Controlling Febrile Seizures in a Model of Dravet Syndrome
| dc.contributor.advisor | Ziburkus, Jokubas | |
| dc.contributor.committeeMember | Dauwalder, Brigitte | |
| dc.contributor.committeeMember | Leasure, J. Leigh | |
| dc.contributor.committeeMember | Rea, Michael A. | |
| dc.creator | Gu, Feng 1978- | |
| dc.date.accessioned | 2018-11-26T22:49:56Z | |
| dc.date.available | 2018-11-26T22:49:56Z | |
| dc.date.created | August 2013 | |
| dc.date.issued | 2013-08 | |
| dc.date.submitted | August 2013 | |
| dc.date.updated | 2018-11-26T22:49:57Z | |
| dc.description.abstract | Severe myoclonic epilepsy of infancy (SMEI) or Dravet syndrome is one of the most devastating types of childhood epilepsies. Children with SMEI suffer from febrile and afebrile seizures (FS and aFS), ataxia, and social and cognitive dysfunctions. SMEI is pharmacologically intractable and can be fatal in 10-20% of patients. 70%-80% of SMEI patients are found to have SCN1A gene mutations. Recent studies of mouse models of SMEI (mSMEI) with SCN1A gene mutations have elucidated molecular and cellular mechanisms that may account for the epileptogenesis. There remains, however, a critical need to further elucidate how SCN1A gene mutation impacts neuronal activity in key anatomical circuits, and to develop new strategies for controlling seizures in SMEI. This dissertation aims to analyze and control neural circuit excitability and hyperthermia-induced FS both in vitro and in vivo using mSMEI carrying a SCN1A gene mutation. Using a combination of electrophysiology and fast voltage-sensitive dye imaging (VSDI) we studied synaptic excitatory/inhibitory balance, characteristics of neural activity propagation, and hyperthermia-induced FS-like events (FSLEs) in the hippocampus of mSMEI in vitro. Our in vitro studies reveal significant excitation and inhibition (E/I) imbalance in mSMEI, showing decreased inhibition, increased excitation, evoked neural activity that is abnormally wide-spread, and a decrease in FSLE threshold in the hippocampal circuits. To control hyperthermia-induced hyperexcitability and seizure activity (also referred to as febrile seizures), we used adenosine A1 receptor (AIR) agonist N6-cyclopentyladenosine (CPA). We found that in vitro, low concentration (50nM) of CPA significantly reduced hippocampal circuit hyperexcitability and blocked hyperthermia-induced FSLEs without blocking excitatory synaptic transmission. Furthermore, we tested whether CPA would have an equivalent effect on hyperthermia-induced FS in vivo. We found that SMEI transgenic animals had significantly lower FS threshold than their wild-type littermates. Acute injection of CPA prior to hyperthermia exposure effectively suppressed FS. In addition to the acute effect of CPA, we also tested if chronic treatment of SMEI mice with CPA during early postnatal development (postnatal days P11-20) can have a long-lasting anti-convulsant effect. We discovered that 24 hours and even 10 days after the last drug treatment (at P20), FS threshold in vivo was still significantly reduced. Our follow-up studies in vitro, following the chronic treatment in vivo, showed that following 10 days of treatment, synaptic excitation was decreased while the inhibitory responses were unaltered. Our findings suggest that A1R agonist CPA may serve as an effective compound to recover the E/I balance and control or prevent epileptogenesis in SMEI. | |
| dc.description.department | Biology and Biochemistry, Department of | |
| dc.format.digitalOrigin | born digital | |
| dc.format.mimetype | application/pdf | |
| dc.identifier.uri | http://hdl.handle.net/10657/3402 | |
| dc.language.iso | eng | |
| dc.rights | The author of this work is the copyright owner. UH Libraries and the Texas Digital Library have their permission to store and provide access to this work. Further transmission, reproduction, or presentation of this work is prohibited except with permission of the author(s). | |
| dc.subject | Epilepsy | |
| dc.subject | Dravet syndrome | |
| dc.subject | Seizure | |
| dc.subject | SCN1A gene | |
| dc.subject | Hyperthermia | |
| dc.subject | Hippocampal Circuit | |
| dc.subject | Hippocampus | |
| dc.subject | Optical Imaging | |
| dc.subject | Excitation/Inhibition balance | |
| dc.subject | Adenosine A1 receptor | |
| dc.title | Controlling Febrile Seizures in a Model of Dravet Syndrome | |
| dc.type.dcmi | Text | |
| dc.type.genre | Thesis | |
| thesis.degree.college | College of Natural Sciences and Mathematics | |
| thesis.degree.department | Biology and Biochemistry, Department of | |
| thesis.degree.discipline | Biology | |
| thesis.degree.grantor | University of Houston | |
| thesis.degree.level | Doctoral | |
| thesis.degree.name | Doctor of Philosophy |