Ionic currents and spiking in cerebellar nuclear neurons

描述(申请人提供)：许多神经元是沉默的，直到突触兴奋。然而，在一些回路中，包括小脑的回路，越来越明显的是，在没有突触输入的情况下，个别神经元本质上是活跃的，自发地发出规则的动作电位。在这类神经元中，突触的兴奋或抑制不是诱导或阻止动作电位，而是调节固有的放电模式。目前的提议是基于这样一个问题，即在一个具有自发活动元素的系统中，什么构成信号，什么构成噪声。其目标是探索“有效”突触信号背后的机制--即那些显著改变突触后放电的因素--并最终测试通过可塑性或病理生理学来调制或破坏突触信号的后果。 拟议的研究集中在浦肯野神经元和小脑核神经元之间的突触传递。组织将来自2-3周龄的野生型和共济失调小鼠。实验将在急性分离的小脑核神经元上进行，或者在小脑切片上进行，其中浦肯野神经元的突触接触是完整的。刺激浦肯野细胞传入引起的抑制性突触反应的电压钳和电流钳记录，抑制性神经递质受体动力学的记录，以及组织学研究将被用来研究浦肯野到核细胞突触的突触抑制的机制。由此产生的数据将提供关于神经回路中自发活动元件的适应性意义的一般信息，以及关于功能和功能失调的小脑中信息传递的细胞基础的具体信息。

DESCRIPTION (provided by applicant): Many neurons are silent until excited synaptically. In some circuits, including those of the cerebellum, however, it is becoming clear that individual neurons are intrinsically active, firing regular action potentials spontaneously, in the absence of synaptic input. In such neurons, rather than inducing or preventing action potentials, synaptic excitation or inhibition modulates the intrinsic firing pattern. The current proposal is motivated by the question of what constitutes signal and what constitutes noise in a system with spontaneously active elements. The goal is to explore the mechanisms underlying "effective" synaptic signals--i.e. , those that significantly modify postsynaptic firing--and ultimately to test the consequences of modulating or disrupting synaptic signals, either by plasticity or by pathophysiology. The proposed research focuses on synaptic transmission between Purkinje neurons and cerebellar nuclear neurons. Tissue will be used from 2-3 week old wild-type and ataxic mice. Experiments will be performed on cerebellar nuclear neurons either in acute isolation or in cerebellar slices in which synaptic contacts from Purkinje neurons are intact. Voltage-clamp and current-clamp recordings of inhibitory synaptic responses evoked by stimulation of Purkinje cell afferents, recordings of inhibitory neurotransmitter receptor kinetics, and histological studies will be used to examine the mechanisms underlying synaptic depression at the Purkinje-to-nuclear cell synapse. The resulting data will provide general information about the adaptive significance of spontaneously active elements in neural circuits, as well as specific information about cellular basis of information transfer in the functional and dysfunctional cerebellum.