Parker, Emily and Sweet, Robert and Meriney, Stephen and Gold, Michael and Rubio, Maria and Sadagopan, Srivatsun and Wills, Zachary and Penzes, Peter
(2020)
CACNB4 Overexpression and Dendritic Spine Loss in Schizophrenia.
Doctoral Dissertation, University of Pittsburgh.
(Unpublished)
Abstract
Reduced density of dendritic spines is an intermediate anatomical phenotype for schizophrenia (Sz). This dissertation is a collection of descriptive studies about dendritic spines and the voltage-gated calcium channel protein β4, a study of a Sz-related β4 manipulation, and the impacts of this manipulation on dendritic spine density and morphology. Chapter 2 is a descriptive study of sex differences in dendritic spines in murine sensory cortex over adolescent neurodevelopment. Chapter 3 is an in-depth assessment of the impacts of CACNB4 overexpression (β4OE) on dendritic spines of male and female adult mice. Chapter 4 is a final descriptive study of sex differences in the β4 interactome of adult mice. Sex differences were deliberately assessed at baseline and in the study of the impacts of β4OE on dendritic spines given the importance of sex as a biological factor and known sex differences in the clinical presentation and expression of Sz. In Chapter 2, we identified sex differences in spine density, and in Chapter 3 evidence for volume- as well as sex-specific β4OE-mediated spine loss; small spines were reduced in female β4OE mice only. These findings provide a model for the intermediate phenotype of small spine loss in primary auditory cortex in Sz and support both our group’s previous suggestion to rethink the Feinberg hypothesis, but also the possibility that small mature spines are eliminated excessively in Sz during adolescence, as Feinberg predicted. In Chapter 4 we found that β1b is significantly enriched in the β4 interactome of male mice only, the presence of which may confer protection for males from the effects of β4OE. Moreover, we detail three pathways through which β4OE could reduce small spine density in female mice. These proposed pathways nominate kinases and MAPs in β4-related spine alterations. Overall, the findings described herein underscore the importance of evaluating the biological sex at baseline, over normal neurodevelopment and following a disease-related manipulation, particularly neurodevelopmental disorders, including Sz.
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| Item Type: |
University of Pittsburgh ETD
|
| Status: |
Unpublished |
| Creators/Authors: |
|
| ETD Committee: |
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| Date: |
30 December 2020 |
| Date Type: |
Publication |
| Defense Date: |
22 September 2020 |
| Approval Date: |
30 December 2020 |
| Submission Date: |
17 December 2020 |
| Access Restriction: |
No restriction; Release the ETD for access worldwide immediately. |
| Number of Pages: |
156 |
| Institution: |
University of Pittsburgh |
| Schools and Programs: |
School of Medicine > Neurobiology |
| Degree: |
PhD - Doctor of Philosophy |
| Thesis Type: |
Doctoral Dissertation |
| Refereed: |
Yes |
| Uncontrolled Keywords: |
schizophrenia, dendritic spines, neurodevelopment, sex differences |
| Date Deposited: |
30 Dec 2020 21:00 |
| Last Modified: |
30 Dec 2020 21:00 |
| URI: |
http://d-scholarship.pitt.edu/id/eprint/40108 |
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