Increased vulnerability to kainic acid-induced epileptic seizures in mice underexpressing the scaffold protein Islet-Brain 1/JIP-1.
Islet-Brain 1, also known as JNK-interacting protein-1 (IB1/JIP-1) is a scaffold protein mainly involved in the regulation of the pro-apoptotic signalling cascade mediated by c-Jun-N-terminal kinase (JNK). IB1/JIP-1 organizes JNK and upstream kinases in a complex that facilitates JNK activation. However, overexpression of IB1/JIP-1 in neurons in vitro has been reported to result in inhibition of JNK activation and protection against cellular stress and apoptosis. The occurrence and the functional significance of stress-induced modulations of IB1/JIP-1 levels in vivo are not known. We investigated the regulation of IB1/JIP-1 in mouse hippocampus after systemic administration of kainic acid (KA), in wild-type mice as well as in mice hemizygous for the gene MAPK8IP1, encoding for IB1/JIP-1. We show here that IB1/JIP-1 is upregulated transiently in the hippocampus of normal mice, reaching a peak 8 h after seizure induction. Heterozygous mutant mice underexpressing IB1/JIP-1 showed a higher vulnerability to the epileptogenic properties of KA, whereas hippocampal IB1/JIP-1 levels remained unchanged after seizure induction. Subsequently, an increasing activation of JNK in the 8 h following seizure induction was observed in IB1/JIP-1 haploinsufficient mice, which also underwent more severe excitotoxic lesions in hippocampal CA3, as assessed histologically 3 days after KA administration. Taken together, these data indicate that IB1/JIP-1 in hippocampus participates in the regulation of the neuronal response to excitotoxic stress in a level-dependent fashion.
Magara
Fulvio
F
Department of Internal Medicine, BH 10-640, University Hospital CHUV, 1011 Lausanne, Switzerland.
Haefliger
Jacques-Antoine
JA
Thompson
Nancy
N
Riederer
Beat
B
Welker
Egbert
E
Nicod
Pascal
P
Waeber
Gérard
G
D048868:Adaptor Proteins, Signal Transducing; D000818:Animals; D015153:Blotting, Western / Q000379:methods; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism*; D016923:Cell Death; D002467:Cell Nucleus / Q000473:pathology; D003593:Cytoplasm / Q000473:pathology; D004827:Epilepsy / Q000139:chemically induced / Q000378:metabolism*; D018690:Excitatory Amino Acid Agonists / Q000008:administration & dosage*; D005260:Female; D015870:Gene Expression / Q000187:drug effects; D006624:Hippocampus / Q000378:metabolism* / Q000648:ultrastructure; D007150:Immunohistochemistry / Q000379:methods; D020287:In Situ Nick-End Labeling / Q000379:methods; D007608:Kainic Acid / Q000009:adverse effects* / Q000031:analogs & derivatives; D008297:Male; D051379:Mice; D008815:Mice, Inbred Strains; D008817:Mice, Mutant Strains; D008854:Microscopy, Electron / Q000295:instrumentation / Q000379:methods; D013997:Time Factors
D048868:Adaptor Proteins, Signal Transducing; D002352:Carrier Proteins; D018690:Excitatory Amino Acid Agonists; C490665:Mapk8ip protein, mouse; D007608:Kainic Acid