Files and links (1)
PDFOpen Access (License Unspecified), Open Access
Dissertation
Neuroprotective actions of the chemokine CXCL12: role of histone modifying enzymes (HDAC), dendritic spines and NMDA receptors
Doctor of Philosophy (Ph.D.), Drexel University
Oct 2010
DOI:
https://doi.org/10.17918/00009045
Abstract
Chemokines are cellular mediators known for their role in immune/inflammatory responses - traditionally, yet simplistically, associated to neuronal damage. However, recent research has not only provided evidence about the beneficial nature of a controlled immune/inflammatory response in the central nervous system (CNS), but also suggested novel protective effects of a few chemokines (and their receptors) that are constitutively expressed in the CNS, namely CXCL12 and its receptor CXCR4. This chemokine/receptor pair is essential to brain development and involved in neuronal-glia communication. Thus, proper function of the CXCL12/CXCR4 axis is of utmost importance at all stages of life and its alterations are thought to contribute to different neuropathologies, including neuroAIDS. To date, the mechanisms implicated in the distinct physiologic and pathologic effects of CXCL12/CXCR4 are not entirely understood. This study focuses on the neuroprotective actions of CXCL12/CXCR4 in central neurons with a primary interest on molecular mechanisms that support survival and function of differentiated neurons. Our previous studies show that CXCL12 protects cultured neurons from NMDA-induced excitotoxicity by up-regulating the gene repressor protein Rb. Rb is involved in recruitment of chromatin modifiers, such as histone deacetylase (HDAC), to gene promoters. In neurons, the Rb/HDAC repression complex controls activity-dependent genes, such as NMDA receptor's subunit NR2B. Considering the reported role of NR2B in excitotoxicity and synaptic activity, we hypothesized that CXCL12 regulates NR2B expression in neurons. The results presented in this thesis show that CXCL12 selectively inhibits NR2B expression in vitro and in vivo altering NMDA-induced calcium responses associated with neuronal death while promoting pro-survival pathways associated with synaptic receptor activation. Importantly, CXCL12 regulates the NR2B subunit through an HDAC dependent mechanism. Further investigation into HDAC regulation indicates that CXCL12 modulates specific HDAC isoforms leading to multiple outcomes on neurons while CXCL12-induced inhibition of NR2B expression can result from HDAC1 recruitment via Rb, the chemokine controls dendritic spines density through a more direct regulation of HDAC4. These novel effects of CXCL12 may both contribute to neuroprotection and synaptic plasticity in the mature brain and suggest important clinical implications related to the therapeutic use and side effects of NMDA receptor antagonists and HDAC inhibitors.
Metrics
19 File views/ downloads
13 Record Views
Details
- Title
- Neuroprotective actions of the chemokine CXCL12
- Creators
- Jaclyn Nicolai
- Contributors
- Alessandro Fatatis (Advisor) - Drexel University, Drexel University (1970-)Olimpia Meucci (Advisor) - Drexel University, Drexel University (1970-)
- Awarding Institution
- Drexel University
- Degree Awarded
- Doctor of Philosophy (Ph.D.)
- Publisher
- Drexel University; Philadelphia, Pennsylvania
- Number of pages
- xiv, 177 pages
- Resource Type
- Dissertation
- Language
- English
- Academic Unit
- Drexel University
- Other Identifier
- 991021888994204721