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Proteolytic fragments of laminin promote excitotoxic neurodegeneration by up-regulation of the KA1 subunit of the kainate receptor.

Chen ZL, Yu H, Yu WM, Pawlak R, Strickland S - J. Cell Biol. (2008)

Bottom Line: Degradation of the extracellular matrix (ECM) protein laminin contributes to excitotoxic cell death in the hippocampus, but the mechanism of this effect is unknown.Interfering with KA1 function with a specific anti-KA1 antibody protected against KA-induced neuronal death both in vitro and in vivo.These results demonstrate a novel pathway for neurodegeneration involving proteolysis of the ECM and KA1 KA receptor subunit up-regulation.

View Article: PubMed Central - PubMed

Affiliation: Laboratory of Neurobiology and Genetics, The Rockefeller University, New York, NY 10065, USA.

ABSTRACT
Degradation of the extracellular matrix (ECM) protein laminin contributes to excitotoxic cell death in the hippocampus, but the mechanism of this effect is unknown. To study this process, we disrupted laminin gamma1 (lamgamma1) expression in the hippocampus. Lamgamma1 knockout (KO) and control mice had similar basal expression of kainate (KA) receptors, but the lamgamma1 KO mice were resistant to KA-induced neuronal death. After KA injection, KA1 subunit levels increased in control mice but were unchanged in lamgamma1 KO mice. KA1 levels in tissue plasminogen activator (tPA)-KO mice were also unchanged after KA, indicating that both tPA and laminin were necessary for KA1 up-regulation after KA injection. Infusion of plasmin-digested laminin-1 into the hippocampus of lamgamma1 or tPA KO mice restored KA1 up-regulation and KA-induced neuronal degeneration. Interfering with KA1 function with a specific anti-KA1 antibody protected against KA-induced neuronal death both in vitro and in vivo. These results demonstrate a novel pathway for neurodegeneration involving proteolysis of the ECM and KA1 KA receptor subunit up-regulation.

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KA specifically up-regulates the KA1 subunit of the KA receptor in the hippocampus in control but not in lamγ1 KO mice. (A) After KA injection, only the KA1 subunit was significantly higher in the hippocampus of control (Con) mice compared with PBS-injected control mice and lamγ1 KO mice injected with PBS or KA. All other subunits' expression levels remained similar between PBS- or KA-injected control and KO mice. Quantitative analyses were performed by one-way ANOVA and are shown as bar graphs (n = 7 per group for each experiment; Western blot signal intensities were normalized to actin). (B) Immunohistochemistry of KA1 subunit in PBS- or KA-injected control and lamγ1 KO mice. (a and b) In PBS-injected control mice, KA1 was expressed in the CA1 and CA3 regions but was not detected in the DG. (c and d) However, 2 h after KA injection, KA1 expression was dramatically increased in the CA1 region. KA1 expression in CA3 and mossy fiber pathway was slightly decreased (arrows), which may suggest early neuronal damage. (e–h) In lamγ1 KO mice, the expression levels of KA1 between PBS- and KA-injected mice were similar. Higher magnification of boxed areas in a, c, e, and g are shown in b, d, f, and h, respectively. Error bars indicate SEM. Bars: (a, c, e, and g) 0.5 mm; (b, d, f, and h) 20 μm.
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fig4: KA specifically up-regulates the KA1 subunit of the KA receptor in the hippocampus in control but not in lamγ1 KO mice. (A) After KA injection, only the KA1 subunit was significantly higher in the hippocampus of control (Con) mice compared with PBS-injected control mice and lamγ1 KO mice injected with PBS or KA. All other subunits' expression levels remained similar between PBS- or KA-injected control and KO mice. Quantitative analyses were performed by one-way ANOVA and are shown as bar graphs (n = 7 per group for each experiment; Western blot signal intensities were normalized to actin). (B) Immunohistochemistry of KA1 subunit in PBS- or KA-injected control and lamγ1 KO mice. (a and b) In PBS-injected control mice, KA1 was expressed in the CA1 and CA3 regions but was not detected in the DG. (c and d) However, 2 h after KA injection, KA1 expression was dramatically increased in the CA1 region. KA1 expression in CA3 and mossy fiber pathway was slightly decreased (arrows), which may suggest early neuronal damage. (e–h) In lamγ1 KO mice, the expression levels of KA1 between PBS- and KA-injected mice were similar. Higher magnification of boxed areas in a, c, e, and g are shown in b, d, f, and h, respectively. Error bars indicate SEM. Bars: (a, c, e, and g) 0.5 mm; (b, d, f, and h) 20 μm.

Mentions: To analyze how KA injection affects the expression of KA receptors, we compared the expression levels of the five subunits between PBS- and KA-injected hippocampi. The KA1 subunit was dramatically increased after KA injection; however, all other subunits were unchanged (Fig. 4 A). These results demonstrate that all five subunits of the KA receptors were expressed in the mouse hippocampus, but after KA injection, only the KA1 subunit was significantly increased.


Proteolytic fragments of laminin promote excitotoxic neurodegeneration by up-regulation of the KA1 subunit of the kainate receptor.

Chen ZL, Yu H, Yu WM, Pawlak R, Strickland S - J. Cell Biol. (2008)

KA specifically up-regulates the KA1 subunit of the KA receptor in the hippocampus in control but not in lamγ1 KO mice. (A) After KA injection, only the KA1 subunit was significantly higher in the hippocampus of control (Con) mice compared with PBS-injected control mice and lamγ1 KO mice injected with PBS or KA. All other subunits' expression levels remained similar between PBS- or KA-injected control and KO mice. Quantitative analyses were performed by one-way ANOVA and are shown as bar graphs (n = 7 per group for each experiment; Western blot signal intensities were normalized to actin). (B) Immunohistochemistry of KA1 subunit in PBS- or KA-injected control and lamγ1 KO mice. (a and b) In PBS-injected control mice, KA1 was expressed in the CA1 and CA3 regions but was not detected in the DG. (c and d) However, 2 h after KA injection, KA1 expression was dramatically increased in the CA1 region. KA1 expression in CA3 and mossy fiber pathway was slightly decreased (arrows), which may suggest early neuronal damage. (e–h) In lamγ1 KO mice, the expression levels of KA1 between PBS- and KA-injected mice were similar. Higher magnification of boxed areas in a, c, e, and g are shown in b, d, f, and h, respectively. Error bars indicate SEM. Bars: (a, c, e, and g) 0.5 mm; (b, d, f, and h) 20 μm.
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fig4: KA specifically up-regulates the KA1 subunit of the KA receptor in the hippocampus in control but not in lamγ1 KO mice. (A) After KA injection, only the KA1 subunit was significantly higher in the hippocampus of control (Con) mice compared with PBS-injected control mice and lamγ1 KO mice injected with PBS or KA. All other subunits' expression levels remained similar between PBS- or KA-injected control and KO mice. Quantitative analyses were performed by one-way ANOVA and are shown as bar graphs (n = 7 per group for each experiment; Western blot signal intensities were normalized to actin). (B) Immunohistochemistry of KA1 subunit in PBS- or KA-injected control and lamγ1 KO mice. (a and b) In PBS-injected control mice, KA1 was expressed in the CA1 and CA3 regions but was not detected in the DG. (c and d) However, 2 h after KA injection, KA1 expression was dramatically increased in the CA1 region. KA1 expression in CA3 and mossy fiber pathway was slightly decreased (arrows), which may suggest early neuronal damage. (e–h) In lamγ1 KO mice, the expression levels of KA1 between PBS- and KA-injected mice were similar. Higher magnification of boxed areas in a, c, e, and g are shown in b, d, f, and h, respectively. Error bars indicate SEM. Bars: (a, c, e, and g) 0.5 mm; (b, d, f, and h) 20 μm.
Mentions: To analyze how KA injection affects the expression of KA receptors, we compared the expression levels of the five subunits between PBS- and KA-injected hippocampi. The KA1 subunit was dramatically increased after KA injection; however, all other subunits were unchanged (Fig. 4 A). These results demonstrate that all five subunits of the KA receptors were expressed in the mouse hippocampus, but after KA injection, only the KA1 subunit was significantly increased.

Bottom Line: Degradation of the extracellular matrix (ECM) protein laminin contributes to excitotoxic cell death in the hippocampus, but the mechanism of this effect is unknown.Interfering with KA1 function with a specific anti-KA1 antibody protected against KA-induced neuronal death both in vitro and in vivo.These results demonstrate a novel pathway for neurodegeneration involving proteolysis of the ECM and KA1 KA receptor subunit up-regulation.

View Article: PubMed Central - PubMed

Affiliation: Laboratory of Neurobiology and Genetics, The Rockefeller University, New York, NY 10065, USA.

ABSTRACT
Degradation of the extracellular matrix (ECM) protein laminin contributes to excitotoxic cell death in the hippocampus, but the mechanism of this effect is unknown. To study this process, we disrupted laminin gamma1 (lamgamma1) expression in the hippocampus. Lamgamma1 knockout (KO) and control mice had similar basal expression of kainate (KA) receptors, but the lamgamma1 KO mice were resistant to KA-induced neuronal death. After KA injection, KA1 subunit levels increased in control mice but were unchanged in lamgamma1 KO mice. KA1 levels in tissue plasminogen activator (tPA)-KO mice were also unchanged after KA, indicating that both tPA and laminin were necessary for KA1 up-regulation after KA injection. Infusion of plasmin-digested laminin-1 into the hippocampus of lamgamma1 or tPA KO mice restored KA1 up-regulation and KA-induced neuronal degeneration. Interfering with KA1 function with a specific anti-KA1 antibody protected against KA-induced neuronal death both in vitro and in vivo. These results demonstrate a novel pathway for neurodegeneration involving proteolysis of the ECM and KA1 KA receptor subunit up-regulation.

Show MeSH
Related in: MedlinePlus