Max Planck研究人員最近證實了“孤獨癥遺傳缺陷”與大腦信號傳導失敗有關(guān),。研究人員在動物模型中，發(fā)現(xiàn)引發(fā)孤獨癥的突變基因?qū)儆诰幋aneuroligin蛋白家族的基因,，研究結(jié)果公布于9月21日《Neuron》,。neuroligin負責神經(jīng)細胞間的信號傳導，在遺傳原因?qū)е耼euroligin缺失的小鼠大腦中,，神經(jīng)細胞間的接觸點——神經(jīng)突觸不能發(fā)揮正常功能,，研究人員推測人類孤獨癥（autistic）與此有關(guān)。
孤獨癥是一種常見的精神疾病,，患者語言學習能力發(fā)育延緩甚至根本沒有語言學習能力,，社交能力喪失，反復進行同一件事情,，有些伴隨有精神障礙?，F(xiàn)實生活中，像電影《雨人》中主人公那樣智商較高,、技術(shù)超群,、經(jīng)常在某個領(lǐng)域中被成為“專家”的孤獨癥患者實際上是少之又少。
一直到上世紀中葉,，研究人員都認為母親的冷情緒行為（cold emotional behaviour）是兒童患有孤獨癥的主要原因,；上世紀90年代，這種“電冰箱媽媽”（refrigerator mom）理論被“麻疹,、腮腺炎和風疹疫苗引發(fā)兒童孤獨癥”觀點取代,，但這種觀點依然沒有任何科學依據(jù)。最近普遍接受的觀點是孤獨癥與遺傳缺陷有關(guān),。同卵雙生研究結(jié)果證實：孤獨癥患者的同卵雙生同胞,，患有孤獨癥的幾率是80－95％。
2003年法國遺傳學專家Thomas Bourgeron通過對有嚴重孤獨癥兒童的家庭進行調(diào)查,，發(fā)現(xiàn)NLGN3和NLGN4X兩個基因發(fā)生突變會導致孤獨癥,。
Bourgeron的發(fā)現(xiàn)為神經(jīng)科學領(lǐng)域研究帶來一股強烈的沖擊波，因為NLGN3和NLGN4X所編碼的兩種蛋白hadneuroligin-3和 neuroligin-4在神經(jīng)細胞連接中發(fā)揮重要作用,。神經(jīng)細胞互相之間通過突觸進行聯(lián)系,。突觸前細胞受到刺激后會產(chǎn)生神經(jīng)遞質(zhì)，神經(jīng)遞質(zhì)到達受體細胞突觸后膜后進入受體細胞影響受體細胞的活動情況,，研究人員推測假如neuroligins缺失,，此過程會被終止。
在Bourgeron獲得上述發(fā)現(xiàn)的同時，Max Planck研究所研究人員Nils Brose 和Frederique Varoqueaux與附近大學醫(yī)學院同事張衛(wèi)齊（Weiqi Zhang,，音譯）,、遺傳學家Thomas Südhof等組成的研究小組已經(jīng)在小鼠模型中對neuroligin進行了10年的研究。Brose說：“我們已經(jīng)得到了neuroligin-3或neuroligin-4缺陷小鼠模型,，從功能學角度講這些小鼠攜帶了同人類孤獨癥類似的突變”,。世界上第一個孤獨癥遺傳動物模型產(chǎn)生于Brose等的實驗室。
Brose,、Varoqueaux 和Zhang在《Neuron》發(fā)表文章說,，這種模型小鼠的神經(jīng)細胞信號傳導存在障礙,。Brose與Varoqueaux的合作得到不僅neuroligin-1/neuroligin-2缺失,，而且是四種已知neuroligin蛋白同時缺失的小鼠品系。這種突變品系比孤獨癥患者遭受的癥狀更為劇烈（孤獨癥患者只有一種neuroligin突變基因）,。沒有任何neuroligin的小鼠,，神經(jīng)系統(tǒng)功能完全喪失，出生后不久即死亡,。Brose認為：“通過研究這些小鼠的神經(jīng)細胞所獲得的信息不僅有助于腦部研究,，而且有助于尋找孤獨癥的原因。我們發(fā)現(xiàn)neuroligin與突觸的成熟有關(guān),，Neuroligin使受體細胞突觸膜表面附有足夠的受體蛋白,。”
“我們在neuroligin突變小鼠中觀察到的現(xiàn)象是孤獨癥患者病情的一種加強效果，”
Brose說“我們推斷為孤獨癥是一種與神經(jīng)突觸有關(guān)的疾病,。” Max Planck研究人員目前正在對缺乏neuroligin-3和neuroligin-4的小鼠的行為進行分析,，因為neuroligin-3和neuroligin-4缺乏的情況與人類neuroligin突變導致的孤獨癥相似。這種相關(guān)的小鼠動物模型在實驗室已經(jīng)獲得有一段時間了,，Brose說：“只是在幾個月前才開始對他們的行為進行研究,。”研究發(fā)現(xiàn)neuroligin-4突變小鼠沒有社交能力，并且伴隨驚惶,、焦慮,。
研究人員從遺傳學角度出發(fā)，得到獨孤癥動物模型,，然而還有一個值得考慮到問題：只有極少數(shù)的孤獨癥是由于neuroligin突變引發(fā)的,，研究人員對于孤獨癥的其它遺傳缺陷原因還是未知的。
英文原文：
When nerve cells can’t make contact
Max Planck scientists have decoded the molecular details of a genetic defect that disrupts signal transmission in the brain and causes autism
Using an animal model, brain researchers in Göttingen have examined the effects of mutations that cause autism in humans. These are mutations in the genes which carry the building instructions for proteins in the neuroligin family. The study published in the scientific journal Neuron (September 21, 2006) shows that neuroligins ensure that signal transmission between nerve cells functions. In the brain of genetically altered mice without neuroligins, the contact points at which the nerve cells communicate, the synapses, do not mature. The researchers assume that similar malfunctions are experienced by autistic patients.
Autism is one of the most common psychiatric illnesses. Around 0.5 percent of all young children have a syndrome belonging to the "autistic spectrum". The main symptoms of this developmental malfunction are delayed language development or no language development at all, disturbed social behaviour and repetitive behaviour patterns. In many patients, the disease is accompanied by mental disability. Autistic individuals exhibiting high intelligence or outstanding skills in a particular area, called "savants", such as the main character in the film "Rain Man", are rare.
Even up to the middle of the last century, exceptionally cold emotional behaviour on the part of the mother was given as the cause for autism. However, the "refrigerator mom" theory has now been refuted. The belief widely held in the 1990s that the measles, mumps and rubella vaccine could cause autism in small children has no scientific basis at all. Today, it is clear that genetic factors are the major cause of the illness. Studies of identical twins have been particularly convincing in demonstrating this fact - the probability that the identical twin of an autistic person will also be autistic lies between 80 and 95 percent.
In 2003, French geneticist Thomas Bourgeron showed in an investigation of families with several autistic children that mutations in the two genes NLGN3 and NLGN4X had lead to a complete loss of function in the genes and triggered autism in affected patients. Bourgeron’s work sent a shock wave through neuro-scientific institutes worldwide, as the a NLGN genes were not unknown. They are responsible for the creation of two proteins, neuroligin-3 and neuroligin-4, which are considered to play an important part in the structure of nerve cell contacts.
Nerve cells communicate with each other at specialized contact points, the synapses. When stimulated, a transmitting nerve cell emits neurotransmitters. These signal molecules reach the receiving cell and affect its activity status - provided the receiving cell has "aerials" on its synapses - receptors that bind the chemical signals. The scientists speculated that this process could be disrupted if the nerve cells have no neuroligins.
At the time of Bourgeron’s discovery, Nils Brose and Frederique Varoqueaux, brain researchers at the Max Planck Institute for Experimental Medicine in Göttingen, in collaboration with colleagues Weiqi Zhang from the neighbouring University Hospital and US geneticist Thomas Südhof, had already been working on neuroligins for ten years - however in mice, not in humans. "We had even already created mutant mice which, in functional terms, were carrying the same mutations as occur in autistic patients. Our mice were also lacking either neuroligin-3 or neuroligin-4," says Brose. The researchers were in possession of the first genetic animal model for autism.
A study published by Brose, Varoqueaux and Zhang in the specialist journal Neuron has shown that this model exhibited a malfunction in the signal transmission between the nerve cells. With his colleague Varoqueaux, Brose has created a mouse line that not only lacked neuroligin-1 or neuroligin-2, both of which have been associated with autism, but were missing all four known variants of the protein simultaneously. The consequences are accordingly more drastic than with autistic patients, who only have one mutated neuroligin gene. Without any neuroligins, the function of the nervous system breaks down completely and the mutant animals die immediately after birth. However, their nerve cells can be examined in detail. According to Brose, "they deliver important findings not only for brain research in general, but also for the possible causes of autism. Our investigations show that the neuroligins regulate the maturation of the synapses. They ensure that there are sufficient receptor proteins on the synaptic membrane of the receiving cell."
What was initially a pure basic research project has consequently acquired direct relevance to medicine. "What we see in our neuroligin mutants is a more intensified form of the malfunction that occurs in the brain of autistic people," says Brose. "I believe that autism is a disease of the synapses, a synaptopathy." The Max Planck researchers in Göttingen now want to carry out an analysis of the behavioural biology of mutant mice lacking not all of the neuroligins, but just neuroligin-3 or neuroligin-4, as is the case of autistic patients with neuroligin mutations. The relevant mutant mice have been available in the laboratory for a long time, "but we only started analyzing their behaviour with specialists a few months ago," says Brose. The first results look most promising - neuroligin-4 mutant mice obviously have disturbed social and anxiety behaviour. "If we succeed in measuring robust, autism-relevant behavioural changes in our mutant mice, then at least the step to experimental diagnosis and therapy in the animal model will be possible."
From the point of view of the geneticist, the scientists in Göttingen have the best known animal model for autism worldwide. However, there is a limitation: only very few cases of autism are caused by neuroligin mutations and, with few exceptions, nobody knows which genetic defects are present in the abundance of other autism patients.
