Targeting astrocytic TDAG8 with delayed CO2 postconditioning improves functional outcomes after controlled cortical impact injury in mice.
Exp Neurol
; 380: 114892, 2024 Oct.
Article
em En
| MEDLINE
| ID: mdl-39047809
ABSTRACT
T-cell death-associated gene 8 (TDAG8), a G-protein-coupled receptor sensing physiological or weak acids, regulates inflammatory responses. However, its role in traumatic brain injury (TBI) remains unknown. Our recent study showed that delayed CO2 postconditioning (DCPC) has neuroreparative effects after TBI. We hypothesized that activating astrocytic TDAG8 is a key mechanism for DCPC. WT and TDAG8-/- mice received DCPC daily by transiently inhaling 10% CO2 after controlled cortical impact (CCI). HBAAV2/9-GFAP-m-TDAG8-3xflag-EGFP was used to overexpress TDAG8 in astrocytes. The beam walking test, mNSS, immunofluorescence and Golgi-Cox staining were used to evaluate motor function, glial activation and dendritic plasticity. DCPC significantly improved motor function; increased total dendritic length, neuronal complexity and spine density; inhibited overactivation of astrocytes and microglia; and promoted the expression of astrocytic brain-derived neurotrophic factor in WT but not TDAG8-/- mice. Overexpressing TDAG8 in astrocytes surrounding the lesion in TDAG8-/- mice restored the beneficial effects of DCPC. Although the effects of DCPC on Days 14-28 were much weaker than those of DCPC on Days 3-28 in WT mice, these effects were further enhanced by overexpressing astrocytic TDAG8. Astrocytic TDAG8 is a key target of DCPC for TBI rehabilitation. Its overexpression is a strategy that broadens the therapeutic window and enhances the effects of DCPC.
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Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Dióxido de Carbono
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Astrócitos
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Lesões Encefálicas Traumáticas
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Camundongos Endogâmicos C57BL
Limite:
Animals
Idioma:
En
Ano de publicação:
2024
Tipo de documento:
Article