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

与 Syngap 突变相关的神经病理生理学：ID/ASD 中 mGluR5 信号轴的进一步证据

• 批准号: MR/K014137/1
• 负责人: Peter Kind
• 金额: $ 83.44万
• 依托单位: University of Edinburgh
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2013
• 资助国家: 英国
• 起止时间: 2013 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=MR%2FK014137%2F1
• 关键词: neuropathophysiology; associated; Syngap; mutations; further

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.

人类大脑包含超过1000亿个神经元（神经细胞），它们形成一个网络，充当“信息高速公路”，不断发送和接收信号，处理这些信号以控制我们行为的各个方面-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，解释我们的感官以及存储和回忆记忆。神经元在被称为突触的特殊部位相互“交流”-一个神经元释放一种化学物质（称为神经递质）的部位，该化学物质与第二个神经元上的特定蛋白质（受体）结合。据估计，人类大脑中大约有100万亿个突触。在患有智力残疾（ID;由IQ <70定义）的人中，人们认为突触传递过程被破坏，使得“高速公路”不能像它应该的那样有效地运作。科学家们已经能够识别出一些功能被破坏或缺失的蛋白质是某些形式的ID。我们的建议侧重于研究其中一种称为SynGAP的蛋白质，当它无法正常发挥功能时，会导致人类ID。使用遗传技术，已经创建了一种小鼠，其改变了SynGAP功能，并且被认为是人类ID的非常好的动物模型。我们的提案假设，在SynGAP功能改变的人类中观察到的突触传递中的一些缺陷可能是共同信号通路变化的结果，该信号通路也见于另一种称为脆性X综合征（FXS）的ID形式。好消息是，目前正在进行临床试验，试图纠正FXS中出现的突触传递的一些变化。我们想看看，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（也许更多）形式的ID实际上是相关的，这为治疗一种形式的ID可能也适用于另一种形式的ID提供了希望。

项目成果

Age-related functional brain changes in FMR1 premutation carriers.

• DOI: 10.1016/j.nicl.2017.12.016
• 发表时间: 2018
• 期刊: NeuroImage. Clinical
• 作者: Brown SSG;Basu S;Whalley HC;Kind PC;Stanfield AC
• 通讯作者: Stanfield AC

Loss of protohaem IX farnesyltransferase in mature dentate granule cells impairs short-term facilitation at mossy fibre to CA3 pyramidal cell synapses.

• DOI: 10.1113/jp273581
• 发表时间: 2017-03-15
• 期刊: The Journal of physiology
• 作者: Booker SA;Campbell GR;Mysiak KS;Brophy PJ;Kind PC;Mahad DJ;Wyllie DJ
• 通讯作者: Wyllie DJ

Altered thalamocortical development in the SAP102 knockout model of intellectual disability.

• DOI: 10.1093/hmg/ddw244
• 发表时间: 2016-09-15
• 期刊: Human molecular genetics
• 影响因子: 3.5
• 作者: Crocker-Buque A;Currie SP;Luz LL;Grant SG;Duffy KR;Kind PC;Daw MI
• 通讯作者: Daw MI

Sustained correction of associative learning deficits after brief, early treatment in a rat model of Fragile X Syndrome.

• DOI: 10.1126/scitranslmed.aao0498
• 发表时间: 2019-05-29
• 期刊: Science translational medicine
• 影响因子: 17.1
• 作者: Asiminas A;Jackson AD;Louros SR;Till SM;Spano T;Dando O;Bear MF;Chattarji S;Hardingham GE;Osterweil EK;Wyllie DJA;Wood ER;Kind PC
• 通讯作者: Kind PC

Experience-Dependent, Layer-Specific Development of Divergent Thalamocortical Connectivity.

• DOI: 10.1093/cercor/bhu031
• 发表时间: 2015-08
• 期刊: Cerebral cortex (New York, N.Y. : 1991)
• 作者: Crocker-Buque A;Brown SM;Kind PC;Isaac JT;Daw MI
• 通讯作者: Daw MI