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 (Jrntell 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 (Jrntell 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.

Public Health Relevance

The cerebellum is a brain area that controls sensory-motor integration and the fine-adjustment of movements through activity-dependent changes in synaptic weights and through adaptive learning within cerebellar circuits. Cerebellar dysfunction leads to motor impairment (ataxia), but has also been linked to non-motor language problems and aspects of autism spectrum disorder (ASD). Here, we plan to develop a novel theory of cerebellar learning and motor control by characterizing and integrating a new type of cerebellar plasticity, non- synaptic (intrinsic) plasticity in cerebellar Purkinje cells, which might provide crucial component of the cerebellar memory engram.

National Institute of Health (NIH)
National Institute of Neurological Disorders and Stroke (NINDS)
Research Project (R01)
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Neurobiology of Learning and Memory Study Section (LAM)
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Chen, Daofen
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University of Chicago
Schools of Medicine
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Ohtsuki, Gen; Hansel, Christian (2018) Synaptic Potential and Plasticity of an SK2 Channel Gate Regulate Spike Burst Activity in Cerebellar Purkinje Cells. iScience 1:49-54
Titley, Heather K; Brunel, Nicolas; Hansel, Christian (2017) Toward a Neurocentric View of Learning. Neuron 95:19-32
Titley, Heather K; Hansel, Christian (2016) Asymmetries in Cerebellar Plasticity and Motor Learning. Cerebellum 15:87-92
Piochon, Claire; Kano, Masanobu; Hansel, Christian (2016) LTD-like molecular pathways in developmental synaptic pruning. Nat Neurosci 19:1299-310
Grasselli, Giorgio; He, Qionger; Wan, Vivian et al. (2016) Activity-Dependent Plasticity of Spike Pauses in Cerebellar Purkinje Cells. Cell Rep 14:2546-53
Piochon, Claire; Titley, Heather K; Simmons, Dana H et al. (2016) Calcium threshold shift enables frequency-independent control of plasticity by an instructive signal. Proc Natl Acad Sci U S A 113:13221-13226
van Beugen, Boeke J; Qiao, Xin; Simmons, Dana H et al. (2014) Enhanced AMPA receptor function promotes cerebellar long-term depression rather than potentiation. Learn Mem 21:662-7
Rinaldo, Lorenzo; Hansel, Christian (2013) Muscarinic acetylcholine receptor activation blocks long-term potentiation at cerebellar parallel fiber-Purkinje cell synapses via cannabinoid signaling. Proc Natl Acad Sci U S A 110:11181-6
Du, Xiaofei; Wang, Jun; Zhu, Haipeng et al. (2013) Second cistron in CACNA1A gene encodes a transcription factor mediating cerebellar development and SCA6. Cell 154:118-33
Ohtsuki, Gen; Piochon, Claire; Adelman, John P et al. (2012) SK2 channel modulation contributes to compartment-specific dendritic plasticity in cerebellar Purkinje cells. Neuron 75:108-20

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