Glutamatergic signaling after rachimedullary trauma: role of glial cells in the inflammatory response and excitotoxicity

• Grant number: 22/06609-6
• Support Opportunities: Generation Project Research Grant
• Start date: August 01, 2023
• End date: July 31, 2028
• Field of knowledge: Biological Sciences - Morphology - Anatomy
• Principal Investigator: Luciana Politti Cartarozzi
• Grantee: Luciana Politti Cartarozzi
• Host Institution: Instituto de Biologia (IB). Universidade Estadual de Campinas (UNICAMP). Campinas , SP, Brazil
• City of the host institution: Campinas
• Associated researchers: Alexandre Leite Rodrigues de Oliveira ; Alline Cristina de Campos ; Frank Kirchhoff ; Xianshu Bai
• Associated research grant(s): 24/02746-4 - Conditional depletion of AMPA receptor subunits (GluA1 and GluA4) in spinal cord astrocytes and the impact after proximal axotomy, AP.R SPRINT
• Associated scholarship(s): 25/16144-9 - Cortical repercussions of proximal axotomy of spinal motoneurons: focus on the glial response, BP.IC; 25/13906-5 - Neuroprotection and Immunomodulation by Demeclocycline (DMC) and Its Doubly Reduced Derivative (DDMC) on Neuronal Survival and Glial Reactivity Following Neonatal Peripheral Axotomy, BP.MS; 24/09098-8 - Modulation of glutamatergic signaling after proximal axotomy: glial response and neuroprotective potential, BP.DR; 24/01736-5 - Microglial response and synaptic plasticity after proximal axotomy and treatment with memantine, BP.IC; 23/12189-2 - Glutamatergic signaling after rachimedullary trauma: role of glial cells in the inflammatory response and excitotoxicity, BP.GR

Abstract

Proximal axotomies are especially severe, leading to up to 50% motoneuron degeneration in the first few weeks, in the case of ventral root crush (VRC). Microglia are the first cells to respond to injury with activation and migration towards the injured motoneurons. Astrocytes also respond through morphofunctional changes, collectively called reactive astrogliosis. Recent evidence indicates that glutamatergic signaling, via AMPA-type receptors, may be related to neuroprotective effects after rachimedulary injuries. Therefore, the present project aims to understand the signaling mechanisms between the injured motoneuron, via AMPA receptors, after the murine model of VRC, and the surrounding glia. To this end, initially a temporal study of the expression of AMPA receptors in glial cells will be carried out (by immunohistochemistry), which will be correlated with the curve of motoneurons loss (by Nissl-staining). Next, the pharmacological blockade of AMPA receptors will be performed after VRC, for a comparative study of glial reaction and neuronal survival. Furthermore, we will study how a known neuroprotective treatment, the cannabidiol, modulates the glial expression of AMPA receptors, and correlate with the results obtained previously. To specifically study the role of astrocytic AMPA receptors in the context of neuronal injury and death, conditional knockout animals (cKO, GFAP-CreERT2::GluA1fl/fl::GluA4fl/fl::R26-tdT) will be used. All animals will undergo motor function recovery analysis through the Catwalk system, as well as electrophysiological analysis to assess muscle reinnervation. Finally, in collaboration with researchers from the Saarland University, Germany, we will study in vivo, through two-photon laser microscopy (2P-LSM), the morphofunctional changes in glial cells after injury, using the cko and transgenic animals expressing fluorescent proteins in specific cell types, as well as the pattern of generation and propagation of calcium waves in astrocytes, through the specific expression of the GCaMP3 reporter. (AU)

Scientific publications

(References retrieved automatically from Web of Science and SciELO through information on FAPESP grants and their corresponding numbers as mentioned in the publications by the authors)

NATALIA SCANAVACHIA DA SILVA; JULIA LOMBARDI; FRANK KIRCHHOFF; RUI SEABRA FERREIRA JR.; BENEDITO BARRAVIERA; ALEXANDRE LEITE RODRIGUES DE OLIVEIRA; LUCIANA POLITTI CARTAROZZI. Effects of local and systemic treatment with human natural killer-1 mimetic peptide (HNK-1) after ventral root avulsion and reimplantation in mice. Journal of Venomous Animals and Toxins including Tropical Diseases, v. 30, 2024-05-20. (21/11936-3, 20/01215-4, 22/06609-6, 18/05006-0)

CARTAROZZI, LUCIANA POLITTI; LIMA, BRUNO HENRIQUE DE MELO; TOMIYAMA, ANA LAURA ROSSI MIDORI; SANTOS, FELIPE RABELO; DE OLIVEIRA, ALEXANDRE LEITE RODRIGUES. Toll-like receptors 2 and 4 influence neuronal survival and glial reactions following ventral root crush injury in mice. Journal of Neuroimmunology, v. 406, p. 15-pg., 2025-09-15. (22/06609-6, 19/02714-7, 18/05006-0, 23/02615-4)

PEREZ, MATHEUS; SPEJO, ALINE BARROSO; CHIAROTTO, GABRIELA BORTOLANCA; GUIMARAES, FRANCISCO SILVEIRA; DE OLIVEIRA, ALEXANDRE LEITE RODRIGUES; CARTAROZZI, LUCIANA POLITTI. Selective blockade of cannabinoid receptors influences motoneuron survival and glial responses after neonatal axotomy. Neuroscience, v. 565, p. 12-pg., 2024-12-10. (22/06609-6, 18/05006-0)