Luận văn thạc sĩ localized hippocampal glutamine synthetase knockout a novel model of mesial temporal lobe epilepsy
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Luận văn thạc sĩ localized hippocampal glutamine synthetase knockout a novel model of mesial temporal lobe epilepsy
Yale UniversityEliScholar - A Digital Platform for Scholarly Publishing at YaleYale Medicine 'Ihesis Digital LibrarySchool of Medicine43466Localized H Luận văn thạc sĩ localized hippocampal glutamine synthetase knockout a novel model of mesial temporal lobe epilepsy Hippocampal Glutamine Synthetase Knockout: A Novel Model OfMesial Temporal Lobe EpilepsyMaxwell Gerard FarinaFollow this and additional works at: https://eljscholar.library.yale.edu/ynitdlRecommended CitationFartiu, Maxwell Gerard, ’Localized Hippocampal Glutamine Synthetase Knockout: A Novel Model Luận văn thạc sĩ localized hippocampal glutamine synthetase knockout a novel model of mesial temporal lobe epilepsy Of Mesial Temporal Lobe Epilepsy’ (2019). Yak Medicine Thais Dijjrwf Library. A491.https://elucholar.hbrary.yale.edu/ymtdl/A491This Open Access IbftisLuận văn thạc sĩ localized hippocampal glutamine synthetase knockout a novel model of mesial temporal lobe epilepsy
a. brought to you for free and open access by the School of Medline at EhScholar - A Digital Platform for -Scholarly Publishing at Yale. It has been Yale UniversityEliScholar - A Digital Platform for Scholarly Publishing at YaleYale Medicine 'Ihesis Digital LibrarySchool of Medicine43466Localized H Luận văn thạc sĩ localized hippocampal glutamine synthetase knockout a novel model of mesial temporal lobe epilepsy g at Yale. For more infbrtniiion. please contact elischctariSyale edo.Localized Hippocampal Glutamine Synthetase Knockout: a Novel Model of Mesial Temporal Lobe EpilepsyA THESIS SUBMITTED TO THE Yale University School of MedicineIN PARTIAL FULFILLMENT FOR THEDECREE OF Doctor of MedicineMaxwell G. Fa Luận văn thạc sĩ localized hippocampal glutamine synthetase knockout a novel model of mesial temporal lobe epilepsy rinaAdvisor: Tore Eid. Ml). PhDThesis Committee Members: Peter Tattersall, PhD, Niiial DeLanerolle, DPiiii . DSc A Ellen Foxman, MD, PhD43586Absirac 1Luận văn thạc sĩ localized hippocampal glutamine synthetase knockout a novel model of mesial temporal lobe epilepsy
I DUALIZED I IIPPOCAMPAI. Cl.u I AMINE SYN I I II.IASE KNOCKOUT: A NOVEL MODEL OE MILSIAL I EMPOR.AL LOBE EPILEPSY.Maxwell Larina and lore Eid. I JepaYale UniversityEliScholar - A Digital Platform for Scholarly Publishing at YaleYale Medicine 'Ihesis Digital LibrarySchool of Medicine43466Localized H Luận văn thạc sĩ localized hippocampal glutamine synthetase knockout a novel model of mesial temporal lobe epilepsy ptimize a model of mesial temporal lolie epilepsy through selective depletion of glutamine synthetase (GS) in the mouse hippixampus. Following validation of the mtxlel, preliminary studies attempted to characterize morphological astrocytic and synaptic changes that re suit Imm GS deficiency. Aim I e Luận văn thạc sĩ localized hippocampal glutamine synthetase knockout a novel model of mesial temporal lobe epilepsy stablished a novel mouse model of GS knockout in hippocampal astrocytes. Aim 2 tested whether localized hippocampal knockout of GS causes mice to exhiLuận văn thạc sĩ localized hippocampal glutamine synthetase knockout a novel model of mesial temporal lobe epilepsy
bit an epilepsy-like phenotype. Aim 3 characterized the cellular effects of localized GS loss. To generate the knockout, Ghil-floxed C57BI76| mice werYale UniversityEliScholar - A Digital Platform for Scholarly Publishing at YaleYale Medicine 'Ihesis Digital LibrarySchool of Medicine43466Localized H Luận văn thạc sĩ localized hippocampal glutamine synthetase knockout a novel model of mesial temporal lobe epilepsy nial depth or screw electnxles and monitored for spontaneous seizures using 24-hour video-EEG recording for two weeks. To assess for provokes! seizure sensitivity, seizures were induced with pentylenetetrazol (PTZ) prior to perfusion fixation. Brains were perfused. sectioned, and unmunostamesl for a Luận văn thạc sĩ localized hippocampal glutamine synthetase knockout a novel model of mesial temporal lobe epilepsy nalysis using standard and STED fluorescence microscopy. Knockout of GSj as evidenced by loss of GS Iinnninorcactivity, was found owe 3 greater area iLuận văn thạc sĩ localized hippocampal glutamine synthetase knockout a novel model of mesial temporal lobe epilepsy
n brain regions injected with the AAV5 CMV and AAV8 GFAP serotypes. In addition, within each GS knockout region. AAV8 GFAP exhibited a significantly gYale UniversityEliScholar - A Digital Platform for Scholarly Publishing at YaleYale Medicine 'Ihesis Digital LibrarySchool of Medicine43466Localized H Luận văn thạc sĩ localized hippocampal glutamine synthetase knockout a novel model of mesial temporal lobe epilepsy (20.2% decreased fluorescence intensity, P=o.ot8). AAV8 GFAP exhibited near perfect target specificity (98.7% of GFP+ cells were astrocytes), while AAV 5 CMV Legacy, AAV5 CMV, and AAV8 CMV targeted mostly neurons with varied degrees astrocyte labeling detected (10.0%, 21.3%, and 12.7% astrocytes, r Luận văn thạc sĩ localized hippocampal glutamine synthetase knockout a novel model of mesial temporal lobe epilepsy espectively. Sixty percent (3/5) of mice injected with AAV8 GFAP exhibited an epilepsy like phenotype including spouta neons recurrent seizures that wLuận văn thạc sĩ localized hippocampal glutamine synthetase knockout a novel model of mesial temporal lobe epilepsy
ere clustered in tile mmning hours. Twenty five jsercent (1/4) of control mice seizes! spontaneously over die same |>eriod. Additionally, fixal GS knoYale UniversityEliScholar - A Digital Platform for Scholarly Publishing at YaleYale Medicine 'Ihesis Digital LibrarySchool of Medicine43466Localized H Luận văn thạc sĩ localized hippocampal glutamine synthetase knockout a novel model of mesial temporal lobe epilepsy 3.2 seconds vs. 65.83 I 12.9 seconds, respectively; P=O.C>44). The effect on lime to convulsive seizure was not statistically significant, though there was a trend of kmx’koiil animals proceeding Io convulsions in less lime (74.2 I 9.4 seconds vs. 100.0 I 18.0 seconds, p=o.2o). Finally, examination Luận văn thạc sĩ localized hippocampal glutamine synthetase knockout a novel model of mesial temporal lobe epilepsy ofsynaptic mark ers revealed decreased expression Ilf PSD 95 surrounding GS astrocytes compared lo GS+ astrocytes, with sampled relative intensity ofLuận văn thạc sĩ localized hippocampal glutamine synthetase knockout a novel model of mesial temporal lobe epilepsy
0,57 * o.ủị (p=0.0O2). Relative intensity (Rl) ofsynaplophysin and gephyrin apjseared to lie unchanged in the sampled areas (synaptopbysin RĨ 0.94 • 0Yale UniversityEliScholar - A Digital Platform for Scholarly Publishing at YaleYale Medicine 'Ihesis Digital LibrarySchool of Medicine43466Localized H Luận văn thạc sĩ localized hippocampal glutamine synthetase knockout a novel model of mesial temporal lobe epilepsy GS in the hippocampal aslnxytes of mice. Development of this nionogenelic knockout model with effects restricted to the bippix-anipus and adjacent structures has the potential to more Hilly elucidate the impact of’GS loss in this treatment-resistant disease. Initial examination of synaptic markers Luận văn thạc sĩ localized hippocampal glutamine synthetase knockout a novel model of mesial temporal lobe epilepsy in GS depleted areas highlights the importance of glutaniatergic synaptic transmission in epilepsy pathology.iiAcknowledgmentsThis work was made possiLuận văn thạc sĩ localized hippocampal glutamine synthetase knockout a novel model of mesial temporal lobe epilepsy
ble by the knowledge, skills, and support conferred by countless friends and mentors through the years. In particular. I am thankful to Tore Eld. who Yale UniversityEliScholar - A Digital Platform for Scholarly Publishing at YaleYale Medicine 'Ihesis Digital LibrarySchool of Medicine43466Localized H Luận văn thạc sĩ localized hippocampal glutamine synthetase knockout a novel model of mesial temporal lobe epilepsy cience class dissect a shark, and in doing so. instilled in me an unending love for science. Its systematic search for truth, and the uniquely fundamental way in which it connects US to one another.Financial support for the work presented in this thesis was provided in part by the National Heart. Lu Luận văn thạc sĩ localized hippocampal glutamine synthetase knockout a novel model of mesial temporal lobe epilepsy ng, and Blood Institute of the National Institutes of Health (Maxwell Farina, award number T35HL007649) and NIH grant S10-OD020142 (Yale Confocal MicrLuận văn thạc sĩ localized hippocampal glutamine synthetase knockout a novel model of mesial temporal lobe epilepsy
oscopy Core).iiiAbbreviationsAAVAdcno-associatcd virusAMPAa-amino-3-hydroxy-5-mcthyl-4-isoxazolcpropionic acidATPAdenosine triphosphateCA 1-3Cornu ammYale UniversityEliScholar - A Digital Platform for Scholarly Publishing at YaleYale Medicine 'Ihesis Digital LibrarySchool of Medicine43466Localized HYale UniversityEliScholar - A Digital Platform for Scholarly Publishing at YaleYale Medicine 'Ihesis Digital LibrarySchool of Medicine43466Localized HGọi ngay
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