetypal SV2A ligand, LEV, potentially acting via an SV2A-dependent, intracellular pathway to inhibit presynaptic Ca2+ influx.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID: uk.bl.ethos.558790  DOI: Not available
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