Abstract
The goal of this study was to determine whether a substantial decrease in adult neurogenesis influences epileptogenesis evoked by the intra-amygdala injection of kainic acid (KA). Cyclin D2 knockout (cD2 KO) mice, which lack adult neurogenesis almost entirely, were used as a model. First, we examined whether status epilepticus (SE) evoked by an intra-amygdala injection of KA induces cell proliferation in cD2 KO mice. On the day after SE, we injected BrdU into mice for 5 days and evaluated the number of DCX- and DCX/BrdU-immunopositive cells 3 days later. In cD2 KO control animals, only a small number of DCX+ cells was observed. The number of DCX+ and DCX/BrdU+ cells/mm of subgranular layer in cD2 KO mice increased significantly following SE (p<0.05). However, the number of newly born cells was very low and was significantly lower than in KA-treated wild type (wt) mice. To evaluate the impact of diminished neurogenesis on epileptogenesis and early epilepsy, we performed video-EEG monitoring of wt and cD2 KO mice for 16 days following SE. The number of animals with seizures did not differ between wt (11 out of 15) and cD2 KO (9 out of 12) mice. The median latency to the first spontaneous seizure was 4 days (range 2 – 10 days) in wt mice and 8 days (range 2 – 16 days) in cD2 KO mice and did not differ significantly between groups. Similarly, no differences were observed in median seizure frequency (wt: 1.23, range 0.1 – 3.4; cD2 KO: 0.57, range 0.1 – 2.0 seizures/day) or median seizure duration (wt: 51 s, range 23 – 103; cD2 KO: 51 s, range 23 – 103). Our results indicate that SE-induced epileptogenesis is not disrupted in mice with markedly reduced adult neurogenesis. However, we cannot exclude the contribution of reduced neurogenesis to the chronic epileptic state.
Highlights
The generation of new neurons occurs in the dentate gyrus of the hippocampal formation throughout the lifespan of adult mammals [1,2]
Adult neurogenesis was proposed to play a role in epilepsy after increased neurogenesis in the dentate gyrus was observed in human patients as well as in experimental models of epilepsy, including status epilepticus (SE)-induced epilepsy [3,4,5]
To determine if SE induced by intra-amygdala injection of kainic acid (KA) leads to the induction of hippocampal cell proliferation, we evaluated the number of DCX+ and DCX/BrdU+ cells in the subgranular layer of the dentate gyrus 8 days after KA treatment (Fig 1)
Summary
The generation of new neurons occurs in the dentate gyrus of the hippocampal formation throughout the lifespan of adult mammals [1,2]. Adult neurogenesis was proposed to play a role in epilepsy after increased neurogenesis in the dentate gyrus was observed in human patients as well as in experimental models of epilepsy, including status epilepticus (SE)-induced epilepsy [3,4,5]. Disturbances in neurogenesis accompany epilepsy, the contribution of neurogenesis to epileptogenesis is not clear, especially because the integration of individual newborn neurons into the epileptic brain is complex and heterogeneous [10]. We aimed to determine if a substantial decrease in adult neurogenesis influences epileptogenesis evoked by intra-amygdala injection of kainic acid (KA). We used cyclin D2 knockout mice (cD2 KO mice) as a model because they almost entirely lack adult neurogenesis due to defects in progenitor proliferation [11,12,13]
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