Journal article
CXCL12 Engages Cortical Inhibitory Neurons to Enhance Dendritic Spine Plasticity and Structured Network Activity
The Journal of neuroscience, v 45(24), pe2213242025
11 Jun 2025
PMID: 40335156
Featured in Collection : UN Sustainable Development Goals @ Drexel
Abstract
The chemokine CXCL12 is a highly conserved peptide that regulates homeostatic processes in the brain throughout life. Recent work shows that CXCL12 increases dendritic spine density in cortical neurons, which requires activation of CXCL12's receptor CXCR4. This same pathway reverses cortical dendritic spine deficits and cognitive impairment in an animal model of neuroHIV. However, it remained unclear if CXCL12 simply preserved existing spines or also engaged spine plasticity processes that drove network-level adaptations. We therefore tested if CXCL12 could regulate dendritic spine turnover, maturation, clustering, and neuronal network activity in primary rat cortical neurons of either sex using live-cell imaging, confocal microscopy, and multielectrode arrays. Intriguingly, CXCL12-treated neurons formed significantly more new spines than controls, and this outcome was blocked by the CXCR4 antagonist AMD3100. CXCL12 also increased the density of thin spines expressing postsynaptic markers, including postsynaptic density protein 95 (PSD-95), phospho-PSD-95
, and GluA1, and allowed neurons to better maintain synaptic PSD-95 puncta size. Thin spines were modestly closer together after CXCL12 treatment, suggesting a possible effect on anatomical spine clustering. These effects translated to structured network activity, as CXCL12 increased spike frequency within network bursts in multielectrode array cultures. Finally, a targeted knockdown of CXCR4 in inhibitory neurons, which mostly lack dendritic spines, prevented CXCL12 from increasing spine density on excitatory neurons. Overall, our findings suggest CXCL12/CXCR4 signaling engages inhibitory neurons along with multiple aspects of spine dynamics and remodeling to shape how broader neuronal networks function.
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Details
- Title
- CXCL12 Engages Cortical Inhibitory Neurons to Enhance Dendritic Spine Plasticity and Structured Network Activity
- Creators
- Chunta Ho - Drexel University, Pharmacology and PhysiologyJared Luchetta - Center for Neuroimmunology and CNS Therapeutics, Institute for Molecular Medicine and Infectious Disease, Drexel University College of Medicine, Philadelphia, Pennsylvania 19102Bradley Nash - Drexel University, Pharmacology and PhysiologyLindsay K Festa - University of PennsylvaniaJames A Johnson - Drexel University, Pharmacology and PhysiologyAhmet Sacan - Drexel University, School of Biomedical Engineering, Science, and Health SystemsJoshua G Jackson - Drexel University, Pharmacology and PhysiologyAntonio Sanz-Clemente - Drexel University, Pharmacology and PhysiologyRenato Brandimarti - Drexel University, Biochemistry and Molecular BiologyOlimpia Meucci - Drexel University, Pharmacology and Physiology
- Publication Details
- The Journal of neuroscience, v 45(24), pe2213242025
- Publisher
- JNeurosci
- Grant note
- R01 DA015014 / NIDA NIH HHS R01 AG069266 / NIA NIH HHS R01 DA032444 / NIDA NIH HHS T32 MH079785 / NIMH NIH HHS
- Resource Type
- Journal article
- Language
- English
- Academic Unit
- Pharmacology and Physiology
- Web of Science ID
- WOS:001512557300010
- Scopus ID
- 2-s2.0-105008034384
- Other Identifier
- 991022051420104721
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- Collaboration types
- Domestic collaboration
- International collaboration
- Web of Science research areas
- Neurosciences