The role of ubiquitin-proteasome cascade in the expression of long-term depression

• Main Authors: Yu-Fei Huang, 黃鈺斐
• Other Authors: Kuei-Sen Hsu
• Format: Others
• Language: zh-TW
• Published: 2005
• Online Access: http://ndltd.ncl.edu.tw/handle/71435680618459214347

碩士 === 國立成功大學 === 藥理學研究所 === 93 === 　　Activity-dependent alteration of synaptic strength is essential for the refinement of neuronal circuitry in developing nervous systems and for the plasticity of mature brain. Much of our understanding of activity dependent synaptic modification and its functional relevance comes from studies on the mammalian hippocampus. In CA1, CA3, and dentate gyrus regions of the hippocampus, brief high-frequency stimulation of afferent pathways can trigger a long-lasting enhancement of synaptic strength, commonly referred to as long-term potentiation (LTP), whereas prolonged low-frequency stimulation results in a long-lasting decrease in synaptic strength, termed as long-term depression (LTD). 　　The availability of proteins likely plays an important role in synaptic function and plasticity in the mammalian brain. Protein synthesis has been clearly shown to play a role in the expression of long-term synaptic plasticity, however, little is known about the potential role of protein degradation. Recently, accumulative evidence has demonstrated the physiological significance of ubiquitin-proteasome pathway regulation in synaptic development, transmission and plasticity. However, the identity of specific mammalian substrates regulated by ubiquitination during synaptic plasticity remains unknown. Thus, the primary goal of this study is to address this issue by using the conventional electrophysiological and biochemical approaches in both acutely isolated rat hippocampal slices and cultured neurons. 　　In conclusion, our results show that proteasome inhibitor MG132 successfully prevented the induction of both low-frequency stimulation- and NMDA-induced LTD in the CA1 region of the hippocampal slices and a proteasome-dependent regulation of PSD-95 level is an important determinant of the expression of AMPA receptors at the synapses. Moreover, PSD-95 is ubiquitinated in response to AMPA receptor activation, whereas NMDA treatment had no effect. NMDA treatment causes the degradation of PSD-95 by NR2B-containg NMDA receptor activation. In contrast, glycine or high K+ stimulation, which stimulates the glutamate release, induces an increase in the PSD-95 protein level through the activation of NR2A-containing NMDA receptors. Together these findings provide a further insight into the role of protein ubiquitination-proteasome degradation system in the induction of LTD in the hippocampal CA1 region and support for a role for PSD-95 in activity-dependent synaptic changes.