Effect Of Chronic Aluminum Exposure On LTP And Bioactivity Of MAPK/ERK In Hippocampus Of Rat

ObjectiveAluminum is one of the most abundant elements in the crust of the earth. Althoughit is a nontoxical kind of metal, which is widely used in every field, a large amount ofaccumulation in the body can cause serious damages to learning and memory. It hasbeen proved by many studies that aluminum is related to many diseases in nervoussystem.The mechanism of learning and memory is most sophisticated and complicated.Hippocampus is the key part for learning and memory and long-term potentiation(LTP)is a NMDA dependent synaptic plasticity enhancement, which is the considered ascellular basis and research model at synaptic level. LTP can be mainly divided into 2stages: The first phase is early LTP, or E-LTP. This phase lasts from 30 min to a fewhours; its expression is mediated by the persistent activation of various protein kinasesand the insertion of glutamate receptors into the postsynaptic membrane. The secondphase is late LTP, or L-LTP; it lasts from a few hours to a few weeks, depending on thetype of tissue preparation (20-25). L-LTP is dependent on changes in gene expression.The mitogen-activated protein kinase (MAPK) family is an evolutionarilyconserved class of proline-directed serine/threonine kinases. In mammals, three majorMAPK pathways have been identified: MAPK/ERK, SAPK/JNK, and p38 MAPK. TheMAPK pathways transduce a large variety of external signals, leading to a wide rangeof cellular responses, including growth, differentiation, inflammation and apoptosis.MAPK/ERK pathway is most important for synaptic plasticity, which is the basisof learning and memory, and the components in this pathway are highly expressed in nervous system, especially in the areas closely related to learning and memory. Manyregulators of MAPK/ERK (e.g., N-Ras, B-Raf, Rapl) are most localized in the centralnervous system. MAPK/ERK is a crucial factor in the inducement of gene expressionand a body of studies shows that MAPK/ERK is involved in the regulation of synapticplasticity. The research on the role in learning and memory has been the pop.In this chapter, we focused on the MAPK/ERK to study the effect of aluminumexposure on learning and memory and the manner of the effect at three levels includingelectrophysiological, signal transduction and molecular experiments.Materials and Methods1. Animal modelsFour groups of weaning Wistar rats (40g～60g, day 21) were obtained from theLaboratory Animal Centre, China Medical University, ShenYang, China. Three groupshad been given 0.2%, 0.4% and 0.6% AlCl3 in drinking water individually for 3months. The rest group was never exposed to aluminum at any time (control group).The temperature in the breeding room were kept between 18℃and 23℃and therelative humidity were 45～55%.2. MethodsElectrophysiological apparatus were used to measure the LTP amplitude;Radioactive isotopeγ-³²P was used to detect the bioactivity of MAPK/ERK in allgroups; The protein expression changes were quantified by Western-Blot method; themRNA expression levels were analyzed and quantified by through reversetranscriptional PCR.Results1. Chronic aluminum exposure can inhibit the formation of LTP in CA1 area ofhippocampus in a dose-dependent manner.2. The bioactivity of MAPK was decreased by chronic aluminum exposure in a dosedependent manner. 3. The protein expression (Total and Pho-protein) of MAPK/ERK was held back bychronic aluminum exposure.4. The mRNA expression level of ERK2 in chronic aluminum exposed groups wassignificantly decreased.DiscussionLTP is an important physiological model for researching the mechanism oflearning and memory and is considered as the basis of learning and memory. In thisexperiment, we have proved that chronic aluminum can inhibit the formation of LTP ina dose dependent manner. That is to say, we should avoid the food or the daily usedfrom exposing to aluminum.The formation of LTP needs involvement of many kinases. Early LTP needs thecovalent modification over kinases but no need of protein synthesis. On the contrary,late LTP, which is related with long term memory, needs brand new protein synthesis.The crucial roles of MAPK/ERK in learning and memory have been identified by manystudies. MAPK/ERK can regulate gene expression through cAMP dependent responseelement protein (CREB) besides phosphorylating directly some transcriptional factors(e.g., c-fos, c-jun) related to learning and memory. The results in this experimentshowed that chronic aluminum exposure can decrease the bioactivity of MAPK/ERKand its protein expression. The mRNA expression of ERK2 in hippocampus ofaluminum treated groups has been diminished comparing with that in control group.From the results above, the aluminum induced impairments to learning andmemory may be due to its inhibitory function on the bioactivity and protein expressionof MAPK/ERK.Conclusions1. Chronic aluminum exposure has an inhibitory effect on the formation of LTPin CA1 area, resulting in the damages to learning and memory.2. The inhibitory effects of aluminum on LTP may be derived from its negativeeffects on the bioactivity of MAPK and the protein expression of ERK1/2. 3. ERK2 of MAPK family plays a central role in CNS and in this text theexpression of ERK2 mRNA was inhibited by which way the LTP and learningand memory were affected finally.