The investigation of the genetic and pharmacological inhibition of striatal-enriched protein tyrosine phosphatase (STEP) and its role in hippocampal excitability and seizure propensity

Walters, Jennifer M.

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https://hdl.handle.net/2142/117766 Copy

Description

Title

The investigation of the genetic and pharmacological inhibition of striatal-enriched protein tyrosine phosphatase (STEP) and its role in hippocampal excitability and seizure propensity

Author(s)

Walters, Jennifer M.

Issue Date

2022-12-01

Director of Research (if dissertation) or Advisor (if thesis)

Chung, Hee Jung

Doctoral Committee Chair(s)

Chung, Hee Jung

Committee Member(s)

• Christian-Hinman, Catherine A
• Llano, Daniel A
• Raetzman, Lori T

Department of Study

Neuroscience Program

Discipline

Neuroscience

Degree Granting Institution

University of Illinois at Urbana-Champaign

Degree Name

Ph.D.

Degree Level

Dissertation

Keyword(s)

temporal lobe epilepsy, seizures, TC-2153, STEP, hippocampus, excitability

Abstract

Temporal Lobe Epilepsy (TLE) is the most common form of focal-onset epilepsy in adults and accounts for 60% of epileptic patients 1. In mesial TLE, seizures often begin in the hippocampus and progressively worsen over time. Current anti-seizure drugs are ineffective for approximately 75% of the patients with advanced mesial TLE, leading to severe consequences including hippocampal sclerosis, high mortality rate, cognitive decline, depression, and temporal lobe resection 1. Furthermore, dysregulation of intrinsic excitability and synaptic transmission has been widely thought to underlie hippocampal hyperactivity that drives the development of spontaneous seizures in TLE 2, underscoring a critical need to identify the underlying mechanisms and novel therapeutic targets. STriatal-Enriched protein tyrosine Phosphatase (STEP) is a brain-specific tyrosine phosphatase – membrane-bound STEP61 is the only isoform expressed in the hippocampus and cortex. Genetic deletion of STEP enhances excitatory synaptic currents and long-term potentiation in the hippocampus. However, whether STEP61 affects seizure susceptibility is unclear. The goal of this dissertation is to investigate the effects of STEP inhibitor TC-2153 and genetic STEP knockout (KO) on seizure propensity and hippocampal excitability. Chapter 1 covers a comprehensive review of STEP and its effect on neuronal excitability and synaptic regulation, as well as the therapeutic potential of STEP inhibition for patients experiencing detrimental neurological disorders. Chapter 2 presents our manuscript 3 published in Epilepsia journal investigating the role of TC-2153 on hippocampal network excitability and seizure severity. By combining techniques such as in vivo kainate-induced seizure modeling using a murine system, GCaMP6s calcium imaging, and electrophysiology, our study revealed that TC-2153 treatment significantly reduced kainate-induced seizure severity, with greater effects seen in females. Ovariectomy of females abolished the TC-2153-induced decrease in seizure severity. TC-2153 application significantly decreased overall hyperexcitability of acute hippocampal slices from both sexes. Surprisingly, TC-2153 treatment also hyperpolarized resting membrane potential and decreased firing rate, sag voltage, and hyperpolarization-induced currents of cultured hippocampal pyramidal neurons in vitro. Chapter 3 discusses our project investigating the effects of spontaneous recurrent seizure development using a repeated, low-dose kainate injection model in a homozygous STEP KO strain. We also demonstrate that STEP expression changes in the hippocampus upon neuronal injury using a cortical controlled impact (CCI) model to induce traumatic brain injury (TBI), which is known to cause epilepsy. In Appendix I, I included the contributions I made to the manuscript our lab published in Neurobiology of Disease, which investigate the impact of epileptic encephalopathy mutations on Kv7.2 expression. Appendix II includes a paper published in Scientific Reports from one of my first projects involved in looking at the effects of kainate-induced stress on PC2 expression in the hippocampus. Appendix III covers our preliminary results investigating how the application of TC-2153 impacts the potassium chloride-evoked activity of neurons and astrocytes derived from mouse neural progenitor stems cells. Our lab’s goal for this project is to advance our collaboration with Dr. Jack Parent at the University of Michigan and examine the effects of TC-2153 on a human iPSC-derived model of differentiated neurons.

Graduation Semester

2022-12

Type of Resource

Thesis

Copyright and License Information

Copyright 2022 Jennifer M. Walters

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