Epilepsy in children is associated with a broad spectrum of cognitive deficits, which is associated with hippocampal mossy fiber sprouting. The underlying molecular mechanisms involved in mossy fiber sprouting in hippocampus following developmental seizures are not completely known. The timing of cognitive dysfunction and the relation of this cognitive impairment to calcium/calmodulin-dependent protein kinaseⅡ (CaMK-Ⅱ), plasticity related gene 3(PRG-3), cholecystokinin(CCK), zinc transporter 1 and 3 (ZnT-1 and ZnT-3) in hippocampus were studied. 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 eleven consecutive days, n=39) and the control group (NS, n=21). At 1.5 h, 3 h, 6 h and 12 h after the last seizure, apoptosis and autophagy were detected by transmission electronmicro-scopy (TEM) or in situ end labeling (TUNNEL). Electro-corticogram was observed after the last seizure. During P51 to P56, P81 to P84 and P92 to P95, the rats were tested for spatial learning and memory abilities with automatic Morris water maze task. On P95, mossy fiber sprouting and gene expressions in hippocampus were determined subsequently by Timm staining and real time RT-PCR methods. The results are as follows: a. TEM revealed the formation of autophagosomes and apoptosis in hippocampus after kindling. In the hippocampal neurons of the controls, chromatin and cytoplasmic organoids showed eumorphism with nuclear membrane integrity; 1.5 h after the last penicilin-induced recurrent seizures, “C”-morphous double membrane structure of dilated endocytoplasmic reticulum could be observed; 3 h after the last seizures, autophagosome appeared with manifest dilated endocytoplasmic reticulum; 6～12 h after the last seizures, the hippocampal neurons showed apoptotic feature such as nuclear chromatinic pyknosis and verge-aggregation. TUNNEL staining also showed elevated number of apoptosis neurons in hippocampus of RS group(P < 0.05). b. Vertex sharp transient wave and sharp wave were soon detected just in a few minutes afer the last seizure in RS group by Electrocorticogram. c. Escape latency. The escape latencies from the water maze were significantly longer in rats of RS group than that of the control at d5 of the first test, at d1 of the second test, and at d2 of the third test. d. Strategy analysis. RIDIT analysis showed that the scores were much worse in rats of RS group than that of the control at d4 and d5 of the first test. Moreover, the scores were much worse in rats of RS group than that of the control at the whole three days of both the second and third maze tests. e. Memory test. As for the value of distance in origin platform quadrant to total distance, the RS group seemed worse than the NS group in three maze tests(P < 0.05). f. Aberrant mossy fiber sprouting was seen in the inner molecular layer of the granule cells and the stratum pyramidale of CA3 subfield in RS group. g. Real time RT-PCR analysis showed decreased expression of CaMKⅡα and ZnT-1 in hippocampus of RS group than that in control group. Moreover, the four genes (CaMKⅡα, PRG-3, CCK and ZnT-3) in NS group and the two genes (CaMKⅡα and ZnT-1) in RS group showed copolymerization characteristic by cluster analysis. In addition, correlation and regression analysis demonstrated positive linear correlation among CaMKⅡα, CCK, PRG-3 and ZnT-3 in NS group and between CaMKⅡα and ZnT-1 in RS group. It was concluded that recurrent developmental kindling induced by penicillin could cause not only autophagy and apoptosis in the earlier stage of brain damage, but also have long- term effects on cognitive function and hippocampal mossy fiber sprouting which may be associated with the down-regulated expression of CaMKⅡα and ZnT-1 in hippocampus.