Logo image
Back
Defining the molecular pathways involved in CXCL12-mediated rescue of dendritic spines and cognitive deficits in an animal model of neuroHIV
Dissertation   Open access

Defining the molecular pathways involved in CXCL12-mediated rescue of dendritic spines and cognitive deficits in an animal model of neuroHIV

Lindsay Kathryne Festa
Doctor of Philosophy (Ph.D.), Drexel University
Apr 2018
DOI:
https://doi.org/10.17918/D8BH3T
pdf
Festa_Lindsay_20184.80 MBDownloadView
PDF Open Access Open Access (License Unspecified)

Abstract

Adaptation (Biology) Chemokines Dendritic cells Pharmacology Physiology
Despite the introduction of antiretroviral therapy (ART), approximately 50% of HIV+ patients still experience some degree of neurological dysfunction. The loss of dendritic spines, the main sites of excitatory input on neurons, is a pathological hallmark of HIV-associated neurocognitive disorders (HAND). The chemokine-receptor pair, CXCL12/CXCR4, is essential for numerous homeostatic processes in the CNS, including neurotransmission, pro-survival signaling, and neuronal-glial interactions. Recently, our laboratory demonstrated that CXCL12 increases dendritic spine number on cortical neurons, though the mechanism modulating this effect is not known. Since CXCL12/CXCR4 signaling plays a critical role in maintaining homeostasis in the CNS and this chemokine-receptor pair is known to be dysfunctional during HAND, restoration of this signaling axis may ameliorate cognitive deficits in HIV+ individuals. Our mechanistic studies in cultured primary rat cortical neurons revealed that CXCL12 depends on the activation of Rac1 and its downstream mediators (PAK1, LIMK1, SSH1, and cofilin) to modulate dendritic spine density. Furthermore, exposure to CXCL12 resulted in functional changes in actin polymerization as assessed by the F-actin to G-actin ratio. CXCL12 upregulated spine number through a specific increase in thin spines, which are associated with learning and plasticity. We extended these mechanistic studies to intact wild-type (WT) animals and showed that exogenous CXCL12 treatment can alter dendritic spine density and morphology in the medial prefrontal cortex (mPFC) in layer II/III pyramidal neurons; this effect, as observed in vitro, depended on Rac1 activation. The therapeutic potential of restoring or enhancing CXCL12/CXCR4 signaling has not been previously explored. We first demonstrated that HIV-Tg rats, a rodent model of neuroinflammation and HAND, are specifically deficient in attentional set-shifting and this was associated with a reduction in dendritic spine density in layer II/III pyramidal neurons. Once a day intracebroventricular (ICV) administration of CXCL12 completely rescued dendritic spine loss and cognitive dysfunction in HIV-Tg rats. As seen in WT rats, the chemokine specifically increased the number of thin dendritic spines in layer II/III pyramidal neurons of the mPFC. In the same animals, the upregulation of spine density was significantly correlated with an improvement in cognitive flexibility, a task mediated exclusively by the mPFC. Therefore, exogenous CXCL12 completely restored both structural and functional deficits in the HIV-Tg rat, even after dysfunction was already present. Overall, these data suggest that targeting neuronal CXCL12/CXCR4 signaling may represent a valid strategy for neurorestorative therapies for HAND and other diseases characterized by spine loss, such as schizophrenia and Alzheimer's disease.

Metrics

56 File views/ downloads
21 Record Views

Details

Logo image