The GluK4 kainate receptor subunit regulates memory, mood, and excitotoxic neurodegeneration.
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. GluK4 knockout mice demonstrated impairments in memory acquisition and recall in a Morris water maze test, suggesting a previously unreported role for kainate receptors in spatial memory. GluK4 knockout mice also showed marked hyperactivity and impaired pre-pulse inhibition, thereby mirroring two of the hallmark endophenotypes of patients with schizophrenia and bipolar disorder. Furthermore, we found that GluK4 is a key mediator of excitotoxic neurodegeneration: GluK4 knockout mice showed robust neuroprotection in the CA3 region of the hippocampus following intrahippocampal injection of kainate and widespread neuroprotection throughout the hippocampus following hypoxia-ischemia. Biochemical analysis of kainate- or sham-treated wild-type and GluK4 knockout hippocampal tissue suggests that GluK4 may act through the JNK pathway to regulate the molecular cascades that lead to excitotoxicity. Together, our findings suggest that GluK4 may be relevant to the understanding and treatment of human neuropsychiatric and neurodegenerative disorders.
Laboratory of Neurobiology & Genetics, The Rockefeller University, 1230 York Avenue, New York, NY 10065, USA.
E R
ER
Lowry
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A
Kruyer
E H
EH
Norris
C R
CR
Cederroth
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S
Strickland
D000339:Affect / Q000502:physiology*; D000818:Animals; D015153:Blotting, Western; D002545:Brain Ischemia / Q000503:physiopathology / Q000523:psychology; D056654:CA3 Region, Hippocampal / Q000502:physiology; D016923:Cell Death / Q000187:drug effects; D016057:Evoked Potentials, Auditory, Brain Stem / Q000187:drug effects; D018690:Excitatory Amino Acid Agonists / Q000008:administration & dosage / Q000633:toxicity; D006624:Hippocampus; D002534:Hypoxia, Brain / Q000503:physiopathology / Q000523:psychology; D048031:JNK Mitogen-Activated Protein Kinases / Q000235:genetics; D007608:Kainic Acid / Q000008:administration & dosage / Q000633:toxicity; D018782:Maze Learning / Q000187:drug effects / Q000502:physiology; D008568:Memory / Q000502:physiology*; D051379:Mice; D018345:Mice, Knockout; D008845:Microinjections; D009043:Motor Activity / Q000187:drug effects; D019636:Neurodegenerative Diseases / Q000139:chemically induced* / Q000235:genetics*; D009474:Neurons / Q000187:drug effects; D018092:Kainic Acid Receptors / Q000235:genetics / Q000502:physiology*; D013216:Reflex, Startle / Q000187:drug effects; D013238:Stereotaxic Techniques; D020521:Stroke / Q000235:genetics / Q000473:pathology
D018690:Excitatory Amino Acid Agonists; D048031:JNK Mitogen-Activated Protein Kinases; D007608:Kainic Acid; D018092:Kainic Acid Receptors; C534874:Grik4 protein, mouse