Regulation of plateau potentials by dendritically targeted inhibitory synaptic transmission.

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？我们的大脑不像电脑那样可靠地、忠实地、平等地转录所有信息——我们有更大的灵活性。但我们如何在灵活性和适应性需求与可靠性和稳定性之间取得平衡呢？大脑中的记忆表征被认为是由神经元之间的连接强度（突触）编码的，每个神经元代表记忆的不同方面。海马体的位置细胞就是一个很好的例子，每个位置细胞代表一个特定的位置，但它们可以通过加强突触连接组合在一起，从而提供对整个环境的表征或记忆。当我们经历一个新的环境时，位置细胞集合必须重新组织形成一个新的表征，每个位置细胞现在可能“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绝佳系统。因此，记忆形成的生物学基础是突触连接强度的改变。这种可塑性使细胞组装得以重组。突触的可塑性是由钙离子通过一种叫做NMDA受体的蛋白质流入突触膜引起的。如果多个兴奋性突触输入同时被激活，则会产生平台电位，这是NMDA受体和钙内流的长期激活。已知这些平台电位在触发突触可塑性以将环境的新方面编码到位置细胞中是重要的。我们认为平台电位是由抑制神经元的一种特殊亚型（称为OLM中间神经元）提供的抑制所控制的。这些抑制性细胞可以抵消兴奋性突触输入，因此处于调节平台电位和由此产生的突触可塑性和记忆形成的完美位置。此外，我们提出OLM自适应对于创建稳定的记忆表示非常重要。在本BBSRC项目中，我们将验证OLM中间神经元通过调节平台电位和突触可塑性来控制新位置细胞何时吸收新信息的假设。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增强还是减弱。我们将在激活OLM中间神经元的同时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，并研究OLM输入是否能保持位置细胞的稳定，并防止新信息破坏先前编码的世界表征。这项工作很重要，因为它将带来大量关于位置细胞和突触可塑性的新信息。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认识，并可能有助于开发新的治疗方法。

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.