Zinc transporter-3 expression and long-term cognitive impairments in a rat model of neonatal concurrent seizure

摘要

BACKGROUND:Developmental seizures,which are pathologically characterized by regenerative sprouting of hippocampal mossy fibers,cause long-term damaging effects to synaptic plasticity.Zn^(2+) metabolism has been shown to contribute to the regenerative sprouting of hippocampal mossy fibers. Furthermore,zinc transporter-3(ZnT3) is responsible for Zn^(2+) transport in the hippocampal mossy fiber pathway. OBJECTIVE:To investigate the effects of long-term recurrent neonatal seizures on learning, memory formation and hippocampal ZnT3 expression in rats. DESIGN,TIME AND SETTING:Based on molecular biological research and behavioral examination, a randomized,controlled,animal experiment was performed at the Laboratory Animal Center, Peking University Health Science Center,between October 2004 and July 2005. MATERIALS:Flurothyl was purchased from Aldrich Chemical Co.,USA.ZnT3 mRNA in situ hybridization kits were provided by Tianjin Haoyang Biological Manufacture Co.,Ltd.,China.Morris water maze was produced by Shanghai Jiliang Science and Technology Co.,Ltd.,China. METHODS:Sixty,6-day old,Wistar rats were randomly divided into three groups:single seizure(n =21),recurrent seizure(n=21,one seizure daily for 6 consecutive days),and control(n=18). Seizures were induced by flurothyl gas inhalation,in the single seizure and recurrent seizure groups. MAIN OUTCOME MEASURES:At postnatal days 12,46 and 90,rat hippocampal ZnT3 mRNA expression was detected by RT-PCR;at postnatal days 46 and 90,ZnT3 mRNA expression was determined by in situ hybridization;and at postnatal days 41-46 and 85-90,rat spatial learning and memory formation were examined by the Morris water maze test. RESULTS:RT-PCR results revealed that at postnatal day 12,ZnT3 expression was significantly greater in the recurrent seizure group than in the control and single seizure groups,and at day 46,it was also significantly greater in the recurrent seizure group compared with the control group(P<0.05).In situ hybridization results showed that at postnatal day 46,the recurrent seizure group exhibited increased hippocampal ZnT3 expression over the control and single seizure groups(P<0.05).Morris water maze test results displayed that,in the first place navigation test at postnatal day 44,and the second test at days 87-88,the recurrent seizure group exhibited significantly higher value of average escape latency compared with the control group(P<0.05).In the two spatial probe tests,the search strategies were significantly inferior in the recurrent seizure group than in the control and single seizure groups(P<0.05). CONCLUSION:Neonatal concurrent seizures produce long-term damaging effects on hippocampal ZnT3 expression and cognitive function,while both of which have no parallel correlation.