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Title: Acute effects of LGI1 on network excitability
Author: Lugara, Eleonora
ISNI:       0000 0004 7965 1534
Awarding Body: UCL (University College London)
Current Institution: University College London (University of London)
Date of Award: 2019
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LGI1 (leucine rich glioma inactivated1) is a secreted trans-synaptic protein and is part of the brain extracellular matrix. LGI1 interacts presynaptically with Kv1.1 potassium channels and ADAM23, a structural transmembrane protein. Postsynaptically, LGI1 also influences AMPA and NMDA receptors via the ADAM22 adhesion protein. Mutations in the gene encoding LGI1 lead to temporal lobe epilepsy in humans and animal models. Autoantibodies against LGI1 have been detected in the serum of adult patients with limbic encephalitis and seizures. Although LGI1 is strongly implicated in the generation and spread of seizures in genetic and developmental forms of epilepsy, the mechanisms by which LGI1 affects neuronal networks are still debated. This thesis aimed to determine whether an acute reduction of LGI1 in the brain leads to network hyperactivity and epilepsy in rodent animals and the mechanisms behind it. Initially, in vivo experiments on rats demonstrated that LGI1 concentrations in the brain are reduced after generation of chronic seizures using the perforant path stimulation model. I then chose and validated a silencing RNA (shRNA) against LGI1 which reduced endogenous LGI1 levels in primary cultures. In the transduced neurons, spontaneous calcium activity was significantly higher, without affecting the viability of the cells. Also the MBR (mean bursting rate) of transduced neuronal cultures measured with a MEA (multielectrode arrays) system was increased. In ex vivo granule cells, shRNA-LGI1 increased neuronal firing. Local field potential (LFP) of ex vivo slices after injection of shRNA-LGI1 in the hippocampus, revealed an increase in the short-term facilitation of mossy fibers to CA3 pyramidal cell synapses. Application of Kv1 family blocker, αDendrotoxin, occluded the increased facilitation in shRNA-LGI1 injected mice. My results indicate that an acute reduction of LGI1 is sufficient to increase neuronal network excitability in in vitro and ex vivo systems and that LGI1 concentrations are reduced in the brains of animals during the development of epilepsy.
Supervisor: Walker, M. ; Lignani, G. Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available