status epilepticus induced alterations in hippocampal anatomy and neurotransmission

288 Pages·2014·6.82 MB·English

by  Denise K. Grosenbaugh

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Theses and Dissertations
8-9-2014
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Denise K. Grosenbaugh
University of South Carolina
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Grosenbaugh, D. K.(2014). Status Epilepticus Induced Alterations in Hippocampal Anatomy and
Neurotransmission. (Doctoral dissertation). Retrieved from https://scholarcommons.sc.edu/etd/2768
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STATUS EPILEPTICUS INDUCED ALTERATIONS IN
HIPPOCAMPAL ANATOMY AND NEUROTRANSMISSION

by

Denise K. Grosenbaugh

Bachelor of Science
Florida State University, 2007

Submitted in Partial Fulfillment of the Requirements

For the Degree of Doctor of Philosophy in

Biomedical Science

School of Medicine

University of South Carolina

2014

Accepted by:

David D. Mott, Major Professor

Janet L. Fisher, Committee Member

Lawrence P. Reagan, Committee Member

Robert L. Price, Committee Member

Roger Newman-Norlund, Committee Member

Lacy Ford, Vice Provost and Dean of Graduate Studies
© Copyright by Denise K. Grosenbaugh, 2014
All Rights Reserved.
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DEDICATION
I would like to dedicate this manuscript to the memory of my beautiful
Grammy, Theresa M. Boileau. I am so lucky to have had such a loving, sweet
and kind soul as a grandmother. Thank you for your unending love. Miss you
forever.
This manuscript is also for my wonderful family who have always given me
unconditional love and support. To my mom and dad, Brenda and Mark, for being
remarkable parents and friends. Thank you for always being so incredibly
supportive of the decisions I’ve made, for teaching me that success comes with
hard work, and for always pushing me to do my best. To my little brother and
sister, Danny and Melanie, thank you for being the best siblings I could have
asked for. You are both amazing people and I truly value our time together and
the laughs that we share. To my incredible extended family for always being so
supportive- Auntie Lori, Uncle Dave, Uncle Gary, Auntie Gail, Aunt Vicki, Uncle
Bob, Grandpa, Grandpa-With-The-Boots, Grandma Pam, Josh, my brother-in-law
Jay, and The Adams Family *snap snap*- Ryan, Jelly, SophieAnn and
Savannah. And finally to my furry friend Zeek for always putting a smile on my
face after a long day. I love you all and I want to thank each one of you for
making this all possible.

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ACKNOWLEDGEMENTS
“There are things known and there are things unknown, and in between are the
doors of perception.” ~Aldous Huxley

Most importantly I would like to thank Dr. David Mott for taking a risk on a psych
major from Florida State. Thank you for your excellent guidance, seemingly
never-ending time to explain both science and non-science related concepts,
paper towel artwork, and for teaching me quite literally everything I know about
neuroscience. I will forever carry with me the many ‘Mott-isms’ I have picked up
during my graduate career. I cannot thank you enough for everything that you
have taught me about science and about life in general.

Thank you to my committee members Drs. Janet Fisher, Larry Reagan, Bob
Price and Roger Newman-Norlund for agreeing to serve on my committee and
always providing constructive criticism and allowing me the opportunity to look at
my data from a different standpoint.

I would like to specifically thank Dr. Larry Reagan for all of his support…literally
since day one. Your advice and perspective on a variety of issues was always
greatly appreciated. You continually gave me your vote of confidence, for which I
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cannot thank you enough.

I would also like to thank Dr. Janet Fisher for all her assistance and input on
essentially every project I have worked on during my graduate career. You are
an extraordinary example of scientific integrity and strong work ethic. Thank you
for everything you have taught me.

I want to acknowledge Dr. Marlene Wilson for her dedication and support of the
entire PPN department, which made it such a pleasurable place to work and
definitely the best department at the SOM!

I have to thank Drs. Sloka Iyengar, Emily Stanley and Shayna Wrighten, for
without you I would have never made it through this program and never found the
joy in going for those lovely walks around the Med school.
Sloky, I am so fortunate to have learned most, if not all, of my lab
techniques from you. Thank you making my first real lab experience so amazing.
I think of you when I listen to Steve F.M., when it ‘rains on my brain’, whenever I
see a BUG, or when things go ‘DOINK!’
Emily, thank you for showing me the ropes around the department during
my first year. I’m glad my desk was next to yours in the student room so we
could read Star Magazine and chat about entertainment gossip instead of
science. And thanks for all of the amazing meals you cooked during your tenure
as head holiday party hostess.
v
Shayna thank you for always helping me put things into perspective.
Outside of my family, you are the only other person I know who can quote any
Golden Girls episode…and for that, I am just so thankful. Thanks for everything,
WaterLilly.

I must also acknowledge Dr. Brittany Law, and soon-to-be Drs. David Elliott,
Sarah Bertrand and Adrian Gomez for being amazing colleagues and even better
friends. And thanks to Mike ‘Scope’ Watson, Wes Reardon and Dr. Eyma
Marrero-Alfonso for also being great friends. You all have become my South
Carolina family and I will miss all of the holiday parties, football games and
general fun we had together. You are an amazing group of friends.

I want to specifically acknowledge the other members of the Mott Lab- Lei Liu,
C’iana Cooper and Dr. James Warren- for making coming to work enjoyable and
making those long lab hours much more manageable. And a special thanks to
James for fostering my love of college football and pop culture.

I am also thankful for all of the other PPN students and post-docs I have had the
pleasure of working with during my graduate career- Janel Hagar, Terika Smith,
Sherika Smith, Jingyi Zhang, Jeffrey Parilla-Carerro, Victoria Macht, Amy
Perkins, Maribel Vazquez, Ross Tanis, Allison Manuel, Stani Day, Dr. Ryan
Butler, Dr. Violeta Zaric Dr. Amanda Sharko, and Dr. Dani Frederick-Duus.
vi
I want to thank the PPN faculty for always providing such an enjoyable and
happy atmosphere- Drs. Jim Fadel, Alex McDonald, Sarah Sweitzer, Gerardo
Piroli, Claudia Grillo, Jim Augustine, Britt Wilson, Susan Wood, Chris Wood,
Michy Kelly, Norma Frizzell, Pavel Ortinski, Paul Housley, Ken Walsh, Jack
Ginsberg and Jim Buggy. I also want to thank Mike Gore and Joey Farrow for all
of their assistance in constructing and fixing pieces of equipment for the lab and
the department. Without your help many of our ideas and experiments would
have never been able to occur.

I would like to acknowledge the staff at the School of Medicine for all of their
helpful assistance over the years- Ansley Roberts, Glenda Fedricci, Eva Howard,
Judy Lawrence and Kris Ford.

I also want to thank Lisa Alfasi, my 4th grade math and science teacher. Mrs.
Alfasi, you’re guidance, mentorship, encouragement, and friendship over the past
20 years have meant so much to me. Thank you for everything.

Finally, I would like to thank my best friends for always supporting me and giving
me something to laugh about-
To Becky Thompson and Nicolette Bidarian- thank you for being
absolutely hysterical and for being such great friends. We have shared countless
laughs over the decades and I look forward to spending many more.
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And to my extraordinary Florida State crew- Martha Schwab, Carly-Jane
Waters, Anastasia Saunders, Meghan Maloney and Nifer Travieso- thank you for
being the best group of friends a girl could ask for. Thank you for always
supporting me and providing me with continuous laughter, highly inappropriate
jokes and countless shenanigans over the years. Your friendship and
encouragement is invaluable and I don’t know where I would be without you
guys! We’ve been through so much together and I look forward to many more
years of unacceptable behavior out of girls our age. NOLE-BLOODED!
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ABSTRACT
Status epilepticus (SE) is a life-threatening neurologic emergency
occurring when the brain is in an unrelenting state of seizure activity.
Approximately 40% of people who encounter a single event of SE go on to
develop epilepsy, characterized by spontaneously occurring seizures. While the
exact mechanisms underlying seizure origin are not understood, at a
fundamental level seizures initiate due to an imbalance between inhibitory and
excitatory neurotransmission. We explored the impact of SE and the
development of epilepsy on GABA receptor mediated inhibitory
A
neurotransmission and kainate receptor (KAR) mediated excitatory
neurotransmission.
Stiripentol (STP), a positive allosteric modulator of the GABA receptor,
A
was found to terminate both brief and prolonged SE with the development of less
pharmacoresistance than is observed with the benzodiazepine (BZD), diazepam
(DZP). In addition STP, but not DZP, retained its ability to potentiate both phasic
and tonic GABAergic transmission post-SE. These findings are supported by
previous studies demonstrating that the actions of STP do not require the BZD-
sensitive γ2-containing GABA Rs which are internalized during prolonged SE.
A
These data demonstrate that prolonged SE significantly impacts the
pharmacological profile of GABA receptors and potential therapeutics.
A
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