Activity and synaptic maturation in the spinal cord

描述(由申请人提供)：平衡网络中兴奋性和抑制性元件的强度对于电路的正常运行至关重要。如果兴奋系统占优势，可能会导致痉挛或癫痫样活动。电路发展的时期是至关重要的，因为正是在那时，平衡才首先建立起来。洞察发育过程中调节兴奋性和抑制性突触强度的机制将为我们理解网络如何达到这种平衡提供关键的一步。在培养的神经元中发现了一种新的突触可塑性，这表明神经元通过调节其突触输入的强度(突触缩放)来稳态地调节其尖峰活动水平。这项应用的目的是确定在脊髓运动网络胚胎发育过程中，突触后神经元的刺激性活动水平驱动突触强度的成熟。为此，我们将阻止运动网络或鸡胚胎卵子中单个脊髓神经元的尖峰活动。通过比较活动阻断神经元和对照神经元中突触输入的强度，我们将测试活动在兴奋性运动神经元(特定目标1和2)和已识别的抑制性GABA能中间神经元(特定目标3和4)中调节突触强度的作用。这是可能的，因为我们最近描述了一类接受运动神经元直接输入的中间神经元。结合分子、电生理、光学和免疫细胞化学技术，我们建议开始一项全面的研究，以了解活动在兴奋性和抑制性脊髓神经元兴奋性和抑制性突触强度发展中的作用。我们提出，活动水平调节胚胎中新形成的突触连接的强度。这项研究的结果将有助于更好地理解网络在发育过程中如何在兴奋性和抑制性成分之间实现平衡。

DESCRIPTION (provided by applicant): Balancing the strength of excitatory and inhibitory elements within a network is essential for the proper function of the circuit. If excitatory systems dominate, spasticity or epileptiform activity could result. The period of circuit development is of crucial importance because it is then that the balance is first established. Insight to mechanisms that regulate excitatory and inhibitory synaptic strength during development would provide a critical step in our understanding of how networks arrive at this balance. A new form of synaptic plasticity has been identified in cultured neurons, which suggests that neurons homeostatically regulate their level of spiking activity by adjusting the strength of their synaptic inputs (synaptic scaling). The objective of this application is to determine the level of spiking activity in the postsynaptic neuron drives the maturation of synaptic strength during embryonic development of spinal motor networks. To this end we will block spiking activity in the motor network or in individual spinal neurons in ovo in the chick embryo. By comparing the strength of the synaptic inputs in activity-blocked and control neurons we will test the role of activity in the regulation of synaptic strength in an excitatory motoneuron (Specific Aim 1 & 2) and in an identified inhibitory GABAergic interneuron (Specific Aim 3 & 4). This is possible because we have recently characterized a class of interneuron that receives direct input from motoneurons. Using a combination of molecular, electrophysiological, optical, and immunocytochemical techniques we are proposing to begin a comprehensive study to understand the role of activity in the development of excitatory and inhibitory synaptic strength in excitatory and inhibitory spinal neurons. We are proposing that the level of activity regulates the strength of newly formed synaptic connections in the embryo. The results of the study will provide a better understanding of how a network achieves a balance between excitatory and inhibitory elements during development.