A novel postsynaptic location for Kv7 channels and their role in memory and nanoparticle advancement for dementia therapeutics

Tracy, Gregory C

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https://hdl.handle.net/2142/120361 Copy

Description

Title

A novel postsynaptic location for Kv7 channels and their role in memory and nanoparticle advancement for dementia therapeutics

Author(s)

Tracy, Gregory C

Issue Date

2023-04-17

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

Chung, Hee Jung

Doctoral Committee Chair(s)

Chung, Hee Jung

Committee Member(s)

• Rhodes, Justin
• Christian-Hinman, Catherine
• Tsai, Nien-Pei

Department of Study

Molecular & Integrative Physl

Discipline

Molecular & Integrative Physi

Degree Granting Institution

University of Illinois at Urbana-Champaign

Degree Name

Ph.D.

Degree Level

Dissertation

Keyword(s)

KCNQ, Kv7, PLGA-b-HA

Abstract

Voltage-gated Kv7 (KCNQ) channels mediate slow-activating and non-inactivating outward potassium currents that regulate resting membrane potential and neuronal excitability. In neurons they are highly expressed at the axonal surface, especially in the axon initial segment and Nodes of Ranvier, where they are potent regulators of action potentials. Dominant mutations in KCNQ genes result in diseases such as epilepsy and neurodevelopmental disorders. Interestingly, homozygous deletion of KCNQ3, which encodes the Kv7.3 subunit, results in a normal phenotype and lifespan while homozygous deletion of KCNQ2, which encodes Kv7.2, causes death within the first postnatal day in mice. While Kv7 channel expression is known in dendrites, little is known about their presence and role in dendritic spines that harbor majority of excitatory synapses where neuronal communications (termed synaptic transmission) occur. Neurodegenerative diseases affect more than 270 million people globally, claiming the second leading cause of death and Alzheimer’s disease (AD) is the most common cause of dementia in older adults. AD is characterized by progressive and irreversible memory loss with neuronal atrophy starting typically from the hippocampus yet most treatments thus far have mostly failed in clinical trials. Among the most challenging aspects to treating disorders of the brain are permeating the blood brain barrier (BBB) and the overcoming the rapid clearing of drugs from the brain due to interstitial flushing. Nanoparticles have arisen as promising transporters for drug delivery across the BBB for disorders such as Alzheimer’s disease. Nanoparticles also have the ability to be coated in polymers which can allow the targeting of and retention in specific microenvironments of the diseased brain. The goal of this dissertation is to investigate the expression of Kv7 channels at excitatory synapses, the molecular mechanism for their postsynaptic localization, the direct role they play in synaptic function, and their effect on learning and memory. Additionally, we aim to improve nanoparticle retention in areas of neuroinflammation to treat Alzheimer’s disease pathogenesis. Chapter 1 provides a review of neuronal Kv7 channels and nanoparticle therapeutics as they relate to brain disorders. Chapter 2 presents our manuscript (Tracy et al., 2022) published in Frontiers in Behavioral Neuroscience on the effects of KCNQ2 haploinsufficiency on learning and memory in mice. In this study we conducted a barrage of behavioral assays on mice that have a heterozygous deletion of the KCNQ2 gene (KCNQ2+/-). We discovered that heterozygous deletion of KCNQ2 is not sufficient to cause significant effects on learning and memory. Chapter 3 discusses our project investigating the presence and role of Kv7 channels in the postsynaptic density (PSD) within dendritic spines of hippocampal and cortical neurons. The PSD is a dense protein-rich domain adjacent to postsynaptic membrane at excitatory synapses where excitatory synaptic transmission is mediated by glutamate receptors including NMDA and AMPA receptors. Using biochemical PSD fractionation, electron microscopy, and immunocytochemistry we have discovered a novel location for Kv7 channels in dendritic spines and the PSD. Since the Ca2+ influx through NMDA receptor in dendritic spines is critical for excitatory synaptic transmission and plasticity underlying learning and memory, we aim to uncover the role of postsynaptic Kv7 channels in hyperpolarizing postsynaptic membrane and thus inhibiting Ca2+ influx in dendritic spines. Chapter 4 presents our submitted manuscript (Tracy, Huang, Hong, et al., 2023, under review) investigating the ability of hyaluronic acid (HA)-coated nanoparticles to cross the BBB and localize to the hippocampi in aged wild-type and Alzheimer’s disease model mice. Here we demonstrate that PLGA-b-HA nanoparticles cross the BBB in aged mice and are retained in the hippocampus. This finding is significant because permeating the BBB and avoiding brain clearance due to interstitial flow have been two of the greatest challenges in pharmacological treatment of many disorders of the brain.

Graduation Semester

2023-05

Type of Resource

Thesis

Copyright and License Information

Copyright 2023 Gregory Tracy

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