Activity-dependent regulation of GIRK and Kv7 channels in homeostatic plasticity and epilepsy

Baculis, Brian

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https://hdl.handle.net/2142/116164 Copy

Description

Title

Activity-dependent regulation of GIRK and Kv7 channels in homeostatic plasticity and epilepsy

Author(s)

Baculis, Brian

Issue Date

2022-07-08

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

Chung, Hee J

Doctoral Committee Chair(s)

Chung, Hee J

Committee Member(s)

• Christian-Hinman, Catherine
• Llano, Daniel
• Ceman, Stephanie

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)

• epilepsy
• homeostatic plasticity

Abstract

Epilepsy is a chronic brain disorder, which will impact about 3% of the general population at some point during their lifetime. Epilepsy manifests as uncontrolled aberrant electrical activity in the brain. Acquired epilepsy can be due to traumatic brain injury from stroke, contusion, or environmental toxins. Temporal lobe epilepsy (TLE), one of the most common forms of focal epilepsy, is often acquired. It is commonly associated with neuronal death, network reorganization, and synaptic sprouting. It is hypothesized that loss of input to the surviving neurons could lead to homeostatic scaling of synaptic strength and intrinsic excitability. Upon the formation of aberrant connections, it may lead to epileptogenesis in TLE. Homeostatic plasticity acts to stabilize neuronal activity by altering synaptic strength and adjusting intrinsic excitability. Homeostatic scaling of intrinsic excitability refers to the mechanism by which a neuron adjusts its intrinsic membrane properties in response to its environment to maintain a stable firing rate. To achieve this, a neuron must be able to sense its activity level and respond in a negative feedback manner. One way to control excitability is through the regulation of specific neuronal location, surface density, and function of ion channels, which contribute to the electrical properties of a neuron by integrating incoming signals, propagating those signals, and ultimately controlling the firing of an action potential. Here I will focus on how two potassium (K+) channels, G protein-activated inwardly rectifying K+ channels (GIRK) and voltage-gated KCNQ/Kv7 channels, are regulated by neuronal activity and contribute to homeostatic plasticity. We will also examine how they are regulated during hyperexcitability in diseases such as epilepsy. In Chapter 1, I will introduce GIRK channels and Kv7 channels. I will examine the brain distribution of these channels, their general channel properties, and their associated channelopathies. I will also explore how these features are regulated and what role these channels play in intrinsic excitability, synaptic transmission, and plasticity in the hippocampus. I will then end the discussion with their role in hippocampus-dependent learning and memory. In Chapter 2, I will summarize my research on the biphasic regulation of GIRK channels upon seizure activity. My research shows that high-frequency epileptiform discharges in cultured hippocampal neurons initially increase surface expression of GIRK1 and GIRK2 within 20 minutes, which homeostatically counteracts excessive seizure-like activity. However, prolonged epileptic activity (>30 minutes) leads to their caspase-3-dependent cleavage. In addition to identifying the caspase-3 cleavage sites, cleaved GIRK2 loses an ER export motif, thereby abolishing surface and current expression of GIRK2 homomeric channels. Since GIRK1 surface expression depends on GIRK2, GIRK1/GIRK2 heteromeric channels would also lose functional expression upon caspase-3-dependent cleavage. Importantly, kainate-induced status epilepticus causes GIRK1 and GIRK2 cleavage in the hippocampus in vivo at 2 hours post kainite injection. These findings suggest the possible role of caspase-3-mediated down-regulation of GIRK channels in aggravating hippocampal neuronal injury during prolonged epileptic seizures when homeostatic regulation fails. In Chapter 3, I will summarize my research on the regulation of Kv7 channels upon prolonged activity blockade which our lab has previously shown to induce homeostatic scaling of intrinsic excitability. My research shows that prolonged activity blockade using voltage-gated sodium channel blocker tetrodotoxin (TTX) decreases the activities of brain-derived neurotrophic factor (BDNF) receptor TrkB and its downstream extracellular signal-regulated kinase (ERK1/2) in cultured hippocampal neurons. Both prolonged activity blockade and prolonged pharmacological inhibition of ERK1/2 led to significant reductions in KCNQ3 and BDNF transcripts as well as the levels of Kv7.3 subunit and ankyrin-G at the axonal initial segments where action potentials are initiated and Kv7 channels are concentrated by binding to ankyrin-G. These findings suggest that downregulation of both ERK1/2 activity and the AIS expression of Kv7.3 may mediate homeostatic scaling of intrinsic excitability in hippocampal neurons.

Graduation Semester

2022-08

Type of Resource

Thesis

Copyright and License Information

Copyright 2022 Brian Baculis

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