Modulation of Neocortical Interneuronal Function

描述(申请人提供)：抑制性中间神经元在正常的新皮质功能中起着许多关键作用。例如，它们塑造感觉感受野，并驱动高频伽马振荡。另一方面，它们的功能缺陷可能导致癫痫发作。我们研究了大鼠新皮质V层的两个主要功能神经元亚类：快速放电(FS)和低阈值放电(ITS)神经元的特性。数据表明，每一组都表达一种新的自我抑制形式，即FS细胞的自举抑制反应和其中间神经元的内源性大麻素介导的慢自抑制。我们将讨论与新皮质中间神经元的自我抑制有关的两个主要问题：1)FS细胞自动在调节棘波计时的精确度和协调快速网络同步方面起什么作用？2)导致其神经元长期抑制的机制是什么，其诱导所需的生理条件是什么？总体而言，这两个实验目标将解决这项拨款的中心主题，即调节和控制新皮质神经元间活动的机制，以及这种调节对新皮质回路功能的功能后果。实验方法包括：单个和成对的全细胞电压和电流钳记录以及可视大鼠新皮质脑片间神经元的穿孔贴片记录；生物细胞素细胞内标记；细胞内和细胞外离子和药物的应用以影响递质释放和受体功能；以及动态钳的使用。这些结果将有助于更好地理解新皮质中间神经元的两个主要亚类的突触调节，并提供与正常和病理生理皮质功能相关的新皮质兴奋性的GABA能调节信息。

DESCRIPTION (provided by applicant): Inhibitory interneurons play a number of key roles in normal neocortical function. For example, they shape sensory receptive fields and drive high frequency gamma oscillations. On the other hand, defects in their function can lead to seizures. We have examined the properties of two major functional interneuronal subclasses: fast spiking (FS) and low-threshold spike firing (ITS) neurons of rat neocortical layer V. Data indicate that each group expresses a novel form of self inhibition, namely autaptic inhibitory responses in FS cells and an endocannabinoid-mediated slow self-inhibition in ITS interneurons. We will address two major questions relevant to self-inhibition of neocortical interneurons: 1) What are the roles of FS cell autapses in regulating precision of spike timing and in coordinating fast network synchrony? 2) What are the mechanisms leading to long-lasting inhibition in ITS neurons, and the physiological conditions necessary for its induction? Overall these two experimental aims will address the central themes of this grant, the mechanisms that modulate and control neocortical interneuronal activities and the functional consequences of such modulation on neocortical circuit function. Experimental approaches will include: single and paired whole cell voltage- and current-clamp recordings and perforated-patch recordings from visualized interneurons in rat neocortical slices; intracellular labeling with biocytin; intracellular and extracellular application of ions and pharmaceutical agents to affect transmitter release and receptor function; and use of dynamic clamp. Results will lead to a better understanding of synaptic modulation of two major subclasses of neocortical interneurons and provide information regarding GABAergic regulation of neocortical excitability relevant to both normal and pathophysiological cortical function.