Reelin Signaling Pathway and Mesial Temporal Lobe Epilepsy: A Causative Link

Tulika Gupta; Mandeep Kaur; Navneet Singla; Bishan Dass Radotra; Daisy Sahni; Parampreet Singh Kharbanda; Sunil K Gupta

doi:10.32598/bcn.2021.2554.1

Reelin Signaling Pathway and Mesial Temporal Lobe Epilepsy: A Causative Link

Basic Clin Neurosci. 2023 Jan-Feb;14(1):57-72. doi: 10.32598/bcn.2021.2554.1. Epub 2023 Jan 1.

Authors

Tulika Gupta¹, Mandeep Kaur¹, Navneet Singla², Bishan Dass Radotra³, Daisy Sahni¹, Parampreet Singh Kharbanda⁴, Sunil K Gupta²

Affiliations

¹ Department of Anatomy, Post Graduate Institute of Medical Education and Research, Chandigarh, India.
² Department of Neurosurgery, Post Graduate Institute of Medical Education and Research, Chandigarh, India.
³ Department of Histopathology, Post Graduate Institute of Medical Education and Research, Chandigarh, India.
⁴ Department of Neurology, Post Graduate Institute of Medical Education and Research, Chandigarh, India.

Abstract

Introduction: Mesial temporal lobe epilepsy (MTLE) is the most frequent form of partial epilepsy. Granule cell dispersion, resulting from aberrant neuronal migration in the hippocampus, is pathognomonic of MTLE. Reelin, a secreted neurodevelopmental glycoprotein has a crucial role in controlling the radial migration of neurons. Several animal studies have implicated Reelin in the MTLE pathogenesis Mesial temporal lobe epilepsy (MTLE) is the most frequent form of partial epilepsy. Granule cell dispersion, resulting from aberrant neuronal migration in the hippocampus, is pathognomonic of MTLE. Reelin, a secreted neurodevelopmental glycoprotein has a crucial role in controlling the radial migration of neurons. Several animal studies have implicated Reelin in the MTLE pathogenesis.

Methods: The aim of this study was to investigate the Reelin signalling pathway in the MTLE patients. Therefore, we studied each step in the Reelin signalling pathway for the gene and protein expressions, in the hippocampal tissue obtained from patients undergoing surgery for MTLE and compared it with age matched normal autopsy cases.

Results: We found statistically significant decrease (P<0.001) in the Reelin mRNA expression in MTLE patients. Among the two reelin receptors, apolipoprotein E receptor 2 (ApoER2) was significantly increased whereas very low density lipoprotein receptor (VLDLR) was decreased among the patients. Disabled 1 (Dab1), the downstream target of reelin, was found to be decreased. Dab1 in turn inhibits Cofilin, which is responsible for cytoskeletal reorganization, thus limiting aberrant neuronal migration. Statistically significant over expression of Cofilin protein was found in the patient group. Matrix metalloproteinase 9 (MMP-9) and tissue inhibitor of metalloproteases-1 (TIMP-1), both of which are involved in processing of Reelin, were down regulated in 70-85% of cases.

Conclusion: The whole pathway was found to be deranged in MTLE. These results indicate that Reelin signalling pathway is disturbed at various points in the MTLE patients and might be involved in the pathogenesis & progression of MTLE. Our results extend the existing information regarding the components of the Reelin pathway and further, establish a link between pathway disturbance and MTLE.

Keywords: Apolipoprotein E receptor 2 (ApoER2); Disabled 1 (Dab1); Matrix metalloproteinase 9 (MMP-9); Reelin; Tissue inhibitor of metalloproteases-1 (TIMP-1); Very low-density lipoprotein receptor (VLDLR).