在神經系統發育過程中，藉由突觸塑性的改變來調控之神經網絡修飾作用，扮演著相當重要的角色。目前有關突觸塑性的生理功能的了解，主要來自哺乳動物海馬迴區域的研究。在海馬迴CA1，CA3，及齒狀回區域，短暫的給予高頻率的電刺激可以誘發神經突觸強度持續性的增強作用，稱之為長期增益（long-term potentiation；LTP）現象，反之，若給予連續性低頻電刺激則會造成突觸強度持續性地減弱，亦即長期抑制（long-term depression；LTD）現象。此兩種現象目前被廣泛認為可能參與學習及記憶之形成機制。

　　哺乳動物腦部蛋白質的改變，在突觸塑性與功能上扮演一個重要的角色。目前已知，蛋白質的生合成與長期突觸塑性的表現有關，然而，對於蛋白質分解是否也參與長期神經塑性之表現則仍不清楚。研究證據顯示，透過活化泛素-蛋白質解體（ubiquitin-proteasome）徑路可能具有調控突觸發育與塑性表現之作用。然而，當突觸塑性改變時，某些特定哺乳動物的受質是如何受到泛素-蛋白質解體的調控，則仍然不清楚。因此，本研究的主要目的在於探討泛素-蛋白質解體訊息對於長期突觸塑性表現之調控。

　　我們的結果發現，處理蛋白質解體抑制劑MG132會抑制經由連續低頻電刺激（low-frequency stimulation；LFS）或直接投予N-methyl-D-aspartate（NMDA）在海馬迴CA1區域所誘發之長期抑制作用。然而，其對於(S)-3,5-dihydroxyphenylglycine（DHPG）所誘發之長期抑制作用則沒有影響。此外，MG132也調控足跡蛋白post synaptic density protein PSD-95被蛋白質解體（proteasome）分解之作用，而這個過程可能決定了α-amino-3-hydroxy-5-methyisoxazole-4-propionic acid（AMPA）受體在突觸上表現的程度。另外，以AMPA活化AMPA受體會選擇性地造成PSD-95受到泛素化。而透過NMDA或AMPA的投予在組織培養的海馬迴神經元上，也會造成神經元表面AMPA受體GluR1 結構單元表現的減少。

　　然而，不論是NMDA或AMPA處理都不會造成GluR1或GluR2結構單元的泛素化（ubiquitination）作用。在NMDA處理組織培養海馬迴神經元會造成PSD-95蛋白表現的減少，此作用與蛋白質解體的活化可能有關，其並非活化ㄧ般蛋白酶所產生的。此外處理NMDA時所產生之PSD-95蛋白表現減少，主要是透過活化突觸外的（extrasynaptic）含NR2B型的NMDA受體而產生的。若藉由KCl或glycine的處理，來促進glutamate的釋放，進而活化突觸區的NMDA受體，反而觀察到PSD-95的表現量增加的現象。此作用係透過活化含NR2A型的NMDA受體所產生。而NMDA也會造成PSD-95-Ca2+/calmodulin-dependent protein kinase II/NR2A複合體的減少。透過以上的觀察，我們認為泛素-蛋白質解體徑路的確參與海馬迴CA1神經網路長期神經塑性之表現，而調控PSD-95的突觸表現對於突觸上麩胺酸受體的表現及功能的執行可能也扮演著相當重要角色。

　　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.

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