Impaired reelin processing and secretion by Cajal-Retzius cells contributes to granule cell dispersion in a mouse model of temporal lobe epilepsy.
Cajal-Retzius cells play a crucial role during ontogeny in regulating cortical lamination via release of reelin. In adult brain, they comprise small calretinin-positive interneurons located in the marginal zone of the cerebral cortex and in the hippocampal fissure. Alterations of reelin signaling or expression have been involved in major neurological disorders, and they underlie granule cell dispersion (GCD) in mesial temporal lobe epilepsy (TLE). Here, we investigated in a mouse model of TLE the contribution of Cajal-Retzius cells to reelin production in epileptic hippocampus and the molecular mechanisms underlying GCD. Following unilateral intrahippocampal Kainic acid injection in adult mice to induce an epileptic focus, we observed that Cajal-Retzius cells gradually became strongly immunopositive for reelin, due to intracellular accumulation. This phenotype resembled the morphology of Cajal-Retzius cells in reeler Orleans (reln (orl/orl) ) mice, which express a secretion-deficient 310-kDa reelin fragment. The possibility that GCD might result from abnormal reelin processing in Cajal-Retzius cells, leading to a lack of reelin secretion, was confirmed by KA injection in reln (orl/+) mice, which induced severe GCD. Furthermore, Western blot analysis in KA-treated wildtype mice revealed increased production of ∼300-kDa reelin fragments, confirming abnormal proteolytic processing. This effect was not seen upon treatment with Botulinum neurotoxin E (BoNT/E), which prevents GCD in KA-lesioned hippocampus by chronic blockade of synaptic transmission. Furthermore, BoNT/E blocked upregulation of TrkB in Cajal-Retzius cells, suggesting that production of truncated reelin in KA-treated hippocampus is activity-dependent and regulated by BDNF. Altogether, these data reveal that GCD results from abnormal reelin processing in Cajal-Retzius cells under the control of BDNF. Our findings highlight the critical role played by Cajal-Retzius cells for hippocampal neuronal reorganization in TLE.
Duveau
Venceslas
V
Institute of Pharmacology and Toxicology, University of Zurich, Zurich, Switzerland.
Madhusudan
Amrita
A
Caleo
Matteo
M
Knuesel
Irene
I
Fritschy
Jean-Marc
JM
D000818:Animals; D001905:Botulinum Toxins / Q000494:pharmacology; D019208:Brain-Derived Neurotrophic Factor / Q000378:metabolism*; D056547:CA1 Region, Hippocampal / Q000378:metabolism / Q000473:pathology; D056654:CA3 Region, Hippocampal / Q000378:metabolism / Q000473:pathology; D064032:Calbindin 2; D015816:Cell Adhesion Molecules, Neuronal / Q000378:metabolism*; D002452:Cell Count; D018891:Dentate Gyrus / Q000378:metabolism / Q000473:pathology; D004195:Disease Models, Animal; D004833:Epilepsy, Temporal Lobe / Q000139:chemically induced / Q000378:metabolism / Q000503:physiopathology*; D018690:Excitatory Amino Acid Agonists / Q000009:adverse effects; D016326:Extracellular Matrix Proteins / Q000378:metabolism*; D006624:Hippocampus / Q000378:metabolism / Q000473:pathology*; D007395:Interneurons / Q000187:drug effects / Q000378:metabolism; D007608:Kainic Acid / Q000009:adverse effects; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008818:Mice, Neurologic Mutants; D008822:Mice, Transgenic; D009419:Nerve Tissue Proteins / Q000378:metabolism*; D020813:Receptor, trkB / Q000378:metabolism; D000091042:Reelin Protein; D064030:S100 Calcium Binding Protein G / Q000378:metabolism; D012697:Serine Endopeptidases / Q000378:metabolism*; D009435:Synaptic Transmission / Q000187:drug effects
D019208:Brain-Derived Neurotrophic Factor; C576511:Calb2 protein, mouse; D064032:Calbindin 2; D015816:Cell Adhesion Molecules, Neuronal; D018690:Excitatory Amino Acid Agonists; D016326:Extracellular Matrix Proteins; D009419:Nerve Tissue Proteins; D000091042:Reelin Protein; D064030:S100 Calcium Binding Protein G; D020813:Receptor, trkB; C000717128:Reln protein, mouse; D012697:Serine Endopeptidases; D001905:Botulinum Toxins; D007608:Kainic Acid; C096326:botulinum toxin type E