Epileptiform Activity Reduces the Proteolytic Processing of Reelin in the Hippocampus
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1
University of Freiburg, Neurosurgery, Germany
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2
Bernstein Center Freiburg, Germany
The extracellular matrix protein Reelin, synthesized and secreted by Cajal-Retzius cells and GABAergic interneurons, is an important regulator for the formation of cortical layers during development and maintains this lamination in the adult hippocampus. In temporal lobe epilepsy (TLE) patients and in a TLE mouse model, Reelin levels are decreased which causes a migration defect of adult granule cells (Haas et al., 2002, Heinrich et al. 2006). However, not only absolute Reelin levels, but also proper proteolytic processing, giving rise to several Reelin isoforms, is important for its biological function. So far, it is unclear whether pathological processing of Reelin contributes to the malpositioning of dentate granule cells under epileptic conditions. To address this question, we used rat organotypic hippocampal slice cultures to investigate the effects of kainate (KA)-induced epileptiform activity on Reelin processing and the impact of Reelin cleavage on dentate granule cell layering.
As a prerequisite we showed that Reelin processing is decreased under epileptic conditions. Treatment of organotypic hippocampal slice cultures with KA resulted in an increase of high molecular weight Reelin isoforms in tissue and a significant decrease of the secreted 180 kDa Reelin fragment. This KA effect could be mimicked by incubation with protease inhibitors. Following epileptiform activity, we found a decrease of MMP-2 and MMP-9 (gelatinases) activity exclusively in the molecular layer and the granule cell layer of the dentate gyrus and elevated levels of the endogenous tissue inhibitor of MMPs-1 (TIMP-1). Both, epileptic conditions and impaired proteolytic cleavage of Reelin by inhibition of MMPs caused a significant widening of the granule cell layer and an extracellular accumulation of unprocessed Reelin. In summary, these experiments indicate that epileptic conditions impair the proteolytic processing of Reelin by an unbalance of MMPs and their inhibitor TIMP-1. As a consequence, Reelin accumulates extracellularly as a biological inactive form and contributes to granule cell dispersion.
Acknowledgements
Supported by the DFG, SFB TR3
References
Haas CA, Dudeck O, Kirsch M, Huszka C, Kann G, Pollak S, Zentner J, Frotscher M. 2002. Role for reelin in the development of granule cell dispersion in temporal lobe epilepsy. J Neurosci 22: 5797-5802.
Heinrich C, et al. 2006. Reelin deficiency and displacement of mature neurons, but not neurogenesis, underlie the formation of granule cell dispersion in the epileptic hippocampus. J Neurosci 26: 4701-4713.
Keywords:
Dentate Gyrus,
Extracellular Matrix,
granule cells,
slice culture,
TIMP-1
Conference:
BC11 : Computational Neuroscience & Neurotechnology Bernstein Conference & Neurex Annual Meeting 2011, Freiburg, Germany, 4 Oct - 6 Oct, 2011.
Presentation Type:
Poster
Topic:
brain disease, network dysfunction and intervention (please use "brain disease, network dysfunction and intervention" as keyword)
Citation:
Tinnes
S,
Ringwald
J and
Haas
C
(2011). Epileptiform Activity Reduces the Proteolytic Processing of Reelin in the Hippocampus.
Front. Comput. Neurosci.
Conference Abstract:
BC11 : Computational Neuroscience & Neurotechnology Bernstein Conference & Neurex Annual Meeting 2011.
doi: 10.3389/conf.fncom.2011.53.00214
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Received:
17 Aug 2011;
Published Online:
04 Oct 2011.
*
Correspondence:
Dr. Stefanie Tinnes, University of Freiburg, Neurosurgery, Freiburg, 79106, Germany, stefanie.tinnes@uniklinik-freiburg.de