Dissertation
Investigating how the chemokine CXCL12 impacts neuronal network function and structural plasticity: the modulatory role of inhibitory neurons
Doctor of Philosophy (Ph.D.), Drexel University
Apr 2023
DOI:
https://doi.org/10.17918/00001640
Abstract
The chemokine CXCL12 and its receptors, CXCR4 and ACKR3, have important roles in the central nervous system, including attracting immune cells, regulating neurogenesis, and modulating structural plasticity. In an animal model of HIV-associated neurocognitive disorders, CXCL12 rescued dendritic spine and cognitive flexibility deficits. Mechanistically, this effect required the Rac1/PAK/Cofilin pathway that is crucial for the structural modification and formation of new dendritic spines. This implicated structural plasticity as a key bottleneck to rescue behavior deficits. However, the specific target cell populations that mediated CXCL12's effect on spines and functional consequences at the network level are not fully understood. This study used genetic targeting, gene expression, and electrophysiology techniques to investigate the cellular mechanisms underlying CXCL12's effect on dendritic spines and cortical network function, with a focus on CXCR4 - its main signaling receptor. The findings suggest that inhibitory neurons are the primary cellular target of CXCL12 in neuron-glia mixed cultures and the prefrontal cortex. Manipulating CXCR4 protein levels in inhibitory neurons changes the established structural plasticity response mediated by CXCL12. Additionally, CXCR4 and ACKR3 likely work in parallel to impact synchronous network function through modulation of network burst duration, the average number of spikes in synchronous network bursts, and the average spike frequency in network bursts. These results suggest inhibitory neuron CXCL12/CXCR4 signaling is a modulator of dendritic spines and highlight the supportive functional roles of ACKR3 in cortical networks. While challenging to investigate, the complexity of this chemokine system may create opportunity for potential therapeutic intervention that was previously problematic considering CXCR4 alone.
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Details
- Title
- Investigating how the chemokine CXCL12 impacts neuronal network function and structural plasticity
- Creators
- Jared Joseph Luchetta
- Contributors
- Olimpia Meucci (Advisor)Seena Ajit (Advisor)
- Awarding Institution
- Drexel University
- Degree Awarded
- Doctor of Philosophy (Ph.D.)
- Publisher
- Drexel University; Philadelphia, Pennsylvania
- Number of pages
- xi, 144 pages
- Resource Type
- Dissertation
- Language
- English
- Academic Unit
- College of Medicine; Pharmacology and Physiology; Drexel University
- Other Identifier
- 991020668711004721