Kainate induces cell death in the CA1 region of the hippocampus in WT mice, but is ineffective in causing degeneration in laminin gamma-1 knockout mice.

Laminin plays important roles in the nervous system. Previous studies show that laminin is implicated in excitotoxic neuronal degeneration. To study the role of laminin in neuronal cell death, members of the Strickland Laboratory knocked out laminin gamma-1 expression specifically in the neurons of the hippocampal CA1 region. We compared neuronal degeneration between wild-type and the knockout mice two days after hippocampal injection of the excitotoxin, kainate. Knockout mice showed significantly less neuronal cell death than wild-type controls. C-fos expression was dramatically induced six hours after kainate injection in wild-type mice, but did not increase significantly in knockout mice. Kainate receptor expression was also compared between wild-type and knockout mice in basal conditions and two hours after kainate injection. Strickland Lab results show that expression of kainate receptor subunits (KA1, KA2, GluR5, and GluR6,7) in wild-type and knockout mice are similar under basal conditions. However, two hours after kainate injection, KA1 subunit expression significantly increased in wild-type mice but remained unchanged in knockout mice. Dependence of the tissue plasminogen activator (tPA) was also investigated in the kainate pathway. The KA1 receptor expression in tPA knockout mice also remained unchanged two hours after kainate injection, indicating that both tPA and laminin are necessary for KA1 receptor upregulation after kainate injection. The infusion of plasmin-digested laminin-1 into the hippocampus of laminin gamma-1 or tPA knockout mice rescued KA1 receptor upregulation and neuronal sensitivity to excitotoxic cell death after kainate injection. The lack of KA1 upregulation after kainate injection led to impaired phosphorylation of JNK and the activation of intracellular death signaling pathways. Results obtained by postdoc Huaxu Yu and research assistant professor Zu-Lin Chen of the Strickland Laboratory suggest that plasmin-catalyzed laminin degradation products play important roles in KA1 receptor upregulation and neuronal cell death after kainate injection.

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