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Dissertation
Effects of the chemokine CXCL12 on dendritic spine dynamics: implication for cognitive improvement
Doctor of Philosophy (Ph.D.), Drexel University
May 2024
DOI:
https://doi.org/10.17918/00010588
Abstract
Dendritic spines are structural substrates for learning and memory and their pruning is associated with cognitive decline in conditions like Alzheimer's Disease and HIV-associated neurocognitive disorders (HAND). Our past studies in a rodent model of HAND (HIV-transgenic rat, HIV-Tg) revealed that dendritic spine loss and related cognitive deficits can be rescued by treatment with the chemokine CXCL12. This requires activation of the chemokine receptor CXCR4 and its downstream Rac1/PAK signaling, which regulates actin polymerization in spines. Similarly, our studies in primary cortical cultures showed that CXCL12 increases spine density through this pathway. However, it remains to be established whether the effect of CXCL12 on spine density results from changes in spine dynamics (formation, elimination, clustering) and/or maturation, and how this ultimately relates to cognitive function. Here, we used a combination of live cell imaging and computational studies on archived brain tissue from animals that underwent cognitive tests to investigate spine turnover, maturation, and clustering during or after CXCL12 treatments. Live cell imaging studies in rat cortical cultures show that CXCL12 increases spine density in a time dependent manner (with a peak effect after 2.5 hours). This effect is primarily due to enhanced spine formation (no changes in spine elimination were detected) and is blocked by the pharmacologic treatment with a CXCR4 antagonist. Next, we examined the expression and distribution of markers of mature spines. CXCL12 consistently increased the density of postsynaptic density protein 95 (PSD-95) in thin spines and the overall spine density, with similar increases in phosphorylated PSD-95Ser295 and GluA1. Concurrently, by labeling endogenous PSD-95, we observed that the synaptic puncta of PSD-95 were larger in the CXCL12 group than in the control group, suggesting CXCL12 promoted spine stabilization. Finally, we evaluated CXCL12's effect on spine clustering both in vitro and in medial prefrontal cortex (mPFC) pyramidal neurons of wild-type and HIV-Tg rats. Clustering was assessed using interspine distance and the nearest neighbor index, which quantifies the deviation of observed interspine distances from a random distribution. CXCL12-treated HIV-Tg rats had a significantly shorter interspine distance and decreased index compared to untreated HIV-Tg controls. We observed similar results in thin spines of CXCL12-treated cultures. These results suggest that CXCL12 likely induces spine clustering. Overall, our findings suggest that CXCL12 regulates multiple components of spine dynamics that favor a more efficient and robust network. Ongoing studies in live brain tissue aim to validate these conclusions and clarify the structural and functional basis of CXCL12-induced cognitive performance in HAND.
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Details
- Title
- Effects of the chemokine CXCL12 on dendritic spine dynamics
- Creators
- Chunta Ho
- Contributors
- Olimpia Meucci (Advisor)
- Awarding Institution
- Drexel University
- Degree Awarded
- Doctor of Philosophy (Ph.D.)
- Publisher
- Drexel University; Philadelphia, Pennsylvania
- Number of pages
- xi, 178 pages
- Resource Type
- Dissertation
- Language
- English
- Academic Unit
- College of Medicine; Pharmacology and Physiology; Drexel University
- Other Identifier
- 991021901610804721