長期增益現象（Longterm potentiation；LTP）是一種被認為與學習及記憶有關的一種細胞分子機制。然而其與學習及記憶形成的相關性如何，仍有待了解。我們實驗室在過去幾年來，已證實長期增益現象並非穩定不變的。倘若在其誘發後的早期給予低頻電刺激或不同的藥物處理，是可以將其逆轉（reverse）的，此現象稱為去增益現象（Depotentiation）。然而去增益現象的生理意義為何？是否與記憶的遺忘（Forgetting）有關，則是我們有興趣進一步探討的課題。
在我的實驗中，採用(S)-3,5-dihydroxyphenylglycine （DHPG）來活化GroupⅠ代謝型glutamate受體（mGluRs），在大鼠海馬迴CA1區域誘發去增益現象的表現，並以電氣生理學及西方點墨法來探求其可能的作用機轉。我們發現DHPG所誘發的去增益現象具有下列特性。第一、DHPG所誘發的去增益現象為time-dependent。第二、DHPG係透過活化mGluR5來產生去增益作用。第三、DHPG所誘發的去增益現象需要p38 Mitogen-activated protein kinase（p38 MAPK）的參與。第四、此為rapamycin-sensitive proteintranslationdependent型式的去增益現象。第五、此去增益現象需要local protein synthesis。同時以西方點墨法發現，surface AMPA receptor的表現量減少有明顯的情形。另一方面我們也使用埋管的方式在大鼠海馬迴CA1區域給予DHPG，並利用被動性動物逃避學習試驗來驗證其生理意義。實驗結果顯示，在學習之前15分給予DHPG，或者是學習後的1、3、6、9、12小時給予DHPG，都會使其有逃避記憶有明顯受損的情形。此外，西方點墨法發現在學習之後會有cAMP response element-binding protein（CREB）磷酸化表現增加的情形，然而在學習後給予DHPG活化 mGluR5卻會抑制CREB磷酸化增加的情形。
而我們也進一步去探討DHPG誘發長期抑制現象作用（long-term depression；LTD）機轉，發現DHPG是透過活化mGluR5來產生LTD，並且不需要extracellular signal-regulated kinase（ERK）及Jun-NH2-terminal kinase（JNK）的參與，但是需要透過P38 MAPK參與及伴隨有P38 MAPK磷酸化增加跟tyrosine phosphatase參與其中。由全細胞記錄實驗結果可知，DHPG作用可能是透過G protrin  subunit 的作用產生。但由免疫沉澱法實驗結果得知，P38 MAPK和G protrin  subunit並沒有相互活化作用（association）。因此DHPG誘發長期抑制現象可能是透過mGluR5去結合上G protrin  subunit，再透過一個未知的激酶將P38 MAPK磷酸化，再活化下游的訊息路徑，進而促進endocytosis，導致surface AMPA receptor表現量減少。
總結以上實驗，大鼠海馬迴CA1區域給予GroupⅠ代謝型glutamate受體作用劑DHPG，會活化 mGluR5及P38 MAPK。而G protrin  subunit-coupled signaling pathway 也參與在DHPG活化P38 MAPK過程，最後導致surface AMPA receptor表現量減少。在生理意義上，去增益現象的作用機轉可能參與了記憶的獲得（acquisition）、固化作用（consolidation）及reconsolidation作用機轉，但是不參與在記憶的回想（retrieval）。而mGluR5可能是記憶儲存的負向調控者（negative regulator）。

Long-term potentiation (LTP) is generally assumed to be a synaptic mechanism underlying learning and memory formation, the processes involved in the depression of synaptic potentiation may contribute to the mechanisms of memory loss or forgetting. However, the relationship between depotentiation and memory forgetting remains to be established.
The ability of activation of group I metabotropic glutamate receptor (mGluR) to induce depotentiation was investigated at the Schaffer collateral-CA1 synapses of rat hippocampal slices. Brief bath application of group I mGluR agonist (S)-3,5-dihydroxyphenylglycine (DHPG) (10 µM) for 5min induced a long-term depression of synaptic transmission or depotentiation (DEP) of previously established long-term potentiation (LTP). This DHPG-DEP was observed when DHPG was delivered 3 min after LTP induction. However, when DHPG was applied at 10 or 30 min after LTP induction, significantly less depotentiation was found. DHPG-DEP (1) is time dependent, (2) requires mGluR5 activation, (3) requires p38 MAPK activation, (4) requires rapamycin-sensitive mRNA translation signaling, (5) requires local protein synthesis. Moreover, the expression of DHPG-DEP is associated with a reduction in the increase of the surface expression of AMPA receptors seen with LTP. To investigate the functional relevance of DEP in the information storage of the mammalian brain, we did the one-trail step-down inhibitory avoidance training test. DHPG was administrated into the CA1 region of the dorsal hippocampus at various time before and after training. DHPG infused bilaterally into CA1 caused memory deficits when given before training (-15 min) or +1, +3, +9, or +12 hr after training. Following an inhibitory avoidance training, there were a significant increase in the phosphorylation of the transcription factor cAMP response element-binding protein (CREB) at Ser-133 in the CA1 region. Consistent with the behavioral observations, DHPG infused bilaterally into CA1 region also attenuated this enhancement effectively.
In this work, we further show that the induction of DHPG-LTD is dependent on the activation of mGluR5, P38 MAPK and tyrosine phosphatase. Also, a G subunit-coupled signaling pathway is functionally involved in the activation of p38 MAPK caused by DHPG.
In conclusion, we have shown that selective activation of group I mGluRs, and of mGluR5 in particular, induces a novel form of DEP. This DHPG-DEP is mechanistically distinct from previously reported forms of hippocampal CA1 DEP evoked under identical conditions and is expressed via a protein synthesis-dependent change of the postsynaptic AMPA receptor expression. These results suggest that the processes involved in the depression of synaptic potentiation may contribute to the mechanisms of memory loss or forgetting and the activation of postsynaptic mGluR5 may be negative regulator in memory formation.

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