Item Details

title

INVESTIGATING VOLTAGE-GATED CALCIUM ION CHANNEL DYSFUNCTION IN A PRECLINICAL MODEL OF TUBEROUS SCLEROSIS COMPLEX

author

Egido-Betancourt, Hailey

abstract

Tuberous Sclerosis Complex (TSC) is a neurodevelopmental disorder caused by mutations in the TSC1 or TSC2 gene, which results in the mammalian/mechanistic target of rapamycin complex (mTORC1) becoming overactive and causing further downstream complications that manifest into a variety of neurological disorders within TSC, such as epilepsy, autism spectrum disorder (ASD), and cognitive dysfunction. There is no cure for TSC, so, determining the neurobiological correlates that underlie epilepsy, ASD, and cognitive dysfunction in TSC is imperative. Indeed, it is thought that alterations in synaptic function lead to cognitive dysfunction, seizure, and ASD in TSC. It is also known that mTORC1 is a master regulator of synaptic protein synthesis which are associated with symptoms of TSC. Interestingly, there are voltage-gated ion channels listed among these synaptic proteins, yet remain under investigated. Here, we demonstrate through multidisciplinary approaches that post-synaptic calcium signaling is dysfunctional and that N-type voltage-gated calcium channel expression and function are disrupted in a preclinical model of TSC. This thesis compares current TSC literature that examined common seizure types, clinical trials, and genomic studies that potentially implicates Na+, K+, and Ca2+ voltage-gated ion channel dysfunction in TSC (Chapter 1). In addition, the experiments listed in chapters 2 and 3 of this dissertation address open questions regarding in the importance of calcium signaling in TSC excitability (Chapter 2) and how N-type voltage-gated calcium channels modulate deficient branch-specific calcium signals (which is considered a model of cognition (Chapter 3)) in TSC hippocampal neurons. Together, my studies demonstrate the importance of calcium signaling in TSC1-null hippocampal neurons and confirm that blocking N-type voltage-gated calcium ion channels can serve as an alternative biomarker for cognitive dysfunction in TSC. This thesis concludes that investigating other ion channels may also reveal new mechanisms that contribute to the manifestations of TSC (Chapter 4).

subject

Cognitive Dysfunction

Dendritic branch-specific calcium

Epilepsy

Excitability

Tuberous Sclerosis Complex

Voltage-gated ion channels

contributor

Raab-Graham, Kimberly (advisor)

Chen, Rong (committee member)

McCool, Brian (committee member)

Weiner, Jeffrey (committee member)

date

2024-05-23T08:36:27Z (accessioned)

2024 (issued)

degree

Neuroscience (discipline)

embargo

2029-05-18 (terms)

2029-05-18 (liftdate)

identifier

http://hdl.handle.net/10339/109459 (uri)

language

en (iso)

publisher

Wake Forest University

type

Dissertation