title: Potential roles of the RGMa-FAK-Ras pathway in hippocampal mossy fiber sprouting in the pentylenetetrazole kindling model.
abstract: Mossy fiber sprouting (MFS) is a unique feature of chronic epilepsy. However, the molecular signals underlying MFS are still unclear. The repulsive guidance molecule A (RGMa) appears to contribute to axon growth and axonal guidance, and may exert its biological effects by dephosphorylating focal adhesion kinase (FAK) at Tyr397, then regulating the activation of Ras. The objective of this study was to explore the expression patterns of RGMa, FAK (Tyr397) and Ras in epileptogenesis, and their correlation with MFS. The epileptic models were established by intraperitoneal pentylenetetrazole (PTZ) injection of Sprague‑Dawley rats. At 3 days and at 1, 2, 4 and 6 weeks after the first PTZ injection, Timm staining was scored at different time points in the CA3 region of the hippocampus and dentate gyrus. The protein levels of RGMa, FAK (Tyr397) and Ras were analyzed at different time points in the CA3 region of the hippocampus using immunofluorescence, immunohistochemistry and western blot analysis. Compared with the control (saline‑injected) group, the expression of RGMa in the CA3 area was significantly downregulated (P<0.05) from 3 days and still maintained the low expression at 6 weeks in the PTZ group. The expression of FAK (Tyr397) and Ras was upregulated (P<0.05) in the PTZ groups. The Timm score in the CA3 region was significantly higher than that in the control group at different time points and reached a peak at 4 weeks. In the CA3 region, no obvious distinction was observed at the different time points in the control group. To the best of our knowledge, these are the first results to indicate that the RGMa‑FAK‑Ras pathway may be involved in MFS and the development of temporal lobe epilepsy.
authors.affiliation: Department of Neurology, Xiangya Hospital, Central South University, Changsha, Hunan 410008, P.R. China.
authors.forename: Ming-Yu
authors.initials: MY
authors.lastname: Song
authors.affiliation: Department of Neurology, Xiangya Hospital, Central South University, Changsha, Hunan 410008, P.R. China.
authors.forename: Fa-Fa
authors.initials: FF
authors.lastname: Tian
authors.affiliation: Department of Neurology, Xiangya Hospital, Central South University, Changsha, Hunan 410008, P.R. China.
authors.forename: Yu-Zhong
authors.initials: YZ
authors.lastname: Wang
authors.affiliation: Department of Neurology, Xiangya Hospital, Central South University, Changsha, Hunan 410008, P.R. China.
authors.forename: Xia
authors.initials: X
authors.lastname: Huang
authors.affiliation: Department of Neurology, Xiangya Hospital, Central South University, Changsha, Hunan 410008, P.R. China.
authors.forename: Jia-Ling
authors.initials: JL
authors.lastname: Guo
authors.affiliation: Department of Neurology, Xiangya Hospital, Central South University, Changsha, Hunan 410008, P.R. China.
authors.forename: Dong-Xue
authors.initials: DX
authors.lastname: Ding
mesh_terms: D000818:Animals; D001522:Behavior, Animal; D056654:CA3 Region, Hippocampal / Q000378:metabolism / Q000473:pathology; D004195:Disease Models, Animal; D004833:Epilepsy, Temporal Lobe / Q000139:chemically induced / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D051416:Focal Adhesion Protein-Tyrosine Kinases / Q000378:metabolism*; D058851:GPI-Linked Proteins; D007150:Immunohistochemistry; D008297:Male; D008565:Membrane Proteins / Q000378:metabolism*; D019599:Mossy Fibers, Hippocampal / Q000378:metabolism*; D009419:Nerve Tissue Proteins / Q000378:metabolism*; D010433:Pentylenetetrazole / Q000009:adverse effects; D016283:Proto-Oncogene Proteins p21(ras) / Q000378:metabolism*; D051381:Rats; D012640:Seizures / Q000139:chemically induced / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D015854:Up-Regulation
chemical_list: D058851:GPI-Linked Proteins; D008565:Membrane Proteins; D009419:Nerve Tissue Proteins; C551856:RGMA protein, rat; D051416:Focal Adhesion Protein-Tyrosine Kinases; D016283:Proto-Oncogene Proteins p21(ras); D010433:Pentylenetetrazole