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，如长期增强（LTP）和长期抑制（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主要的细胞学习相关，但经典的mar - albus - ito理论认为，相反，小脑运动学习是由与浦肯野细胞相连的平行纤维（PF）突触上的LTD介导的，随后抑制浦肯野细胞输出的减少。突触后PF-LTP直到最近才被描述（Lev-Ram等人，2002），并被认为为LTD提供了一种逆转机制（Jörntell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了比预期更积极的作用。我们发现浦肯野细胞特异性敲除磷酸酶PP2B （L7-PP2B）的小鼠-不影响LTD，但阻止LTP和内在可塑性（非突触增强）-表现出小脑运动学习受损（Schonewille等人，2010）。LTP已经有了一些详细的描述，其诱导需要适度的钙瞬态和磷酸酶1、2A和2B的激活（Coesmans等，2004；Belmeguenai和Hansel， 2005）。相比之下，内在可塑性仍然是LTP和LTD的一个鲜为人知的兄弟。已经证明，兔子的眨眼条件反射与浦肯野细胞兴奋性增强有关，这可能是由a型K电流的调制引起的（Schreurs等人，1998）。此外，研究表明，PF破伤风引起浦肯野细胞接受野大小的变化（Jörntell and Ekerot, 2002），正如我们现在所知道的，这可能是由LTP共同诱导的内在兴奋性增加引起的（Belmeguenai et al., 2010）。最后，L7-PP2B小鼠两种增强机制的遗传阻断会损害运动学习（见上文）。这些研究表明浦肯野细胞的内在可塑性可能是小脑记忆印记的重要组成部分。本研究的内在可塑性类型需要-就像ltp -磷酸酶激活一样，并通过sk2型K通道的下调介导，从而导致浦肯野细胞spike放电增加（Belmeguenai等，2010；Hosy等，2011）。此外，内在可塑性增强脊柱

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 (Jörntell 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 (Jörntell 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.