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：
8807947
负责人：
Christian Robert Hansel
金额：
$ 33.86万
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/8807947
关键词：
Action Potentials Affect Apamin Area Ataxia Blinking Brain Calcineurin Calcium Calcium Signaling Calcium Spikes Cerebellar Diseases Cerebellum Chemosensitization Complement Coupling Dendrites Down-Regulation Equilibrium Excitatory Postsynaptic Potentials Fiber Fire - disasters Frequencies Funding Gait Genetic Germany Goals Golgi Apparatus Health Hippocampus (Brain)Image In Vitro Individual Information Storage Institutes Knock-out Knockout Mice Language Learning Link Lobule Long-Term Depression Long-Term Potentiation Mediating Memory Monitor Morphology Motor Motor Skills Movement Mus Muscarinic Acetylcholine Receptor N-Methyl-D-Aspartate Receptors Oryctolagus cuniculus Output Pattern Phosphoric Monoester Hydrolases Play Potassium Channel Probability Process Property Purkinje Cells Rattus Receptor Activation Role Sensory Sensory Process Siblings Signal Transduction Slice Structure Synapses Synaptic plasticity System Testing Time Universities Vertebral column Vibrissae Weight Wild Type Mouse autism spectrum disorder awake calbindin conditioning experience 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 receptive field research study 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（由申请人提供）：突触重量的依赖于经验的变化——例如长时程增强（LTP）和长时程抑制（LTD）——是现代记忆形成理论的核心。是大多数神经回路中主要的细胞学习相关性，经典的 Marr-Albus-Ito 理论表明，相反，小脑运动学习是由位于浦肯野细胞的平行纤维 (PF) 突触处的 LTD 介导的，抑制性浦肯野细胞输出的随后减少最近才被描述（Lev-Ram 等人，2002），并被建议为 LTD 提供逆转机制（J¿rntell 和 Hansel，2006）。然而，在过去的资助期间，我们发现，增强机制在小脑学习中发挥着比预期更积极的作用，我们发现浦肯野细胞特异性敲除的小鼠。磷酸酶 PP2B (L7-PP2B) - 不影响 LTD，但会阻止 LTP 和内在可塑性（非突触增强） - 显示小脑运动学习受损（Schonewille 等人，2010）对其 LTP 进行了详细描述。诱导需要适度的钙瞬变和磷酸酶 1、2A 和 2B 的激活（Coesmans 等人， 2004 年；Belmeguenai 和 Hansel，2005 年）相比之下，LTP 和 LTD 的兄弟姐妹仍然知之甚少，已经证明，兔子的眨眼调节与浦肯野细胞兴奋性的增强有关，这可能是由于 A- 的调节所致。 K 型电流（Schreurs 等人，1998）此外，研究表明 PF 强直作用会导致 PF 的变化。浦肯野细胞感受野大小 (J¿最后，L7-PP2B 小鼠中两种增强机制的基因阻断会损害运动学习（见上文）。这些研究表明，浦肯野细胞内在可塑性可能提供小脑记忆印迹的关键组成部分。此处研究需要 - 就像 LTP 磷酸酶激活一样，并且由 SK2 型 K 通道下调介导，从而导致浦肯野细胞放电尖峰增加（Belmeguenai 等人，2010；Hosy 等人，2011）此外，内在的可塑性增强了脊柱钙瞬变并阻止随后的 LTP 诱导（Belmeguenai 等人，2010）。此外，内在可塑性以特定的方式放大树突信号，表明兴奋性变化可能仍然受到局部限制（Ohtsuki 等人，2012）。在该项目中，我们将研究内在可塑性和突触可塑性如何在小脑学习和生成记忆印迹中相互补充。我们将检验以下假设：a) 内在可塑性。可塑性改变了控制 LTD / LTP 平衡的指导性 CF 信号，b) 它缩短了爆发后的尖峰暂停，从而调节浦肯野细胞输出。我们将检查 SK2 敲除小鼠的运动控制和学习，并将使用膜片钳记录。研究体内的内在可塑性特性我们的目标是开发一种新的小脑学习理论，该理论整合了突触和内在可塑性的特征。