Discussion and Conclusion
CORT is one of the main glucocorticoids secreted by adrenal gland in rodents. In recent years, large amount of evidences showed that hypercorticolism was harmful to the function of central nervous system (CNS), especially to the hippocampus-related learning and memory function. In the present study, CORT administrated one hour before tetanus significantly inhibited the formation of LTP, suggesting that CORT decreased the hippocampal plasticity. This effect of CORT may be one important mechanism underlying the CORT-induced endangerment to the hippocampus.
In our experiment, it was found that CORT application to rats had a trend to elevate the basal PS amplitude induced by single test stimulation though no statistical significance was observed. Because the basal PS reflects the excitability of the afferent nerve fiber from perforant pathway to dentate gyrus, it seemed that CORT may have regulatory effect on the tension of this fiber or affect the excitability of dentate gyrus directly. In our study, Persistent spraying CORT to the surface of hippocampal neurons, both the frequencies and events of synaptic activity were increased, suggesting that CORT may enhance the excitability of hippocampal neurons. Meanwhile, CORT application directly facilitated the Ca2+ influx through VDCC. Because cytosolic free Ca2+ is essential to maintain the excitability of nerve fiber, it is reasonable to postulate that CORT application to rats may increase the synaptic excitability of dentate gyrus. The CORT-induced trend to increase the basal PS amplitudes may be related to t his effect. On the other hand, CORT was injected intraperitoneally and the basal PS amplitudes in control group also showed a trend to increase, thus, the possibility that the mechanical stimulation to rats caused the elevation of PS amplitudes could not be rule out. However, the mechanisms accounting for this phenomenon are to be studied further.
It has been presumed that LTP consisted of several phases, including induction phase, early maintenance phase and late maintenance phase and different phases were mediated by different mechanisms. It was found that LTP induction required the transient elevation of intracellular Ca2+ level and injection of Ca2+ chelator, EGTA or BAPTA or Ca2+ channel antagonist, nifedipine to postsynapse of hippocampal neurons blocked the formation of LTP, suggesting the importance of the cytosolic Ca2+ in LTP induction phase. Early maintenance of LTP was thought to be mediated mainly by phosphoration of some protein kinases, such as protein kinase C and cGMP-dependent protein kinase (PKG) etc. On the other hand, excessive influx of Ca2+ into neurons may do harm to synaptic plasticity. It was found that the Ca2+-related synaptic plasticity was impaired severely in aged rats with significant reduction of frequency potential (FP, a similar phenomenon with LTP). Mg2+, an endogenous Ca2+ channel antagonist, facilitated the F P while high concentration of Ca2+ reduced it. Supplementation with dietary rich in Mg2+ to old animals promoted the amplitude of FP and enhanced the spatial memory in water maze test, suggesting that the inhibitory effect of elevated intracellular Ca2+ level on Ca2+-dependent postsynapse response may be a predominant characteristic of brain aging. In the present study, CORT pretreatment instantly inhibited the PS amplitudes immediately after tetanus and reduced the PS amplitudes within the observing period, suggesting that CORT inhibited both the LTP induction and LTP early maintenance phases. The present patch-clamp experiment showed that application of COTR dose-dependently facilitate the Ca2+ influx through VDCC, indicting that CORT enhances the Ca2+ influx into the hippocampal neurons. In addition, supplementation with CORT to serum-free hippocampal neurons reduced the intracellular ATP level. CORT-induced energetic deficiency may affect the Ca2+ extruding mechanism. So, CORT-induced facilitation of Ca2+ influx into neurons may further cause over-load of Ca2+, which then inhibits the formation of LTP and impairs the synaptic plasticity in hippocampus.
Because CORT belongs to a superfamily of glucocortiocids. It used to think that interaction and binding between glucocorticoids and their corresponding receptors triggered a genomic mechanism and then produced delayed biological effects for at least several hours or even several days. However, in our present study, CORT application instantly facilitated Ca2+ influx through VDCC, suggesting that this effect may involved in triggering of a rapid membrane receptor mechanism.
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|Zhou, JZ; Zhang, YX; Zheng, JQ; Zhou, JH; (1998). Effect of Corticosterone on Hippocampal Synaptic Plasticity and Voltage-dependent Calcium Channel on the Membrane of Hippocampal Neurons. Presented at INABIS '98 - 5th Internet World Congress on Biomedical Sciences at McMaster University, Canada, Dec 7-16th. Available at URL http://www.mcmaster.ca/inabis98/|
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