Action Potential Signaling in Axons of CNS Interneurons

描述（由申请人提供）：神经元可能是体内最复杂的细胞，具有分化的结构，包括索马、树突和轴突。这种结构多样化允许在这些神经元元件中的每一个内具有专门的功能。电信号在树突上的突触输入位点处产生，在索马处编译，然后在轴突起始段（AIS）中起始后作为动作电位（AP）被传输到轴突上的突触输出位点。在投射（主）神经元的有髓鞘轴突中，快速的敬礼传导确保了所产生的AP以刻板的方式快速传播到释放位点，从而确保了神经传递的可靠触发。直觉上，AP传播的再生性质在长距离上表明，AIS在确定尖峰波形的影响应在空间上区分从网站的释放。相比之下，AP信号在致密的中间神经元的无髓鞘轴突知之甚少。我们假设中间神经元的轴突不是AIS的严格中继设备，相反，这些过程也被赋予了本地确定和雕刻AP波形的能力，并且这种特性是确定神经传递动力学的重要因素。在这个提议中，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隔室中离子通道的组织相关联，以及（3）确定离子通道的位置特异性分布和性质是否赋予轴突激发和释放的活性依赖性控制。以这种方式，这项工作的目的是确定的特点，可能使房室组织的轴突电发生在中间神经元与相关的具体和动态参数的轴突生理学的神经回路中的信息处理的目标。该项目将有助于告知针对轴突功能障碍疾病的治疗策略的发展，其中可能需要AP启动，传播和释放的分化来改善这些功能中的每一个特定的病理条件。

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.