Exogenous reelin prevents granule cell dispersion in experimental epilepsy.
Temporal lobe epilepsy (TLE) is often accompanied by granule cell dispersion (GCD), a migration defect of granule cells in the dentate gyrus. We have previously shown that a decrease in the expression of reelin, an extracellular matrix protein important for neuronal positioning, is associated with the development of GCD in TLE patients. Here, we used unilateral intrahippocampal injection of kainate (KA) in adult mice which is also associated with GCD formation and a decrease of reelin expression. In this mouse epilepsy model we aimed to prevent GCD development by the application of exogenous reelin. As a prerequisite we analyzed whether the reelin signaling transduction cascade was preserved in the KA-injected hippocampus. Using in situ hybridization and Western blot analysis we found that the expression of the reelin signaling components, apolipoprotein E receptor 2, the very-low-density lipoprotein receptor and the intracellular adaptor protein disabled 1, was maintained in dentate granule cells after KA injection. Next, recombinant reelin was infused into the KA-injected hippocampus by osmotic minipumps over a period of 2 weeks. Quantitative analysis of granule cell layer width revealed a significant reduction of GCD in reelin-treated, but not in saline-infused animals when compared to KA injection alone. Our findings highlight the crucial role of reelin for the maintenance of granule cell lamination in the dentate gyrus of adult mice and show that a reelin deficiency is causally involved in GCD development.
Müller
Martin C
MC
Experimental Epilepsy Group, Neurocenter, University of Freiburg, Breisacher Strasse 64, D-79106 Freiburg, Germany.
Osswald
Matthias
M
Tinnes
Stefanie
S
Häussler
Ute
U
Jacobi
Anne
A
Förster
Eckart
E
Frotscher
Michael
M
Haas
Carola A
CA
D033961:Adaptor Protein Complex 1 / Q000235:genetics / Q000378:metabolism; D000704:Analysis of Variance; D000818:Animals; D015816:Cell Adhesion Molecules, Neuronal / Q000378:metabolism / Q000627:therapeutic use*; D002452:Cell Count / Q000379:methods; D002465:Cell Movement / Q000187:drug effects; D018891:Dentate Gyrus / Q000187:drug effects / Q000473:pathology; D004195:Disease Models, Animal; D016503:Drug Delivery Systems; D004827:Epilepsy / Q000139:chemically induced / Q000188:drug therapy* / Q000473:pathology*; D018690:Excitatory Amino Acid Agonists / Q000633:toxicity; D016326:Extracellular Matrix Proteins / Q000378:metabolism / Q000627:therapeutic use*; D005786:Gene Expression Regulation / Q000187:drug effects; D007608:Kainic Acid / Q000633:toxicity; D026502:LDL-Receptor Related Proteins; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009419:Nerve Tissue Proteins / Q000378:metabolism / Q000627:therapeutic use*; D009433:Neural Inhibition / Q000187:drug effects*; D009474:Neurons / Q000187:drug effects*; D018696:Neuroprotective Agents / Q000627:therapeutic use*; D012333:RNA, Messenger / Q000378:metabolism; D011973:Receptors, LDL / Q000235:genetics / Q000378:metabolism; D018110:Receptors, Lipoprotein / Q000235:genetics / Q000378:metabolism; D000091042:Reelin Protein; D012697:Serine Endopeptidases / Q000378:metabolism / Q000627:therapeutic use*; D013997:Time Factors
D033961:Adaptor Protein Complex 1; D015816:Cell Adhesion Molecules, Neuronal; D018690:Excitatory Amino Acid Agonists; D016326:Extracellular Matrix Proteins; D026502:LDL-Receptor Related Proteins; D009419:Nerve Tissue Proteins; D018696:Neuroprotective Agents; D012333:RNA, Messenger; D011973:Receptors, LDL; D018110:Receptors, Lipoprotein; D000091042:Reelin Protein; C036053:VLDL receptor; C098773:low density lipoprotein receptor-related protein 8; C000717128:Reln protein, mouse; D012697:Serine Endopeptidases; D007608:Kainic Acid