Acute post-injury blockade of a2d-1 calcium channel subunits on pathological autonomic plasticity after T3 crush spinal cord injury in female mice

DOI:10.34945/F5V30C

DATASET CITATION

Brennan F. H., Noble B. T., Wang Y., Guan Z., Davis H., Mo X., Harris C., Eroglu C., Ferguson A. R., Popovich P. G. (2021) Acute post-injury blockade of a2d-1 calcium channel subunits on pathological autonomic plasticity after T3 crush spinal cord injury in female mice. Open Data Commons for Spinal Cord Injury. ODC-SCI: 555 http://doi.org/10.34945/F5V30C

ABSTRACT

STUDY PURPOSE: After a spinal cord injury (SCI), normally innocuous visceral or somatic stimuli can trigger uncontrolled reflex activation of sympathetic circuitry, causing pathological dysautonomia. Here, we tested the hypothesis that SCI causes remarkable structural remodeling and synaptic plasticity, creating abnormal spinal sympathetic reflexes that promote dysautonomia. We also tested whether treating mice with prophylactic gabapentin (GBP), an FDA-approved drug that inhibits a2d-1-mediated synaptogenesis in the brain, can prevent these pathologies.

DATA COLLECTED: The dataset includes n = 183 adult female mice on a C57BL/6J background and n=16 adult female mice on a 129SVE background with a2d-1 overexpression or wild type littermates. Mice received a T3 crush SCI or sham control surgery. Mice were injected subcutaneously 3x/d with GBP (66.7 mg/kg) or Saline from 1 day post-injury (dpi) until 28 or 35 days post-injury, and were perfused at 28, 35, 42, or 56 dpi. Additional mice were used for pharmacokinetic studies and time-course studies of anatomical reorganization (sham, 7 dpi, 14 dpi, 21 dpi, 28 dpi). Anatomical reorganization was assessed using Vglut2+ pre-synaptic puncta, Vglut2+Homer1+ excitatory synapse count, quantification of spinal PRV+ neurons that control lymphoid tissue, lumbar CGRP fiber sprouting, and FosB+ neuron counts. Dysautonomia was assessed using spleen weight, spleen B and T cell quantification, and spontaneous and induced autonomic dysreflexia experiments. Additional outcome measures include a2d-1+ cell number, percent a2d-1+ area, thrombospondin mRNA and protein levels, and principal component analysis results (spinal sympathetic reflex index).

DATA USAGE NOTES: We show that remarkable structural remodeling and synaptic plasticity occur within spinal autonomic circuitry after SCI, creating abnormal spinal sympathetic reflexes that promote dysautonomia. If SCI mice are treated with human equivalent doses of GBP, beginning at one day post-injury, well before the onset of post-injury plasticity and dysautonomia, both structural plasticity and pathological dysautonomia can be prevented. This prophylactic GBP regimen blocks multi-segmental excitatory synaptogenesis, and abolishes sprouting of autonomic neurons that innervate immune organs and sensory afferents that trigger pain and autonomic dysreflexia (AD). Prophylactic GBP decreases the frequency and severity of AD and protects against SCI-induced immune suppression. These benefits persist even one month after stopping GBP treatment. GBP could be repurposed to prevent dysautonomia in at-risk individuals with a high-level SCI.

KEYWORDS

Synaptogenesis, Spinal cord injury, Neuroplasticity, Autonomic Dysreflexia, Immunosuppression, Dysautonomia

PROVENANCE / ORIGINATING PUBLICATIONS

• Brennan FH, Noble BT, Wang Y, Guan Z, Davis H, Mo X, Harris C, Eroglu C, Ferguson AR, Popovich PG. Acute post-injury blockade of α2δ-1 calcium channel subunits prevents pathological autonomic plasticity after spinal cord injury. Cell Rep. 2021 Jan 26;34(4):108667. doi: 10.1016/j.celrep.2020.108667. PMID: 33503436; PMCID: PMC8817229.

DATASET INFO

Contact: Popovich Phillip (Phillip.Popovich@osumc.edu)

Lab: Phillip Popovich

ODC-SCI Accession:555

Records in Dataset: 199

Fields per Record: 85

Last updated: 2021-01-26

Date published: 2021-01-26

Downloads: 11

Files: 2

LICENSE

Creative Commons Attribution License (CC-BY 4.0)

FUNDING AND ACKNOWLEDGEMENTS

US Department of Defense (W81XWH-13-1-0358, PGP), Craig H. Neilsen Foundation (457267, FHB), Wings for Life (Harnessing microglia to improve neurological recovery, FHB), Wings for Life (Innate immune vaccination as a novel approach to promote recovery and prevent infection after spinal cord injury, PGP), The National Institutes of Health (R01NS099532, PGP), The National Institutes of Health (R01NS083942, PGP), The National Institutes of Health (R35NS111582, PGP), Ray W. Poppleton Endowment (PGP), The National Institutes of Health (P40OD010996, Center for Neuroanatomy with Neurotropic Viruses)

CONTRIBUTORS

Brennan, Faith H.. [ORCID:0000-0002-9201-2476]

Department of Neuroscience, Center for Brain and Spinal Cord Repair, Belford Center for Spinal Cord Injury, The Ohio State University Wexner Medical,Columbus, OH 43210

Noble, Benjamin T.. [ORCID:0000-0002-8992-2479]

Department of Neuroscience, Center for Brain and Spinal Cord Repair, Belford Center for Spinal Cord Injury, The Ohio State University Wexner Medical,Columbus, OH 43210

Wang, Yan [ORCID:0000-0002-1540-1179]

Department of Neuroscience, Center for Brain and Spinal Cord Repair, Belford Center for Spinal Cord Injury, The Ohio State University Wexner Medical,Columbus, OH 43210

Guan, Zhen

Department of Neuroscience, Center for Brain and Spinal Cord Repair, Belford Center for Spinal Cord Injury, The Ohio State University Wexner Medical Center, Columbus, OH 43210

Davis, Hayes

Department of Neuroscience, Center for Brain and Spinal Cord Repair, Belford Center for Spinal Cord Injury, The Ohio State University Wexner Medical Center, Columbus, OH 43210

Mo, Xiaokui [ORCID:0000-0002-9797-2687]

Center for Biomedical Informatics, The Ohio State University, Columbus, OH 43210

Harris, Clay

Department of Chemistry and Biochemistry, The Ohio State University, Columbus, OH 43210

Eroglu, Cagla [ORCID:0000-0002-7204-0218]

Department of Cell Biology, Duke University Medical Center and Duke Institute for Brain Sciences; Durham, NC 27710

Ferguson, Adam R.. [ORCID:ORCID:0000-0001-7102-1608]

Brain and Spinal Injury Center (BASIC), Department of Neurological Surgery, Weill Institute for Neurosciences, University of California San Francisco (UCSF), CA, 94142; San Francisco Veterans Affairs Healthcare System (SFVAHCS)

Popovich, Phillip G.. [ORCID:ORCID:0000-0003-1329-7395]

Department of Neuroscience, Center for Brain and Spinal Cord Repair, Belford Center for Spinal Cord Injury, The Ohio State University Wexner Medical Center, Columbus, OH 43210