The neuropathophysiology associated with Syngap mutations: further evidence for an mGluR5 signaling axis in ID/ASD

人类大脑包含超过1000亿个神经元(神经细胞)，它们形成了一个网络，充当着持续发送和接收信号的“信息高速公路”，对这些信号进行处理以控制我们行为的方方面面--从简单但基本的任务，如呼吸和行走，到复杂的任务，如感知情感，解释我们的感觉，存储和回忆记忆。神经元之间在被称为突触的特殊位置进行“交流”，突触是一个神经元释放一种化学物质(称为神经递质)，与第二个神经元上的特定蛋白质(受体)结合的地方。据估计，人类大脑中大约有100万亿个突触。在患有智障的人类(智商定义为70)中，人们认为突触传递过程被扰乱，导致“高速公路”不能像应有的那样有效地运行。科学家们已经能够识别出某些蛋白质的功能被破坏或缺失是某些形式的ID。我们的计划集中在研究其中一种蛋白质，称为SynGAP，当它无法正常功能时，会导致人类ID。利用基因技术，已经创造了一种改变了SynGAP功能的小鼠，它被认为是研究人类ID的非常好的动物模型。我们的建议假设，SynGAP功能改变的人在突触传递方面的一些缺陷可能是共同信号通路改变的结果，该通路也见于另一种形式的ID，称为脆性X综合征(FXS)。好消息是，目前正在进行临床试验，试图纠正FXS中看到的突触传递的一些变化。我们想知道，在我们的动物模型中，SynGAP的缺陷是否可以通过目前正在试验的治疗FXS的药物来纠正。如果我们的假设是正确的，这将证明两种(或许更多)形式的ID实际上是有联系的，这提供了希望，即对一种ID有效的治疗方法可能对另一种ID也有用。

The human brain contains upwards of 100 billion neurones (nerve cells) which form a network that acts as an 'information superhighway' that continuously sends and receives signals, processing these to control every aspect of our behaviour - from simple, but fundamental, tasks such as breathing and walking to the complex such as perceiving emotion, interpreting our senses and storing and recalling memories. Neurons 'communicate' with each other at specialized sites known as synapses - a site where one neuron releases a chemical (known as a neurotransmitter) that binds to specific proteins (receptors) on the second neuron. It is estimated that there are around 100 trillion synapses in the human brain. In humans suffering from intellectual disability (ID; defined by an IQ <70) it is thought than the process of synaptic transmission is disrupted such that the "superhighway" does not operate as effectively as it should. Scientists have been able to identify some of the proteins whose function is disrupted or which are missing is certain forms of ID. Our proposal focuses on studying one of these proteins, called SynGAP, which when it fails to function normally results in ID in humans. Using genetic techniques, a mouse has been created which has altered SynGAP function and which is considered to be a very good animal model for ID in humans. Our proposal hypothesises that some of the defects in synaptic transmission that are seen in humans with altered SynGAP function might be the result of changes in a common signalling pathway that is also seen in another form of ID called fragile X syndrome (FXS). The good news is that clinical trials are presently underway which are attempting to correct some of the changes in synaptic transmission seen in FXS. We want to see if, in our animal model, the defects seen with SynGAP can be corrected by drugs which are currently being trialed for the treatment of FXS. If our hypothesis is correct this will demonstrate that two (and perhaps more) forms of ID are actually linked, providing hope that treatments that work in one form of ID might also be useful in another.