Degeneration and Regeneration of GABA ergic Interneurons in the Dentate Gyrus of Adult Mice in Experimental Models of Epilepsy

摘要

Summary Aims Mounting evidence showed that GABA ergic interneurons play an important role in the generation of seizures by regulating excitatory/inhibitory balance in the hippocampus; however, there is a continuous debate regarding the alteration in the number of hippocampal GABA ergic interneurons during epileptogenesis. Here, we investigated the degeneration and regeneration of GABA ergic interneurons in the dentate gyrus during epileptogenesis using glutamic acid decarboxylase‐green fluorescence protein ( GAD 67‐ GFP ) knock‐in mice. Methods and Results Pentylenetetrazol ( PTZ )‐induced chronic kindling model and lithium–pilocarpine‐induced status epilepticus ( SE ) model were used in this study. We found a progressive loss of GABA ergic interneurons in the dentate gyrus during post‐ SE epileptogenesis rather than PTZ kindling. Both types of epileptogenic insults significantly promoted the proliferation of neural progenitor cells in the dentate gyrus; however, compared to 80% neuronal differentiation ratio in the control group, there was a remarkable decrease in PTZ kindling and pilocarpine models, that is 58% and 29%, respectively. Double/triple immunofluorescence labeling revealed no newborn neurons colabeled with GFP in both intact and epileptic dentate gyrus. In addition, valproate (a first‐line antiepileptic drug) treatment prevented the loss of GABA ergic interneurons but still failed to induce the regeneration of GAD 67‐positive interneurons in the dentate gyrus during post‐ SE epileptogenesis. Conclusions These results indicate that degeneration of GABA ergic interneurons may depend on the type of epileptogenic insult and that no newborn GABA ergic interneurons occur in the adult dentate gyrus during epileptogenesis.