Intrinsic Plasticity and Information Storage in Cerebellar Purkinje Cells

描述（由申请人提供）：突触重量的经验依赖性变化-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。虽然LTP被认为是大多数神经回路中的主要细胞学习相关，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）突触上介导的，并且随后减少抑制性浦肯野细胞输出。突触后PF-LTP最近才被描述（Lev-Ram等人，2002），并已建议为LTD提供逆转机制（J？rntell和Hansel，2006）。然而，在过去的资助期间，我们证明了增强机制在小脑学习中发挥的作用比预期的更积极。我们发现，浦肯野细胞特异性敲除磷酸酶PP 2B（L7-PP 2B）的小鼠-其不影响LTD，但阻止LTP和内在可塑性（非突触增强）-显示出受损的小脑运动学习（Schonewille等人，2010年）。LTP已被详细描述，并且其诱导显示需要适度的钙瞬变和磷酸酶1、2A和2B的活化（Coesmans等人，2004; Belmeguenai and Hansel，2005）。相反，内在可塑性仍然是LTP和LTD的一个知之甚少的兄弟。已经证明，兔的眨眼条件反射与增强的浦肯野细胞兴奋性相关，这可能是由A型K电流的调节引起的（Schreurs等人，1998年）。此外，已经表明PF强直化引起浦肯野细胞感受野大小的变化（J rntell和Ekerot，2002），正如我们现在所知道的，这可能是由可以与LTP共同诱导的内在兴奋性增加引起的（Belmeguenai等人，2010年）。最后，L7-PP 2B小鼠中两种增强机制的遗传阻断损害运动学习（见上文）。这些研究表明，浦肯野细胞的内在可塑性可能提供了一个小脑记忆印迹的重要组成部分。这里研究的内在可塑性的类型需要-就像LTP-磷酸酶激活一样，并且由SK2型K通道的下调介导，这导致浦肯野细胞尖峰放电的增加（Belmeguenai等人，2010; Hosy等人，2011年）。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年）。此外，内在可塑性以区室特异性方式放大树突信号，表明兴奋性变化可以保持局部限制（Ohtsuki等人，2012年）。在这个项目中，我们将研究内在和突触可塑性如何在小脑学习和产生记忆印迹中相互补充。我们将检验以下假设：a）内在可塑性改变了控制LTD / LTP平衡的指导性CF信号，b）它缩短了爆发后的尖峰停顿，从而调节了浦肯野细胞的输出。我们将研究SK2基因敲除小鼠的运动控制和学习，并将使用膜片钳记录来研究体内的内在可塑性。我们的目标是发展一种新的小脑学习理论，整合突触和内在可塑性的特征。

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.