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Regulation of plateau potentials by dendritically targeted inhibitory synaptic transmission.

通过树突靶向抑制性突触传递调节平台电位。

基本信息

批准号：
BB/V001728/1
负责人：
Jack Mellor
金额：
$ 62.42万
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：
2021
资助国家：
英国
起止时间：
2021 至无数据
项目状态：
已结题

来源：
https://gtr.ukri.org/projects?ref=BB%2FV001728%2F1
关键词：
Regulation plateau potentials dendritically targeted

项目摘要

Experience-dependent memory is the foundation on which we make all our decisions. Reliable memory encoding is therefore essential for good decision making and our mental health. But what determines the durability of memories and how are they protected from interference by subsequent events? Our brains are not like computers which reliably transcribe all information faithfully and equally - we have a much greater capacity for flexibility. But how do we balance the needs for flexibility and adaptation with reliability and stability?Memory representations in the brain are thought to be encoded in the strength of connections (synapses) between neurons creating assemblies where each neuron represents a distinct aspect of the memory. An excellent example of this are place cells of the hippocampus which each represent one specific location but can group together by strengthening their synaptic connections into assemblies that provide a representation or memory of the whole environment. When we experience a new environment the place cell assemblies must reorganise to form a new representation where each place cell may now "re-map" to a different location. The hippocampus is therefore an excellent system to study the flexibility and stability of memory representations.The biological substrate for memory formation is therefore modifications in the strength of synaptic connections. This plasticity enables the reorganisation of cell assemblies. Synaptic plasticity is triggered by the influx of calcium ions across the synaptic membrane through proteins called NMDA receptors. If multiple excitatory synaptic inputs are activated simultaneous, a plateau potential is generated which is a long-lasting activation of NMDA receptors and calcium influx. These plateau potentials are known to be important in triggering synaptic plasticity to encode new aspects of our environment into place cells. We propose that plateau potentials are controlled by inhibition provided by a specialised subtype of inhibitory neuron termed an OLM interneuron. These inhibitory cells can counteract excitatory synaptic input and are therefore perfectly positioned to regulate plateau potentials and the resulting synaptic plasticity and memory formation. Furthermore, we propose that OLM adaptation is important for creating stable memory representations.In this BBSRC project, we will test the hypothesis that OLM interneurons can control when new place cells can incorporate new information by regulating plateau potentials and synaptic plasticity. To do this we will fill neurons with dyes that fluoresce when calcium ions are present and measure whether a synapse has strengthened or weakened by recording electrical activity from the neurons. We will do this while activating OLM interneurons to test how these cells regulate neuronal calcium and synapse strength. We will then record place cells in the hippocampus and investigate if OLM inputs can keep a place cell stable and prevent new information from destabilising previously encoded representations of the world. This work is important because it will lead to a wealth of new information about place cells and synaptic plasticity. Dysfunctional synaptic plasticity is thought to underlie the altered neuronal activity in several brain diseases, such as Alzheimer's disease and schizophrenia. 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.

依赖经验的记忆是我们做出所有决定的基础。因此，可靠的记忆编码对于良好的决策和我们的心理健康至关重要。但是，是什么决定了记忆的持久性，又是如何保护它们不受后续事件的干扰呢？我们的大脑不像计算机那样可靠地忠实地、平等地转录所有信息--我们有更大的灵活性。但是，我们如何平衡灵活性和适应性与可靠性和稳定性的需求？大脑中的记忆表征被认为是在神经元之间的连接（突触）强度中编码的，这些神经元创建组件，其中每个神经元代表记忆的不同方面。一个很好的例子是海马体中的位置细胞，每一个都代表一个特定的位置，但通过加强它们的突触连接，它们可以聚集在一起，形成对整个环境的代表或记忆。当我们经历新的环境时，位置单元集合必须重新组织以形成新的表示，其中每个位置单元现在可以“重新映射”到不同的位置。因此，海马体是研究记忆表征的灵活性和稳定性的一个极好的系统，因此，记忆形成的生物学基础是突触连接强度的改变。这种可塑性使得细胞组装能够重组。突触可塑性是由钙离子通过称为NMDA受体的蛋白质穿过突触膜的流入触发的。如果同时激活多个兴奋性突触输入，则产生平台电位，这是NMDA受体和钙内流的持久激活。已知这些平台电位在触发突触可塑性以将我们环境的新方面编码到位置细胞中方面是重要的。我们建议，高原电位控制的抑制提供了一个专门的亚型的抑制神经元称为OLM中间神经元。这些抑制性细胞可以抵消兴奋性突触输入，因此完全定位于调节平台电位和由此产生的突触可塑性和记忆形成。此外，我们提出，OLM适应是重要的创造稳定的记忆representations.In这个BBSRC项目，我们将测试的假设，即OLM中间神经元可以控制时，新的位置细胞可以通过调节高原电位和突触可塑性纳入新的信息。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，并通过记录神经元的电活动来测量突触是加强还是减弱。我们将在激活OLM中间神经元的同时进行这项工作，以测试这些细胞如何调节神经元钙和突触强度。然后，我们将记录海马体中的位置细胞，并调查OLM输入是否可以保持位置细胞稳定，并防止新信息破坏先前编码的世界表征。这项工作很重要，因为它将导致大量关于位置细胞和突触可塑性的新信息。突触可塑性功能障碍被认为是几种脑部疾病（如阿尔茨海默病和精神分裂症）中神经元活动改变的基础。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了解，并可能有助于开发新的治疗方法。

项目成果

期刊论文数量（4）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Reduced expression of the psychiatric risk gene DLG2 (PSD93) impairs hippocampal synaptic integration and plasticity.

DOI：
10.1038/s41386-022-01277-6
发表时间：
2022-06
期刊：
NEUROPSYCHOPHARMACOLOGY
影响因子：
7.6
作者：
Griesius, Simonas;O'Donnell, Cian;Waldron, Sophie;Thomas, Kerrie L.;Dwyer, Dominic M.;Wilkinson, Lawrence S.;Hall, Jeremy;Robinson, Emma S. J.;Mellor, Jack R.
通讯作者：
Mellor, Jack R.

Acetylcholine Boosts Dendritic NMDA Spikes in a CA3 Pyramidal Neuron Model.

DOI：
10.1016/j.neuroscience.2021.11.014
发表时间：
2022-05-01
期刊：
Neuroscience
影响因子：
3.3
作者：
Humphries R;Mellor JR;O'Donnell C
通讯作者：
O'Donnell C

Acetylcholine prioritises direct synaptic inputs from entorhinal cortex to CA1 by differential modulation of feedforward inhibitory circuits.

DOI：
10.1038/s41467-021-25280-5
发表时间：
2021-09-16
期刊：
Nature communications
影响因子：
16.6
作者：
Palacios-Filardo J;Udakis M;Brown GA;Tehan BG;Congreve MS;Nathan PJ;Brown AJH;Mellor JR
通讯作者：
Mellor JR

Separable actions of acetylcholine and noradrenaline on neuronal ensemble formation in hippocampal CA3 circuits.