The reinvestigation of angiotensin IV on hippocampal LTP and its possible connection with PKMzeta in memory

• Main Authors: Lin,Yuhui, 林玉惠
• Other Authors: Huang, Eagle Yi-Kung
• Format: Others
• Language: zh-TW
• Published: 2011
• Online Access: http://ndltd.ncl.edu.tw/handle/90690635878596062679

碩士 === 國防醫學院 === 藥理學研究所 === 99 === Angiotensin IV (Ang IV) is an endogenous peptide with the length of six amino acids, which is generated from the degradation of angiotensin II by aminopeptidase A and aminopeptidase N. Ang IV has been proved to be distributed in many tissues and bind to insulin-regulated aminopeptidase (IRAP) as an inhibitor. Despite that IRAP could be one of the targets of Ang IV, the possible mechanisms of Ang IV to exert its physiological and pharmacological actions are still unknown. One of the most important functions of Ang IV was its effects to enhance memory. In many reports, Ang IV was found to enhance learning and the storage of memory. In addition, Ang IV was shown to potentiate long-term potentiation (LTP) at the hippocampus of rats in both in vivo and in vitro electrophysiological experiments. In search of the possible biomarker of memory, protein kinase Mzeta (PKMzeta) was identified to be an active fragment of protein kinase Czeta (PKCzeta). Its continuous activation has been proved to be positively correlated with the formation of memory in the hippocampus. Serving as the only biomarker for memory so far, the expression and activity of PKMzeta could be related to the enhancing effect of Ang IV on memory. Therefore, we first investigated the possible effect of Ang IV on non-spatial memory in the novel object recognition (NOR) test in rats. Using the blocker of PKMzeta, ZIP, the possible connection between PKMzeta activation and memory enhancement by Ang IV was examined. Our data showed that Ang IV (1 nmole, i.c.v.) could increase the exploratory time on novel object. Under the dose of 10 nmole (i.c.v.), ZIP alone did not cause any effect in the NOR test. However, the co-administration of ZIP with Ang IV completely blocked the effect by Ang IV. In electrophysiological experiments, Ang IV was re-tested for its effect on hippocampal LTP at the CA1 region. Our results showed a different effect of Ang IV on LTP. Instead of potentiating LTP, Ang IV caused a failed maintenance of LTP and the strength of EPSP was turned to be close to the basal value. For the effect of Ang IV on EPSP itself, Ang IV significantly increased the amplitude and slope of the EPSPs, which is consistent with the results from the other reports. After the quantification of PKCzeta and PKMzeta expression in the hippocampus, there was no significant change induced by Ang IV and/or ZIP. Taken together, our data re-confirmed the finding of the positive effect of Ang IV to enhance memory and possibly even recognition. The increase of EPSP at the hippocampus may contribute and correlate to the in vivo effect by Ang IV. Nevertheless, the increased amplitude and slope of the EPSPs induced by Ang IV could be also of certain functional relevance (e.g. to increase the memory capacity), but it required further investigations. Although Ang IV did not increase the expression of PKMzeta in our results of Western blot, the enhancement of memory by Ang IV could rely on the increase of PKMzeta activity, since the behavioral results suggested the involvement of PKMzeta. Overall, the present study provided some information about the actions of Ang IV in the hippocampus, although its detailed mechanisms remained in question.