Effects of penicillin-induced developmental epilepticus on hippocampal regenerative sprouting, related gene expression and cognitive deficits in rats

Abstract

For the purpose of investigating the long-term effects of seizures in developmental rats on spatial learning ability and hippocampal mossy fiber sprouting related gene expressions in adult rat brain, a seizure was induced by penicillin quaque die alterna in Sprague-Dawley rats from postnatal day 29 (P29). Rats were assigned into the recurrent seizure group (RS, seizures were induced in 11 consecutive days) and the control group. During P51-P56, P81-P84 and P92-P95, the rats were tested for spatial learning ability with the Morris water maze task. On P95, the authors examined mossy fiber sprouting and gene expression of zinc transporters 1 and 3 (ZnT-1, ZnT-3), calcium/calmodulin-dependent protein kinase IIalpha (CaMK-IIalpha), NMDA receptor 2C (NR2C) and glutamate receptor 2 (GluR2) in hippocampus by Timm staining and real-time RT-PCR analysis. The escape latencies from the water maze of the rats in the RS group were significantly longer than those of the control rats at d5 of the first test, at d1 of the second test, and at d2 of the third test. In the spatial probe test, the ratio between the swim time in the third quadrant and the total swim time in control group was significantly higher than RS group (p<0.05) in the entire three probe tests. The Timm scores in CA3 and dentate gyrus in the RS animals were significantly higher than that in the control. Compared with the control rats, the expressions of ZnT-1, CaMK-IIalpha and GluR2 transcripts in the hippocampus of the RS group was significantly decreased while unchanged in transcriptional levels of ZnT-3 and NR2C. There were positive linear correlations among ZnT-3, CaMKIIalpha, and NR2C in control group and among CaMKIIalpha, ZnT-1 and GluR2 in RS group. The results suggest that recurrent seizures induced in developmental rats could cause long-term disturbance on the hippocampal mossy fiber sprouting related gene expressions, which might play an important role in long-term cognitive deficit and hippocampal aberrant mossy fiber sprouting.