Dissertation
Investigating the role of ASIC2 subunits in synaptic and behavioral responses to drugs of abuse
University of Iowa
Doctor of Philosophy (PhD), University of Iowa
Spring 2024
DOI: 10.25820/etd.007523
Abstract
Drugs of abuse produce rearrangements at glutamatergic synapses thought to contribute to drug-reinforced behaviors. Acid-Sensing Ion Channels (ASICs) have been suggested to oppose these effects, largely due to observations in mice lacking the ASIC1A subunit. However, the ASIC2A and ASIC2B subunits are known to interact with ASIC1A, and their potential roles in mediating responses to drugs of abuse have not yet been investigated. Therefore, we tested the effects of disrupting ASIC2 subunits in mice exposed to drugs of abuse. We found conditioned place preference (CPP) to both cocaine and morphine were increased in Asic2-/- mice, which is similar to what was observed in Asic1a-/- mice. Because the nucleus accumbens (NAc) is an important site of ASIC1A action, we examined expression of ASIC2 subunits there. By western blot ASIC2A was readily detected in wild-type mice, while ASIC2B was not, suggesting ASIC2A is the predominant subunit in the NAc core. An adeno-associated virus vector (AAV) was used to drive recombinant ASIC2A expression in the NAc core of Asic2-/- mice, resulting in near normal protein levels. Moreover, recombinant ASIC2A integrated with endogenous ASIC1A subunits to form functional channels in medium spiny neurons (MSNs). However, unlike ASIC1A, region-restricted restoration of ASIC2A in the NAc core was not sufficient to affect cocaine or morphine CPP, suggesting effects of ASIC2 differ from those of ASIC1A. Supporting this contrast, we found that AMPA receptor subunit composition and the ratio of AMPA receptor-mediated current to NMDA receptor-mediated current (AMPAR/NMDAR) were normal in Asic2-/- mice and responded to cocaine withdrawal similarly to wild-type animals. However, disruption of ASIC2 significantly altered dendritic spine morphology, and these effects differed from those reported previously in mice lacking ASIC1A. We conclude that ASIC2 plays an important role in drug-reinforced behavior, and that its mechanisms of action may differ from ASIC1A.
Details
- Title: Subtitle
- Investigating the role of ASIC2 subunits in synaptic and behavioral responses to drugs of abuse
- Creators
- Margaret J. Fuller
- Contributors
- John A. Wemmie (Advisor)Jason J. Radley (Committee Member)Hanna E. Stevens (Committee Member)N. Charles Harata (Committee Member)Mark W. Chapleau (Committee Member)Rainbo Hultman (Committee Member)
- Resource Type
- Dissertation
- Degree Awarded
- Doctor of Philosophy (PhD), University of Iowa
- Degree in
- Molecular Physiology and Biophysics
- Date degree season
- Spring 2024
- Publisher
- University of Iowa
- DOI
- 10.25820/etd.007523
- Number of pages
- xi, 81 pages
- Copyright
- Copyright 2023 Margaret J. Fuller
- Language
- English
- Date submitted
- 01/31/2023
- Description illustrations
- Illustrations, graphs, charts
- Description bibliographic
- Includes bibliographical references (pages 69-81).
- Public Abstract (ETD)
Acid-sensing ion channels (ASICs) are proteins in brain neurons that respond to changes in brain pH. Previous work suggested that these proteins are involved in addiction-related behaviors in animals. ASICs are made up of multiple components called subunits, and most of the previous work focused on one key subunit ASIC1A. However, little is known about the other major subunits in the brain, ASIC2A and ASIC2B, which are the focus of the current study. Results suggest that not only are ASIC2 subunits also involved in behaviors induced by addictive drugs but surprisingly, their effects on neuron structure and function are distinct from ASIC1A. This work provides new insights into how ASIC subunits contribute to addiction-related behaviors. Understanding how ASICs function in the brain could be critical in the development of future therapies for people suffering from addiction disorders.
- Academic Unit
- Molecular Physiology and Biophysics
- Record Identifier
- 9984647456502771
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