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NLRP3 Deficiency Attenuates Secondary Degeneration of Visual Cortical Neurons Following Optic Nerve Injury.

ABSTRACT: In the visual pathway, optic nerve (ON) injury may cause secondary degeneration of neurons in distal regions, such as the visual cortex. However, the role of the neuroinflammatory response in regulating secondary impairment in the visual cortex after ON injury remains unclear. The NOD-like receptor family pyrin domain containing 3 (NLRP3) is an important regulator of neuroinflammation. In this study, we established a mouse model of unilateral ON crush (ONC) and showed that the expression of NLRP3 was significantly increased in the primary visual cortex (V1) as a response to ONC and that the NLRP3 inflammasome was activated in the contralateral V1 1 days-14 days after ONC. Ablation of the NLRP3 gene significantly decreased the trans-neuronal degeneration within 14 days. Visual electrophysiological function was improved in NLRP3^-/- mice. Taken together, these findings suggest that NLRP3 is a potential therapeutic target for protecting visual cortical neurons against degeneration after ON injury.

SUBMITTER: Zhang Z

PROVIDER: S-EPMC7056795 | biostudies-literature | 2020 Mar

REPOSITORIES: biostudies-literature

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NLRP3 Deficiency Attenuates Secondary Degeneration of Visual Cortical Neurons Following Optic Nerve Injury.

Zhang Zhou Z Liu Wenyi W Huang Yubin Y Luo Linlin L Cai Xiaofeng X Liu Yunjia Y Ai Liqianyu L Yan Jun J Lin Sen S Ye Jian J

Neuroscience bulletin 20191126 3

In the visual pathway, optic nerve (ON) injury may cause secondary degeneration of neurons in distal regions, such as the visual cortex. However, the role of the neuroinflammatory response in regulating secondary impairment in the visual cortex after ON injury remains unclear. The NOD-like receptor family pyrin domain containing 3 (NLRP3) is an important regulator of neuroinflammation. In this study, we established a mouse model of unilateral ON crush (ONC) and showed that the expression of NLRP ...[more]

PMID: 31768783

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Project description:PurposeTo investigate anterograde degenerative changes along the visual pathway in a rat model of optic nerve axotomy.MethodsOptic nerve transection was performed in adult Sprague-Dawley rats. Animals were sacrificed at regular time intervals and tissues harvested. Immunoblotting followed by densitometric analysis was used to determine the phosphorylation profile of Akt in the dorsal lateral geniculate nucleus (dLGN) and the primary visual cortex (V1). The neuronal cell size and cell density were measured in the dLGN and the V1 using Nissl staining. The prevalence of apoptosis was characterized by terminal deoxynucleotidyl-transferase-mediated biotin-dUTP nick end labelling (TUNEL) histochemistry. Caspase-3 antibodies were also used to identify apoptotic cells. Neurons and astrocytes were detected using NeuN and glial fibrillary acidic protein (GFAP), respectively.ResultsAn early and sustained loss of Akt phosphorylation was observed after optic nerve transection in both dLGN and V1. At week one, a decrease in the neuronal cell size (50.5±4.9 vs 60.3±5.0 µm(2), P = 0.042) and an increase of TUNEL positive cells (7.9±0.6 vs 1.4±0.5 ×10(2) cells/mm(2), P<0.001) were evident in the dLGN but not in V1. A significant decline in neuronal cell number (14.5±0.1 vs 17.4±1.3 ×10(2) cells/mm(2), P = 0.048), cell size (42.5±4.3 vs 62.1±4.7 µm(2), P = 0.001) and an increase in apoptotic cells (5.6±0.5 vs 2.0±0.4 ×10(2) cells/mm(2), P<0.001) appeared in V1 initially at one month post-transection. The changes in the visual pathway continued through two months. Both neuronal cells and GFAP-positive glial cells were affected in this anterograde degeneration along the visual pathway.ConclusionsAnterograde degeneration along the visual pathway takes place in target relay (LGN) and visual cortex following the optic nerve injury. Apoptosis was observed in both neural and adjacent glial cells. Reduction of Akt phosphorylation preceded cellular and apoptotic changes.

Project description:Partial transection (PT) of the optic nerve is an established experimental model of secondary degeneration in the central nervous system. After a dorsal transection, retinal ganglion cells (RGCs) with axons in ventral optic nerve are intact but vulnerable to secondary degeneration, whereas RGCs in dorsal retina with dorsal axons are affected by primary and secondary injuries. Using microarray, we quantified gene expression changes in dorsal and ventral retina at 1 and 7 days post PT, to characterize pathogenic pathways linked to primary and secondary degeneration.In comparison to uninjured retina Cryba1, Cryba2 and Crygs, were significantly downregulated in injured dorsal retina at days 1 and 7. While Ecel1, Timp1, Mt2A and CD74, which are associated with reducing excitotoxicity, oxidative stress and inflammation, were significantly upregulated. Genes associated with oxygen binding pathways, immune responses, cytokine receptor activity and apoptosis were enriched in dorsal retina at day 1 after PT. Oxygen binding and apoptosis remained enriched at day 7, as were pathways involved in extracellular matrix modification. Fewer changes were observed in ventral retina at day 1 after PT, most associated with the regulation of protein homodimerization activity. By day 7, apoptosis, matrix organization and signal transduction pathways were enriched. Discriminant analysis was also performed for specific functional gene groups to compare expression intensities at each time point. Altered expression of selected genes (ATF3, GFAP, Ecel1, TIMP1, Tp53) and proteins (GFAP, ECEL1 and ATF3) were semi-quantitatively assessed by qRT-PCR and immunohistochemistry respectively.There was an acute and complex primary injury response in dorsal retina indicative of a dynamic interaction between neuroprotective and neurodegenerative events; ventral retina vulnerable to secondary degeneration showed a delayed injury response. Both primary and secondary injury resulted in the upregulation of numerous genes linked to RGC death, but differences in the nature of these changes strongly suggest that death occurred via different molecular mechanisms.

Dataset Information

NLRP3 Deficiency Attenuates Secondary Degeneration of Visual Cortical Neurons Following Optic Nerve Injury.

Publications

NLRP3 Deficiency Attenuates Secondary Degeneration of Visual Cortical Neurons Following Optic Nerve Injury.

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