生物谷報(bào)道：得克薩斯大學(xué)西南醫(yī)學(xué)中心研究人員領(lǐng)銜的研究團(tuán)隊(duì)發(fā)現(xiàn)：在大腦中缺乏一種單酶的轉(zhuǎn)基因小鼠比尋常小鼠的學(xué)習(xí)能力更強(qiáng),，能更快的發(fā)現(xiàn)它們周?chē)h(huán)境的變化,。發(fā)表于最新一期《自然神經(jīng)科學(xué)》網(wǎng)絡(luò)版的該研究成果揭示了一個(gè)新的大腦學(xué)習(xí)機(jī)制。研究人員稱(chēng)可利用該機(jī)制治療人類(lèi)創(chuàng)傷后應(yīng)激障礙,、阿爾茨海默病或藥物依賴(lài)等疾病,。“使小鼠變得聰明（的例子）是非常罕見(jiàn)的,，所以一旦成功將具有非比尋常的意義。” James Bibb博士說(shuō),，他是一名心理學(xué)副教授,，也是該研究的主要作者,。“對(duì)這些小鼠來(lái)說(shuō)一切都是有意義的，”他說(shuō),，“看起來(lái)對(duì)周?chē)h(huán)境敏感性的增加使這些小鼠更 聰明,。”轉(zhuǎn)基因小鼠能更快的學(xué)會(huì)怎樣通過(guò)水迷宮，能記住在某一個(gè)盒子里的震動(dòng)是緩和的,。同樣重要的是,，Bibb博士說(shuō)，當(dāng)環(huán)境改變后,，比如重新放置水迷宮,，轉(zhuǎn)基因小鼠能更快的認(rèn)識(shí)到事情的變化并尋找到新的解決途徑。該小組同時(shí)也在著手尋找一種不依賴(lài)轉(zhuǎn)基因手段但能產(chǎn)生同樣效果的藥物,，并對(duì)小鼠的健康和行為進(jìn)行長(zhǎng)期監(jiān)測(cè),。Bibb博士警告說(shuō)盡管小鼠學(xué)習(xí)能力提高，但對(duì)大腦中缺失Cdk5酶的遠(yuǎn)期效果的研究將繼續(xù)進(jìn)行,。該研究成果可用于治療創(chuàng)傷后應(yīng)激障礙,， 該疾病的主要治療目的是讓病人認(rèn)識(shí)到曾經(jīng)有威脅的環(huán)境不再具有危害性。而且,，Cdk5酶與阿爾茨海默病及藥物成癮密切相關(guān),，所以如果了解了這種酶影響大腦與行為的途徑，就可以有助于尋找一種新的對(duì)這兩種疾病及其他疾病的治療方法,。Bibb博士說(shuō),。這項(xiàng)研究的關(guān)鍵是能夠在小鼠成年后僅敲除掉腦中的Cdk5基因（而不影響其他部位的Cdk5基因）。這一最近才開(kāi)展的被稱(chēng)為有條件敲除的技術(shù)使進(jìn)行更復(fù)雜的實(shí)驗(yàn)成為可能,，表現(xiàn)出了比傳統(tǒng)敲除技術(shù)的優(yōu)越之處,，因?yàn)楹笳咧荒馨颜麄€(gè)基因全部敲除。“關(guān)掉腦部中的某個(gè)基因的表達(dá)是一項(xiàng)很先進(jìn)的技術(shù),，”Bibb博士說(shuō),，“盡管這一技術(shù)早已被證實(shí)是可行的，但（只有）我們把它 融匯貫通,，并用于實(shí)際,。” 正常情況下，Cdk5與另一個(gè)酶協(xié)作可以分解一個(gè)稱(chēng)為NR2B的分子,，NR2B是在神經(jīng)細(xì)胞膜上發(fā)現(xiàn)的一種分子,，當(dāng)神經(jīng)細(xì)胞信號(hào)分子或神經(jīng)遞質(zhì)與它結(jié)合后 能刺激細(xì)胞放電。早先NR2B就被認(rèn)為與學(xué)習(xí)的早期階段有關(guān),。這一新研究表明當(dāng)從大腦中敲除Cdk5后,，NV2B的水平顯著升高，此時(shí)小鼠已為學(xué)習(xí)做好準(zhǔn) 備,。Bibb博士說(shuō),。“我們成功地使這些動(dòng)物變得更聰明,，但在利用這一技術(shù)進(jìn)行操作過(guò)程中，我們也發(fā)現(xiàn)了一些生化物質(zhì),，這些物質(zhì)為發(fā)展對(duì)各種認(rèn)知障礙的治療指明了方向,。”他說(shuō)。研究者們還記錄了大腦中海馬部位神經(jīng)細(xì)胞的放電,，海馬是大腦中與學(xué)習(xí)有關(guān)的一個(gè)區(qū)域,。從敲除掉基因的小鼠海馬部切除的組織對(duì)電刺激 的反應(yīng)更加強(qiáng)烈，這一事實(shí)也支持（轉(zhuǎn)基因）小鼠學(xué)習(xí)能力更強(qiáng)的研究結(jié)果,。
Figure 1. Conditional loss of Cdk5 in adult mouse hippocampus.
(a) Cdk5 gene targeting strategy. Inset, PCR genotyping of wild-type (+) and floxed (fl) alleles. (b) Radiolabeled in situ with quantification for hippocampus (Hip), striatum (Str), cortex (Ctx), cerebellum (Cer) and hippocampal layers (n = 6–8) of wild-type (WT) and knockout (KO) mice. (c) Quantitative immunoblots of Cdk5, Cre and -tubulin (Tub) in hippocampal homogenates (n = 20). (d) Cdk5 kinase activity immunoprecipitated from hippocampus. Radiolabeled (32P-H1) and Coomassie-stained (CBB) H1 histone from WT and KO mice were compared with roscovitine (Ros) and IgG controls (n = 6). (e) Radiolabeled in situ for hippocampal Cdk5 mRNA with pseudocolor quantification (+ = high, - = low) (f) Cdk5 and Cre mRNA fluorescent in situ hybridizations with Nissl counterstains in WT and KO CA1 pyramidal neurons. Arrows show neurons with no Cre mRNA or no Cdk5 loss. Data represent mean s.e.m.; * P < 0.05, ** P < 0.01, versus WT; Student's t-test.
Cyclin-dependent kinase 5 governs learning and synaptic plasticity via control of NMDAR degradation
Ammar H Hawasli, David R Benavides, Chan Nguyen, Janice W Kansy, Kanehiro Hayashi, Pierre Chambon, Paul Greengard, Craig M Powell, Donald C Cooper & James A Bibb
Published online: 27 May 2007 | doi:10.1038/nn1914
Abstract | Full text | PDF (451K) | Supplementary Information
相關(guān)基因:
CDK5
Official Symbol CDK5 and Name: cyclin-dependent kinase 5 [Homo sapiens]
Other Aliases: PSSALRE
Other Designations: protein kinase CDK5 splicing
Chromosome: 7; Location: 7q36
Annotation: Chromosome 7, NC_000007.12 (150385928..150381831, complement)
MIM: 123831
GeneID: 1020
作者簡(jiǎn)介:
James Bibb, Ph.D.
Name:
James A. Bibb, Ph.D.
Academic Title:
Assistant Professor
Administrative Title:
Assistant Professor
Primary Appointment:
Psychiatry
School:
Graduate School of Biomedical Sciences
Degree Program:
Cell Regulation
Neuroscience
Department Website:
The Department of Psychiatry Basic Research Laboratories
Lab Website:
The Bibb Laboratory
Physician Profile:
James Bibb, Ph.D.
EDUCATION
1986 University of Kentucky MS Microbiology
1994 SUNY At Stony Brook Ph.D. Cell & Dev. Biol.
HONORS AND AWARDS
2002 President?s Research Council Distinguished Young Researcher Award The University of Texas Southwestern Medical Center at Dallas 2000 Young Investigator Award from National Alliance for Research on Schizophrenia and Depression (NARSAD) 1998 1997-1998 Huntington's Disease Society of America Research Fellow 1998 National Research Service Award Fellow National Institute of Health, Neurological Diseases and Stroke, National Institute of Health 1993 Sigma Xi Scientific Research Society Award for Excellence in Research
