Regulation of Intrinsic Plasticity by CaMKII

描述(申请人提供)：CaMKII在果蝇和其他动物的学习和记忆形成中起着重要的作用。我们最近发现CaMKII改变了果蝇三龄幼虫神经系统中已识别的神经元的兴奋性。我们将研究这种调节的机制，并探索其在神经元可塑性中的可能作用。通过遗传途径获得这些已识别的神经元，将允许对内在特性调节进行机械性研究，这在其他系统中是不可能的。 我们的具体目标是：1)确定CaMKII的遗传和药物操作对中枢神经元兴奋性和行为的影响。我们将观察CaMKII对放电特性的影响，如阈值、尖峰幅度、尖峰波形和放电频率。我们将定义电压依赖的电流，它由短期和长期的激酶活性变化所调制。 2)确定活性依赖的内在特性调节的细胞机制。我们已经证明，活动可以诱导果蝇运动神经元神经元兴奋性的长期增加。我们将对这一现象进行研究，以确定突触后细胞的放电模式、钙内流和活性在诱导过程中的作用。我们将确定活动是否可以改变神经元对其正常突触前伙伴的反应。3)确定活性依赖的内在特性调节的信号转导机制。我们将定义受这一过程调节的电导，并利用转基因和药物研究CaMKII的作用。这些研究将深入了解可塑性的基本机制，并确定CaMKII在调节兴奋性的短期和长期变化中的新角色。了解这些途径将促进我们对塑造行为的基本过程的了解。

DESCRIPTION (provided by applicant): CaMKII plays an important role in learning and memory formation in Drosophila as well as in other animals. We have recently found that CaMKII alters the excitability of identified neurons in the third instar larval nervous system of Drosophila. We will study the mechanisms of this modulation and explore its possible role in neuronal plasticity. Genetic access to these identified neurons will allow mechanistic studies of intrinsic property modulation that have not been possible in other systems. Our specific aims are: 1) Determine the effects of genetic and pharmacological manipulation of CaMKII on the excitability and behavior of central neurons. We will look at the effects of CaMKII on firing properties such as threshold, spike amplitude, spike waveform and firing frequency. We will define the voltage-dependent currents that are modulated by short-term and long-term alteration of kinase activity. 2) Determine the cellular mechanisms of activity-dependent modulation of intrinsic properties. We have shown that activity can induce a long-lasting increase in neuronal excitability in Drosophila motor neurons. We will investigate this phenomenon to determine the roles of firing pattern, calcium influx and activity of the postsynaptic cell in induction. We will determine if activity can change the response of the neuron to its normal presynaptic partners. 3) Determine the signal transduction mechanisms of activity-dependent modulation of intrinsic properties. We will define the conductances that are modulated by this process and investigate the role of CaMKII using transgenes and drugs. These studies will provide insight into a fundamental mechanism of plasticity and define novel roles for CaMKII in the regulation of short-term and long-term changes in excitability. Understanding these pathways will advance our knowledge of the basic processes that shape behavior.