Action Potential Signaling in Axons of CNS Interneurons

描述（申请人提供）：神经元可能是体内最复杂的细胞，具有分化的结构，包括体细胞，树突和轴突。这种结构多样化使得每个神经元元素都具有专门的功能。电信号在树突上的突触输入位点产生，在体细胞编译，然后在轴突初始段（AIS）启动后以动作电位（ap）的形式传递到轴突上的突触输出位点。在有髓鞘的投射（主）神经元轴突中，快速的有益传导确保产生的ap以刻板的方式迅速传播到释放位点，确保可靠地触发神经传递。直观地说，远距离AP传播的再生特性表明，AIS在确定尖峰波形方面的影响应该在空间上与释放点区分开来。相比之下，紧密中间神经元的无髓鞘轴突中的AP信号知之甚少。我们假设中间神经元的轴突不是AIS的严格中继装置，相反，这些过程也被赋予了局部决定和塑造AP波形的能力，并且这种特性是决定神经传递动力学的重要因素。在本研究中，我们将研究三个关键参数，这些参数将定义和支持小脑星状细胞中间神经元轴突电发生的位置特异性控制：(1)直接测量轴突中的AP波形，(2)将这些发现与轴突形态和轴突室中离子通道的组织联系起来，(3)确定离子通道的位置特异性分布和性质是否赋予轴突兴奋和释放的活动依赖性控制。通过这种方式，这项工作旨在确定可能使中间神经元轴突电发生的区隔组织的特征，目的是将轴突生理学的特定和动态参数与神经回路中的信息处理联系起来。该项目将有助于发展针对轴突功能障碍疾病的治疗策略，其中AP的起始，繁殖和释放的分化可能需要改善特定于这些功能的病理条件。

DESCRIPTION (provided by applicant): Neurons are likely the most complex cell in the body with differentiated structures including a soma, dendrites, and axons. This structural diversification allows for a specialized functionality within each of these neuronal elements. Electrical signals develop at synaptic input sites on the dendrite, are compiled at the soma, and are then transmitted to synaptic output sites on the axon as action potentials (APs) following initiation in the axon initial segment (AIS). In myelinated axons of projection (principal) neurons fast salutatory conduction ensures that the resulting APs are rapidly propagated to release sites in a stereotyped manner ensuring a reliable trigger for neurotransmission. Intuitively, the regenerative nature of AP propagation over long distances suggests that the influence of the AIS in determining spike waveform should be spatially differentiated from sites of release. In comparison, AP signaling in the unmyelinated axons of compact interneurons is poorly understood. We hypothesize that axons of interneurons are not exacting relay devices of the AIS, rather, that these processes are also endowed with a capacity to locally determine and sculpt AP waveforms and that this property is an important element in determining dynamics of neurotransmission. In this proposal, we will examine three key parameters that would define and support location-specific control of axonal electrogenesis in cerebellar stellate cell interneurons: (1) directly measure AP waveforms in axons, (2) relate these findings to axon morphology and to the organization of ion channels in axonal compartments, and (3) determine whether the location-specific distribution and properties of ion channels confers activity-dependent control of axonal excitation and release. In this way, this work aims to identify the characteristics that may enable compartmental organization of axonal electrogenesis in interneurons with the goal of relating the specific and dynamic parameters of axon physiology to information processing in neural circuits. This project will help inform the development of therapeutic strategies targeting diseases of axon dysfunction where differentiation of AP initiation, propagation, and release may be required to ameliorate pathological conditions specific to each of these functions.