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Regulation of spine Ca2+ dynamics and spike timing-dependent synaptic plasticity by muscarinic acetylcholine receptors

毒蕈碱乙酰胆碱受体对脊柱 Ca2 动力学和尖峰时间依赖性突触可塑性的调节

基本信息

批准号：
BB/K000454/1
负责人：
Jack Mellor
金额：
$ 46.79万
依托单位：
University of Bristol
依托单位国家：
英国
项目类别：
Research Grant
财政年份：
2012
资助国家：
英国
起止时间：
2012 至无数据
项目状态：
已结题

来源：
https://gtr.ukri.org/projects?ref=BB%2FK000454%2F1
关键词：
Regulation spine Ca2+dynamics spike

项目摘要

Our memories define who we are and are therefore fundamental to our existence and mental health. Furthermore, having a "good" memory is perceived to be a major advantage throughout life. Conversely, the loss of memory in pathological diseases such as Alzheimer's disease is tremendously debilitating and stressful. One of the key mechanisms that underlie memory is the ability of nerve cells (neurons) to change the strength of their connections with other neurons. These connections are called synapses and so any change in their strength is called "synaptic plasticity". This process is thought to underlie learning and memory, because memories are likely to be stored in a circuit of interconnected neurons. Synaptic plasticity is triggered by the influx of calcium ions into small compartments of neurons called spines. Calcium ions pass across the synaptic membrane through proteins called NMDA receptors which are activated by coincident activity in the two neurons that form the synapse. The sensitivity to coincident activity regulates how many calcium ions are allowed into the neuron by the NMDA receptor and therefore controls the induction of synaptic plasticity. We have recently found that the neurotransmitter acetylcholine that is released in the brain during specific behavioural states can regulate the intrinsic properties of spines and thus control the opening of NMDA receptors and induction of synaptic plasticity. This provides an explanation for the common observation that behavioural states play a major role in determining whether we remember things, or forget them. We are going to investigate the mechanisms by which acetylcholine controls memory by performing experiments to find out how acetylcholine regulates calcium ion influx through NMDA receptors and therefore the induction of synaptic plasticity. To do this we will fill neurons with dyes that fluoresce when calcium ions are present. We will also measure whether a synapse has strengthened or weakened by recording electrical activity from the neurons. These techniques will enable us to visualize the influx of calcium ions during the process of synaptic plasticity. This work is important because it will lead to a wealth of new information about synaptic plasticity, and hence learning and memory mechanisms. Dysfunctional synaptic plasticity is thought to underlie the altered neuronal activity in several brain diseases, such as Alzheimer's disease, schizophrenia and autism. The most common and effective treatment currently available for Alzheimer's patients are drugs that mimic or enhance the actions of acetylcholine. Therefore, the mechanisms that we will study in this research will add to our knowledge about these debilitating diseases, and may contribute to developing novel therapies.

我们的记忆定义了我们是谁，因此对我们的存在和心理健康至关重要。此外，拥有“良好”的记忆力被认为是一生的主要优势。相反，病理性疾病（如阿尔茨海默病）的记忆丧失会极大地使人衰弱和紧张。记忆背后的关键机制之一是神经细胞（神经元）改变与其他神经元连接强度的能力。这些连接被称为突触，因此它们强度的任何变化都被称为“突触可塑性”。这一过程被认为是学习和记忆的基础，因为记忆很可能存储在相互连接的神经元回路中。突触的可塑性是由钙离子流入神经元的小隔间引起的。钙离子通过一种叫做NMDA受体的蛋白质穿过突触膜，这种蛋白质被形成突触的两个神经元的同步活动激活。对一致活动的敏感性调节了NMDA受体允许多少钙离子进入神经元，从而控制突触可塑性的诱导。我们最近发现，在特定的行为状态下，大脑中释放的神经递质乙酰胆碱可以调节脊柱的内在特性，从而控制NMDA受体的开放和突触可塑性的诱导。这就解释了一个常见的现象，即行为状态在决定我们是记住还是忘记它们方面起着重要作用。我们将通过实验来研究乙酰胆碱是如何通过NMDA受体调节钙离子流入从而诱导突触可塑性的，从而研究乙酰胆碱控制记忆的机制。为了做到这一点，我们将在神经元中填充染料，当钙离子存在时，染料会发出荧光。我们还将通过记录神经元的电活动来测量突触是否增强或减弱。这些技术将使我们能够可视化在突触可塑性过程中钙离子的流入。这项工作很重要，因为它将导致大量关于突触可塑性的新信息，从而导致学习和记忆机制。功能失调的突触可塑性被认为是一些脑部疾病（如阿尔茨海默病、精神分裂症和自闭症）中神经元活动改变的基础。目前对阿尔茨海默病患者最常见和有效的治疗方法是模仿或增强乙酰胆碱作用的药物。因此，我们将在这项研究中研究的机制将增加我们对这些使人衰弱的疾病的认识，并可能有助于开发新的治疗方法。

项目成果

期刊论文数量（10）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Inhibition of post-synaptic Kv7/KCNQ/M channels facilitates long-term potentiation in the hippocampus.

DOI：
10.1371/journal.pone.0030402
发表时间：
2012
期刊：
PloS one
影响因子：
3.7
作者：
Petrovic MM;Nowacki J;Olivo V;Tsaneva-Atanasova K;Randall AD;Mellor JR
通讯作者：
Mellor JR

Neuromodulation of the Feedforward Dentate Gyrus-CA3 Microcircuit.

DOI：
10.3389/fnsyn.2016.00032
发表时间：
2016
期刊：
Frontiers in synaptic neuroscience
影响因子：
3.7
作者：
Prince LY;Bacon TJ;Tigaret CM;Mellor JR
通讯作者：
Mellor JR

Cholinergic modulation of hippocampal network function.

DOI：
10.3389/fnsyn.2013.00002
发表时间：
2013
期刊：
Frontiers in synaptic neuroscience
影响因子：
3.7
作者：
Teles-Grilo Ruivo LM;Mellor JR
通讯作者：
Mellor JR

Wavelet transform-based de-noising for two-photon imaging of synaptic Ca2+ transients.

基于小波变换的突触 Ca2 瞬变双光子成像去噪。

DOI：
10.1016/j.bpj.2013.01.015
发表时间：
2013
期刊：
Biophysical journal
影响因子：
3.4
作者：
Tigaret CM
通讯作者：
Tigaret CM

Activation of Muscarinic M1 Acetylcholine Receptors Induces Long-Term Potentiation in the Hippocampus.

DOI：
10.1093/cercor/bhv227
发表时间：
2016-01
期刊：
Cerebral cortex (New York, N.Y. : 1991)
影响因子：
0
作者：
Dennis SH;Pasqui F;Colvin EM;Sanger H;Mogg AJ;Felder CC;Broad LM;Fitzjohn SM;Isaac JT;Mellor JR
通讯作者：
Mellor JR