Synaptic inhibition of Purkinje cells mediates consolidation of vestibulo-cerebellar motor learning

Wulff, Peer; Schonewille, Martijn; Renzi, Massimiliano; Viltono, Laura; Sassoè‐Pognetto, Marco; Badura, Aleksandra; Gao, Zhenyu; Hoebeek, Freek E.; Dorp, Stijn van; Wisden, William; Farrant, M; Zeeuw, Chris I. De

doi:10.1038/nn.2348

Cited by 266 publications

(349 citation statements)

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“…However, mutant mice with blocked AMPAR internalization showed no deficits in VOR gain-increase and gain-decrease learning despite the lack of LTD (13). The absence of LTD might be compensated by feed-forward inhibition from the ML inhibitory interneurons to PCs (28). Other contributors including long-term potentiation of PF-PC synapses might be also relevant for VOR gain increase and gain decrease (15).…”

Section: Discussionmentioning

confidence: 99%

Distinct cerebellar engrams in short-term and long-term motor learning

Wang

Nakadate

Masugi-Tokita

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

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Cerebellar motor learning is suggested to be caused by long-term plasticity of excitatory parallel fiber-Purkinje cell (PF-PC) synapses associated with changes in the number of synaptic AMPA-type glutamate receptors (AMPARs). However, whether the AMPARs decrease or increase in individual PF-PC synapses occurs in physiological motor learning and accounts for memory that lasts over days remains elusive. We combined quantitative SDS-digested freeze-fracture replica labeling for AMPAR and physical dissector electron microscopy with a simple model of cerebellar motor learning, adaptation of horizontal optokinetic response (HOKR) in mouse. After 1-h training of HOKR, short-term adaptation (STA) was accompanied with transient decrease in AMPARs by 28% in target PF-PC synapses. STA was well correlated with AMPAR decrease in individual animals and both STA and AMPAR decrease recovered to basal levels within 24 h. Surprisingly, long-term adaptation (LTA) after five consecutive daily trainings of 1-h HOKR did not alter the number of AMPARs in PF-PC synapses but caused gradual and persistent synapse elimination by 45%, with corresponding PC spine loss by the fifth training day. Furthermore, recovery of LTA after 2 wk was well correlated with increase of PF-PC synapses to the control level. Our findings indicate that the AMPARs decrease in PF-PC synapses and the elimination of these synapses are in vivo engrams in short-and long-term motor learning, respectively, showing a unique type of synaptic plasticity that may contribute to memory consolidation.long-term depression | high-voltage electron microscope | Golgi staining I mage stabilization in the visual field via the vestibulo-ocular reflex and optokinetic response requires accurate extraocular muscle synergies that rely on long-term plastic calibrations in the cerebellar flocculus (FL) and its downstream target vestibular nuclei (VN) (1-8). Long-term depression (LTD) in parallel fiber-Purkinje cell (PF-PC) synapses has been postulated as a possible mechanism for this plastic calibration based on many lines of mutant mice that lack both LTD and learning (9-12). However, LTD's role in motor learning has been recently questioned by a few mutant mice lines (13) and mice with pharmacological treatments (14) that showed lack of LTD but no impairment of learning. Furthermore, long-term potentiation in PF-PC synapses has been also shown to be involved in the motor learning (15). Recent evidence indicates that various forms of synaptic plasticity works synergistically and can compensate each other when one is missing in cerebellar motor learning (16). Despite the apparently contradictory results, no direct evidence for the decrease or increase of synaptic AMPA receptors (AMPARs) has been shown in physiological motor learning. To elucidate in vivo neuronal substrates for motor learning in wildtype mouse, we examined individual PF-PC synapses using quantitative SDS-digested freeze-fracture replica labeling (SDS-FRL) (17) combined with morphometric EM analysis after adaptation of ho...

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Section: Discussionmentioning

confidence: 99%

Distinct cerebellar engrams in short-term and long-term motor learning

Wang

Nakadate

Masugi-Tokita

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

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“…Extracellular recordings of Purkinje cell activity patterns were performed as described previously (Wulff et al, 2009). In short, 2-to 3-month-old WT and Cacna1a S218L mice were immobilized using head-fixed pedestals constructed of stainless steel screws of 1 mm diameter equipped with custom-made connectors that were located in the frontal, medial, and temporal bones and embedded in dental acrylic.…”

Section: Methodsmentioning

confidence: 99%

Cerebellar Ataxia by Enhanced Ca_V2.1 Currents Is Alleviated by Ca²⁺-Dependent K⁺-Channel Activators inCacna1a^S218LMutant Mice

et al. 2012

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Mutations in the CACNA1A gene are associated with neurological disorders, such as ataxia, hemiplegic migraine, and epilepsy. These mutations affect the pore-forming ␣ 1A -subunit of Ca V 2.1 channels and thereby either decrease or increase neuronal Ca 2ϩ influx. A decreased Ca V 2.1-mediated Ca 2ϩ influx has been shown to reduce the regularity of cerebellar Purkinje cell activity and to induce episodic cerebellar ataxia. However, little is known about how ataxia can be caused by CACNA1A mutations that increase the Ca 2ϩ influx, such as the S218L missense mutation. Here, we demonstrate that the S218L mutation causes a negative shift of voltage dependence of Ca V 2.1 channels of mouse Purkinje cells and results in lowered thresholds for somatic action potentials and dendritic Ca 2ϩ spikes and in disrupted firing patterns. The hyperexcitability of Cacna1a S218L Purkinje cells was counteracted by application of the activators of Ca 2ϩ-dependent K ϩ channels, 1-EBIO and chlorzoxazone (CHZ). Moreover, 1-EBIO also alleviated the irregularity of Purkinje cell firing both in vitro and in vivo, while CHZ improved the irregularity of Purkinje cell firing in vitro as well as the motor performance of Cacna1a S218L mutant mice. The current data suggest that abnormalities in Purkinje cell firing contributes to cerebellar ataxia induced by the S218L mutation and they advocate a general therapeutic approach in that targeting Ca 2ϩ -dependent K ϩ channels may be beneficial for treating ataxia not only in patients suffering from a decreased Ca 2ϩ influx, but also in those suffering from an increased Ca 2ϩ influx in their Purkinje cells.

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“…In each experimental group about half of the mice were male. Mice were prepared for chronic head-restrained experiments, as described (21). The experimental protocol was approved by the Animal Experimentation Committee (DEC) of the Royal Dutch Academy of Sciences (KNAW).…”

Section: Expression In Xenopus Oocytes and Two-electrode Voltagementioning

confidence: 99%