Intrinsic Plasticity and Information Storage in Cerebellar Purkinje Cells

小脑浦肯野细胞的内在可塑性和信息存储

基本信息

批准号：
9244852
负责人：
Christian Robert Hansel
金额：
$ 30.14万
依托单位：
UNIVERSITY OF CHICAGO
依托单位国家：
美国
项目类别：
财政年份：
2008
资助国家：
美国
起止时间：
2008-09-30 至 2019-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9244852
关键词：
Action Potentials Affect Apamin Area Ataxia Blinking Brain Calcineurin Calcium Calcium Signaling Calcium Spikes Cerebellar Diseases Cerebellum Chemosensitization Closure by clamp Complement Coupling Dendrites Down-Regulation Electrophysiology (science)Equilibrium Excitatory Postsynaptic Potentials Fiber Fire - disasters Frequencies Funding Gait Genetic Germany Goals Golgi Apparatus Hippocampus (Brain)Image Impairment In Vitro Individual Information Storage Institutes Instruction Knock-out Knockout Mice Language Learning Link Lobule Long-Term Depression Long-Term Potentiation Mediating Memory Modernization Monitor Morphology Motor Motor Skills Movement Mus Muscarinic Acetylcholine Receptor N-Methyl-D-Aspartate Receptors Oryctolagus cuniculus Output Pattern Pharmacology Phosphoric Monoester Hydrolases Play Potassium Channel Probability Property Purkinje Cells Rattus Receptor Activation Role Sensory Siblings Signal Transduction Slice Structure Synapses Synaptic plasticity System Testing Universities Vertebral column Vibrissae Weight Wild Type Mouse adaptive learning autism spectrum disorder awake calbindin conditioning experience experimental study in vivo large-conductance calcium-activated potassium channels memory encoding motor control motor impairment motor learning neural circuit neuronal cell body novel patch clamp postsynaptic prevent public health relevance receptive field response sensory stimulus theories

项目摘要

DESCRIPTION (provided by applicant): Experience-dependent changes in synaptic weight-such as in long-term potentiation (LTP) and long-term depression (LTD)-are at the core of modern theories on memory formation. While LTP is considered to be the main cellular learning correlate in most neural circuits, classic Marr-Albus-Ito theories suggest that, in contrast, cerebellar motor learning is mediated by LTD at parallel fiber (PF) synapses onto Purkinje cells, and a subsequent reduction of the inhibitory Purkinje cell output. Postsynaptic PF-LTP was only recently described (Lev-Ram et al., 2002) and has been suggested to provide a reversal mechanism for LTD (J�rntell and Hansel, 2006). During the past funding period we demonstrated, however, that potentiation mechanisms play a more active role in cerebellar learning than anticipated. We found that mice with a Purkinje cell-specific knockout of phosphatase PP2B (L7-PP2B)-which does not affect LTD, but prevents LTP and intrinsic plasticity (non-synaptic potentiation)-show impaired cerebellar motor learning (Schonewille et al., 2010). LTP has been described in some detail and its induction was shown to require moderate calcium transients and activation of phosphatases 1, 2A and 2B (Coesmans et al., 2004; Belmeguenai and Hansel, 2005). Intrinsic plasticity, in contrast, remains a poorly understood sibling of LTP and LTD. It has been demonstrated that eyeblink conditioning in rabbits is associated with enhanced Purkinje cell excitability that may result from a modulation of A-type K currents (Schreurs et al., 1998). Moreover, it has been shown that PF tetanization causes changes in Purkinje cell receptive field size (J�rntell and Ekerot, 2002) that might-as we know now-well result from intrinsic excitability increases that can be co-induced with LTP (Belmeguenai et al., 2010). Finally, genetic blockade of both potentiation mechanisms in L7-PP2B mice impairs motor learning (see above). These studies show that Purkinje cell intrinsic plasticity might provide a crucial component of a cerebellar memory engram. The type of intrinsic plasticity studied here requires-just like LTP-phosphatase activation, and is mediated by a down-regulation of SK2-type K channels, which causes an increase in Purkinje cell spike firing (Belmeguenai et al., 2010; Hosy et al., 2011). Moreover, intrinsic plasticity enhances spine calcium transients and prevents subsequent LTP induction (Belmeguenai et al., 2010). In addition, intrinsic plasticity amplifies dendritic signals in a compartment-specific manner, suggesting that excitability changes can remain locally restricted (Ohtsuki et al., 2012). In this project, we will study how intrinsic and synaptic plasticity may complement each other in cerebellar learning and in generating a memory engram. We will test the hypothesis that a) intrinsic plasticity alters the instructive CF signal that controls the LTD / LTP balance, and thatb) it shortens spike pauses that follow bursts, thus modulating the Purkinje cell output. We will examine motor control and learning in SK2 knockout mice and will use patch-clamp recordings to study intrinsic plasticity properties in vivo. Our goal is to develop a novel theory of cerebellr learning that integrates features of both synaptic and intrinsic plasticity.

描述（由适用提供）：突触体重的经验依赖性变化，例如长期增强（LTP）和长期抑郁症（LTD） - 在现代理论的核心记忆形成方面。尽管LTP在大多数中性电路中被认为是主要的细胞学习相关性，但经典的Marr-Albus-Ito理论表明，相反，小脑运动学习是由LTD在平行纤维（PF）突触到Purkinje细胞上的LTD介导的，随后降低了抑制Purkinje Cellje Cellje Cellje Cell Jell Jullje Cell的输出。突触后PF-LTP最近才被最近描述（Lev-Ram等，2002），并被建议为LTD提供逆转机制（J. Rntell和Hansel，2006）。然而，在过去的资金期间，我们证明了增强机制在小脑学习中起着比预期的更为积极的作用。我们发现，磷酸酶PP2B（L7-PP2B）的Purkinje细胞特异性敲除 - 不影响LTD的小鼠，但可以防止LTP和内在可塑性（非突触增强） - 展示小脑运动障碍（Schoonewille等人，2010年）。 LTP已被详细描述，其诱导表明需要中等的钙瞬变和磷酸酶1、2a和2b的激活（Coesmans等，2004； Belmegueenai和Hansel，2005）。相比之下，固有的可塑性仍然是LTP和LTD的兄弟姐妹的知识。已经证明，兔子中的眉毛条件与增强的浦肯野细胞兴奋性有关，这可能是由于A型K电流的调节而导致的（Schreurs等，1998）。此外，已经表明，PF四烷化会导致Purkinje细胞受体场大小的变化（J.Rntell和Ekerot，2002年），这可能 - 我们现在知道，现在可以与LTP共同引起的固有令人兴奋的增长所致（Belmegueenai等人，2010年）。最后，在L7-PP2B小鼠中对两种增强机制的遗传阻塞都损害运动学习（请参见上文）。这些研究表明，浦肯野细胞的内在可塑性可能是小脑记忆器官的关键组成部分。此处的内在可塑性研究类型需要像LTP-磷酸酶激活一样，并且是由SK2型K通道的下调介导的，这会导致Purkinje Cell Spike Direing的增加（Belmegueenai等，2010； Hosy等，2010; Hosy et al。，2011）。此外，内在的可塑性增强脊柱钙瞬变并防止随后的LTP诱导（Belmeguenai等，2010）。此外，内在的可塑性放大器以隔室特异性的方式树突状信号，这表明令人兴奋的变化可以在局部受到限制（Ohtsuki等，2012）。在这个项目中，我们将研究固有和合成可塑性如何在小脑学习和产生记忆器官中相互补充。我们将测试以下假设：a）内在可塑性改变了控制LTD / LTP平衡的指导性CF信号，并且该假设缩短了随后爆发的尖峰暂停，从而调节了Purkinje Cell的输出。我们将检查SK2敲除小鼠中的运动控制和学习，并将使用贴片钳记录研究体内内在的可塑性特性。我们的目标是开发一个新颖的小脑学习理论，该理论整合了突触可塑性和内在可塑性的特征。