Date of Award
Though the GluK4 kainate receptor subunit shows limited homology and a restricted expression pattern relative to other kainate receptor subunits, its ablation results in distinct behavioral and molecular phenotypes. To study the function of GluK4, I generated a global GluK4 knockout mouse line by crossing a germline-expressed cre transgenic mouse line with a GluK4-floxed mouse line in which exon 16 of GRIK4, the gene encoding GluK4, was flanked by lox-P sites (floxed). Thorough characterization of GluK4 expression in the resulting knockout mice using RT-PCR and a custom-designed anti-GluK4 antibody revealed that GRIK4 mRNA expression persisted though GluK4 protein expression was ablated. In keeping with genome-wide studies in humans that have implicated GluK4 in bipolar disorder and schizophrenia, I found that GluK4 mice displayed reduced anxiety, increased risk-taking behavior, reduced depressive behavior, impaired sensorimotor gating, and hyperlocomotion relative to wild-type mice. GluK4 knockout mice also demonstrated impaired fear memory and spatial memory. Furthermore, my findings indicate that GluK4 is a key mediator of excitotoxic neurodegeneration: GluK4 knockout mice showed robust neuroprotection in the Cornu Ammonis 3 (CA3) region of the hippocampus following intrahippocampal injection of kainate, a potent excitotoxin, and widespread neuroprotection throughout the hippocampus following hypoxia-ischemia. Molecular and biochemical analysis of kainate- and sham-treated wild-type and GluK4 knockout hippocampal tissue revealed that GluK4 may act through the c-Jun N-terminal Kinase (JNK) pathway to regulate the molecular cascades that lead to excitotoxicity. Finally, I found preliminary evidence to suggest that GluK4 may regulate hippocampal seizure activity following intraperitoneal injection of kainate. Together, these findings suggest that GluK4 may be relevant to the understanding and treatment of human neuropsychiatric and neurodegenerative disorders.
Lowry, Emily Rhodes, "The GluK4 Kainate Receptor Subunit Regulates Mood, Memory and Excitotoxic Neurodegeneration" (2012). Student Theses and Dissertations. 167.