Max Planck研究人员最近证实了“孤独症遗传缺陷”与大脑信号传导失败有关。研究人员在动物模型中，发现引发孤独症的突变基因属于编码neuroligin蛋白家族的基因，研究结果公布于9月21日《Neuron》。neuroligin负责神经细胞间的信号传导，在遗传原因导致neuroligin缺失的小鼠大脑中，神经细胞间的接触点——神经突触不能发挥正常功能，研究人员推测人类孤独症（autistic）与此有关。
孤独症是一种常见的精神疾病，患者语言学习能力发育延缓甚至根本没有语言学习能力，社交能力丧失，反复进行同一件事情，有些伴随有精神障碍。现实生活中，像电影《雨人》中主人公那样智商较高、技术超群、经常在某个领域中被成为“专家”的孤独症患者实际上是少之又少。
一直到上世纪中叶，研究人员都认为母亲的冷情绪行为（cold emotional behaviour）是儿童患有孤独症的主要原因；上世纪90年代，这种“电冰箱妈妈”（refrigerator mom）理论被“麻疹、腮腺炎和风疹疫苗引发儿童孤独症”观点取代，但这种观点依然没有任何科学依据。最近普遍接受的观点是孤独症与遗传缺陷有关。同卵双生研究结果证实：孤独症患者的同卵双生同胞，患有孤独症的几率是80－95％。
2003年法国遗传学专家Thomas Bourgeron通过对有严重孤独症儿童的家庭进行调查，发现NLGN3和NLGN4X两个基因发生突变会导致孤独症。
Bourgeron的发现为神经科学领域研究带来一股强烈的冲击波，因为NLGN3和NLGN4X所编码的两种蛋白hadneuroligin-3和 neuroligin-4在神经细胞连接中发挥重要作用。神经细胞互相之间通过突触进行联系。突触前细胞受到刺激后会产生神经递质，神经递质到达受体细胞突触后膜后进入受体细胞影响受体细胞的活动情况，研究人员推测假如neuroligins缺失，此过程会被终止。
在Bourgeron获得上述发现的同时，Max Planck研究所研究人员Nils Brose 和Frederique Varoqueaux与附近大学医学院同事张卫齐（Weiqi Zhang，音译）、遗传学家Thomas Südhof等组成的研究小组已经在小鼠模型中对neuroligin进行了10年的研究。Brose说：“我们已经得到了neuroligin-3或neuroligin-4缺陷小鼠模型，从功能学角度讲这些小鼠携带了同人类孤独症类似的突变”。世界上第一个孤独症遗传动物模型产生于Brose等的实验室。
Brose、Varoqueaux 和Zhang在《Neuron》发表文章说，这种模型小鼠的神经细胞信号传导存在障碍。Brose与Varoqueaux的合作得到不仅neuroligin-1/neuroligin-2缺失，而且是四种已知neuroligin蛋白同时缺失的小鼠品系。这种突变品系比孤独症患者遭受的症状更为剧烈（孤独症患者只有一种neuroligin突变基因）。没有任何neuroligin的小鼠，神经系统功能完全丧失，出生后不久即死亡。Brose认为：“通过研究这些小鼠的神经细胞所获得的信息不仅有助于脑部研究，而且有助于寻找孤独症的原因。我们发现neuroligin与突触的成熟有关，Neuroligin使受体细胞突触膜表面附有足够的受体蛋白。”
“我们在neuroligin突变小鼠中观察到的现象是孤独症患者病情的一种加强效果，”
Brose说“我们推断为孤独症是一种与神经突触有关的疾病。” Max Planck研究人员目前正在对缺乏neuroligin-3和neuroligin-4的小鼠的行为进行分析，因为neuroligin-3和neuroligin-4缺乏的情况与人类neuroligin突变导致的孤独症相似。这种相关的小鼠动物模型在实验室已经获得有一段时间了，Brose说：“只是在几个月前才开始对他们的行为进行研究。”研究发现neuroligin-4突变小鼠没有社交能力，并且伴随惊惶、焦虑。
研究人员从遗传学角度出发，得到独孤症动物模型，然而还有一个值得考虑到问题：只有极少数的孤独症是由于neuroligin突变引发的，研究人员对于孤独症的其它遗传缺陷原因还是未知的。
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.
