Svirsky, Sarah
(2024)
The Role of Neurogranin in Synaptic Dysfunction after Experimental Traumatic Brain Injury.
Doctoral Dissertation, University of Pittsburgh.
(Unpublished)
Abstract
Traumatic brain injury (TBI) is known to cause short- and long-term synaptic changes in the brain, possibly underlying downstream cognitive impairments. Neurogranin (Ng) is a calcium-sensitive calmodulin (CaM)-binding protein essential for Ca2+/CaM-dependent kinase II (CaMKII) autophosphorylation (P-CaMKII) which modulates synaptic plasticity and is crucial to normal cognitive function. The overall hypothesis is that decreased Ng expression contributes to dysfunctional synaptic plasticity and associated anatomical and behavioral metrics after TBI. Therefore, increasing Ng expression after TBI will improve post-synaptic signaling and functional outcomes. We found that controlled cortical impact (CCI) lowers Ng expression with temporal and regional specificity and this occurs independently of post-synaptic loss. There were significant injury and sex-dependent alterations in the hippocampal synaptic expression of Ng and associated synaptic proteins such as phosphorylated Ng, CaMKII, P-CaMKII, and CaM up to 4 weeks post-CCI, demonstrating TBI alters hippocampal post-synaptic signaling. To investigate Ng’s role in the observed synaptic pathology, an adeno-associated viral vector (AAV) was developed to selectively increase hippocampal Ng expression by the 4-week time-point after CCI. We demonstrated that although there are limited effects of increasing Ng expression on downstream signaling protein expression, distinct, TBI-dependent effects on synaptic plasticity proteins were observed. Assessment of spatial learning and memory, as well as CA1 dendritic spine density and morphology, 4 weeks-post-injury also revealed a TBI-dependent effect of increased Ng. Although increasing Ng expression had limited effects on motor and cognitive behaviors, increased Ng demonstrated a TBI-dependent effect on the density of distinct hippocampal CA1 dendritic spine morphological sub-types. Finally, all-trans Retinoic Acid (ATRA) has been identified as a potential pharmacotherapeutic for increasing expression of synaptic plasticity proteins, such as Ng, and improving hippocampal learning and memory. ATRA treatment significantly recovered Ng synaptic protein expression 2 weeks after CCI. There was a limited therapeutic effect of daily ATRA treatment on motor and learning and memory outcomes. This study was also examined the effect of experimental TBI on RA signaling proteins, of which expression was unchanged 2 weeks after CCI. Altogether, this study was the first to investigate the role of Ng in hippocampal synaptic deficits in an experimental TBI model and furthered the field’s understanding of molecular mechanisms of cognitive dysfunction.
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| Item Type: |
University of Pittsburgh ETD
|
| Status: |
Unpublished |
| Creators/Authors: |
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| ETD Committee: |
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| Date: |
16 September 2024 |
| Date Type: |
Publication |
| Defense Date: |
4 December 2023 |
| Approval Date: |
16 September 2024 |
| Submission Date: |
15 December 2023 |
| Access Restriction: |
1 year -- Restrict access to University of Pittsburgh for a period of 1 year. |
| Number of Pages: |
235 |
| Institution: |
University of Pittsburgh |
| Schools and Programs: |
School of Medicine > Neurobiology |
| Degree: |
PhD - Doctor of Philosophy |
| Thesis Type: |
Doctoral Dissertation |
| Refereed: |
Yes |
| Uncontrolled Keywords: |
traumatic brain injury, controlled cortical impact, hippocampus, synapse, neurogranin, adeno-associated virus, learning and memory |
| Date Deposited: |
16 Sep 2024 18:55 |
| Last Modified: |
16 Sep 2024 18:55 |
| URI: |
http://d-scholarship.pitt.edu/id/eprint/45712 |
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