Silencing of dentate gyrus inhibits mossy fiber sprouting and prevents epileptogenesis through NDR2 kinase in pentylenetetrazole kindling rat model of TLE

by Chen Zhang, Zixian He, Zheren Tan, Fafa Tian

Epileptogenesis is a potential process. Mossy fiber sprouting (MFS) contributes to epileptogenesis. Silencing of the dentate gyrus (DG) suppressed spontaneous seizures model of epilepsy and hyperactivity of granule cells resulted in MFS in vitro. However, the role of DG’s excitability in epileptogenesis have not yet been well explored, and underlying mechanisms has not been elucidated. Using chemical genetics, we studied whether MFS and epileptogenesis could be modulated by silencing of DG in the PTZ kindling rat model of epilepsy. MFS and protein expression was measured by Timm staining, Western blotting, and Immunofluorescence. Previous studies demonstrated that MFS and epileptogenesis could be modulated by a regulator of axonal growth (e.g. RGMa, PTEN). NDR2 kinase regulate neuronal polarity and prevents the formation of supernumerary axons in the hippocampus. We experimentally confirmed chemogenetic inhibition in DG resulted in decreased MFS and NDR2 expression, and alleviated epileptogenesis. Furthermore, our results showed that injection of AVV vector expressing NDR2 into DG induced upregulation of NDR2 in the hippocampus, and over expression of NDR2 in the hippocampus promote MFS and block protective effect of chemogenetic silencing of DG on epileptogenesis. Overall, we concluded that silencing of DG inhibits MFS and prevents epileptogenesis through NDR2 in the hippocampus in the PTZ kindling rat model of TLE, thereby providing a possible strategy to prevent epileptogenesis.