加拿大麥吉爾大學(xué)分子生物學(xué)家納胡姆·索伯格教授帶領(lǐng)的研究小組,，發(fā)現(xiàn)一種特定基因突變的實(shí)驗(yàn)室老鼠,，其學(xué)習(xí)和記憶的能力相比于一般正常老鼠有明顯的提高?？茖W(xué)家期望,，基于這個(gè)發(fā)現(xiàn)，可以研發(fā)出治療老年癡呆病等癡呆病癥的藥物,。研究文章刊載于4月6日出版的《細(xì)胞》雜志上,。
研究人員在實(shí)驗(yàn)中比較了基因突變老鼠和正常老鼠在一系列標(biāo)準(zhǔn)實(shí)驗(yàn)中的表現(xiàn)，特別是在水迷宮試驗(yàn)中,，基因突變鼠比正常鼠的學(xué)習(xí)記憶能力提高了一倍,，這種不明基因通常會(huì)提高一種自然記憶堵塞蛋白的水平。研究人員認(rèn)為,，在那些發(fā)生基因變化的老鼠中,，這種起抑制作用的蛋白產(chǎn)生得較少，導(dǎo)致老鼠學(xué)得更快,，記憶時(shí)間更長(zhǎng),。
研究人員表示，他們的工作就是使老鼠發(fā)生基因突變,，這個(gè)突變的基因生產(chǎn)一種蛋白,，這種蛋白可以控制在細(xì)胞內(nèi)生成其它蛋白的速度。當(dāng)突變基因產(chǎn)生后,，對(duì)學(xué)習(xí)和記憶有抑制作用的蛋白數(shù)量產(chǎn)生得就少了,。
索伯格表示，下一步工作將是尋找一種可以促使基因發(fā)生突變的化合物,，也許這種化合物就是可以提高記憶的藥物,。如果能夠找到這種化合物，也許就有機(jī)會(huì)為治療老年癡呆等病癥找到一種新的途徑,。也許這種藥物無(wú)法治療疾病本身,，但至少可以幫助緩解疾病的癥狀。
部分英文原文：
Cell
Volume 129, Issue 1 , 6 April 2007, Pages 195-206
eIF2α Phosphorylation Bidirectionally Regulates the Switch from Short- to Long-Term Synaptic Plasticity and Memory
Mauro Costa-Mattioli1, , , Delphine Gobert6, Elad Stern7, Karine Gamache2, Rodney Colina1, Claudio Cuello3, Wayne Sossin4, Randal Kaufman8, Jerry Pelletier1, Kobi Rosenblum7, Krešimir Krnjević5, Jean-Claude Lacaille6, Karim Nader2 and Nahum Sonenberg1, ,
1Department of Biochemistry and McGill Cancer Center, McGill University, Montreal, Quebec, H3G 1Y6, Canada
2Department of Psychology, McGill University, Montreal, Quebec, H3G 1Y6, Canada
3Department of Pharmacology, McGill University, Montreal, Quebec, H3G 1Y6, Canada
4Departments of Neurology and Neurosurgery, McGill University, Montreal, Quebec, H3G 1Y6, Canada
5Department of Physiology, McGill University, Montreal, Quebec, H3G 1Y6, Canada
6Département de Physiologie, Université de Montréal, Montréal, Québec, H3C 3J7, Canada
7Center for Brain and Behavior, University of Haifa, Haifa, 30905, Israel
8Department of Biological Chemistry, Howard Hughes Medical Institute, University of Michigan, Ann Arbor, MI, 49109-0650, USA
Received 9 July 2006; revised 4 December 2006; accepted 29 January 2007. Published: April 5, 2007. Available online 5 April 2007.
Summary
The late phase of long-term potentiation (LTP) and memory (LTM) requires new gene expression, but the molecular mechanisms that underlie these processes are not fully understood. Phosphorylation of eIF2α inhibits general translation but selectively stimulates translation of ATF4, a repressor of CREB-mediated late-LTP (L-LTP) and LTM. We used a pharmacogenetic bidirectional approach to examine the role of eIF2α phosphorylation in synaptic plasticity and behavioral learning. We show that in eIF2α+/S51A mice, in which eIF2α phosphorylation is reduced, the threshold for eliciting L-LTP in hippocampal slices is lowered, and memory is enhanced. In contrast, only early-LTP is evoked by repeated tetanic stimulation and LTM is impaired, when eIF2α phosphorylation is increased by injecting into the hippocampus a small molecule, Sal003, which prevents the dephosphorylation of eIF2α. These findings highlight the importance of a single phosphorylation site in eIF2α as a key regulator of L-LTP and LTM formation.
Author Keywords: MOLNEURO; RNA; SYSNEURO
