Motor Learning Requires Purkinje Cell Synaptic Potentiation through Activation of AMPA-Receptor Subunit GluA3

Gutiérrez-Castellanos, Nicolás; Silva-Matos, Carla M. Da; Zhou, Kai; Canto, Cathrin B.; Renner, Maria; Koene, Linda M. C.; Ozyildirim, Ozgecan; Sprengel, Rolf; Kessels, Helmut W.; Zeeuw, Chris I. De

doi:10.1016/j.neuron.2016.11.046

Cited by 99 publications

(117 citation statements)

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“…, ; Gutierrez‐Castellanos et al . ), 1 Hz‐LTP was normally observed in MLI/PC‐ Grin1 cKO mice that showed impaired hOKR adaptation. Together, these results support the view that NMDARs in MLIs play crucial roles in the induction of LTD to mediate motor learning in vivo .…”

Section: Discussionmentioning

confidence: 84%

“…, ; Gutierrez‐Castellanos et al . ). In addition, 1 Hz PF stimulation is shown to induce postsynaptic LTP that requires concomitant NO production (Lev‐Ram et al .…”

Section: Resultsmentioning

confidence: 97%

“…, ; Gutierrez‐Castellanos et al . ). Interestingly, although 1 Hz‐LTP does not rely on NMDARs (Wang et al .…”

Section: Introductionmentioning

confidence: 97%

“…LTP or LTD) remains controversial. While various genetically engineered mice with disruptions in the expression of key molecules necessary for LTD induction in vitro displayed impaired motor learning in vivo (Yuzaki, 2013;Ito et al 2014), only LTP induced by low-frequency stimulation (1 Hz-LTP) of PFs was correlated with motor learning in other mutant mice (Schonewille et al 2010(Schonewille et al , 2011Gutierrez-Castellanos et al 2017). Interestingly, although 1 Hz-LTP does not rely on NMDARs (Wang et al 2014), LTD requires NMDAR activation in cerebellar slice preparations (Casado et al 2002;Shin & Linden, 2005;Piochon et al 2010;Kakegawa et al 2011).…”

Section: Introductionmentioning

confidence: 99%

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Interneuronal NMDA receptors regulate long‐term depression and motor learning in the cerebellum

Kono

Kakegawa

Yoshida

et al. 2018

The Journal of Physiology

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Key points NMDA receptors (NMDARs) are required for long‐term depression (LTD) at parallel fibre–Purkinje cell synapses, but their cellular localization and physiological functions in vivo are unclear. NMDARs in molecular‐layer interneurons (MLIs), but not granule cells or Purkinje cells, are required for LTD, but not long‐term potentiation induced by low‐frequency stimulation of parallel fibres. Nitric oxide produced by NMDAR activation in MLIs probably mediates LTD induction. NMDARs in granule cells or Purkinje cells are dispensable for motor learning during adaptation of horizontal optokinetic responses. Abstract Long‐term potentiation (LTP) and depression (LTD), which serve as cellular synaptic plasticity models for learning and memory, are crucially regulated by N‐methyl‐d‐aspartate receptors (NMDARs) in various brain regions. In the cerebellum, LTP and LTD at parallel fibre (PF)–Purkinje cell (PC) synapses are thought to mediate certain forms of motor learning. However, while NMDARs are essential for LTD in vitro, their cellular localization remains controversial. In addition, whether and how NMDARs mediate motor learning in vivo remains unclear. Here, we examined the contribution of NMDARs expressed in granule cells (GCs), PCs and molecular‐layer interneurons (MLIs) to LTD/LTP and motor learning by generating GC‐, PC‐ and MLI/PC‐specific knockouts of Grin1, a gene encoding an obligatory GluN1 subunit of NMDARs. While robust LTD and LTP were induced at PF–PC synapses in GC‐ and PC‐specific Grin1 (GC‐Grin1 and PC‐Grin1, respectively) conditional knockout (cKO) mice, only LTD was impaired in MLI/PC‐specific Grin1 (MLI/PC‐Grin1) cKO mice. Application of diethylamine nitric oxide (NO) sodium, a potent NO donor, to the cerebellar slices restored LTD in MLI/PC‐Grin1 cKO mice, suggesting that NO is probably downstream to NMDARs. Furthermore, the adaptation of horizontal optokinetic responses (hOKR), a cerebellar motor learning task, was normally observed in GC‐Grin1 cKO and PC‐Grin1 cKO mice, but not in MLI/PC‐Grin1 cKO mice. These results indicate that it is the NMDARs expressed in MLIs, but not in PCs or GCs, that play important roles in LTD in vitro and motor learning in vivo.

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Section: Discussionmentioning

confidence: 84%

“…, ; Gutierrez‐Castellanos et al . ). In addition, 1 Hz PF stimulation is shown to induce postsynaptic LTP that requires concomitant NO production (Lev‐Ram et al .…”

Section: Resultsmentioning

confidence: 97%

“…, ; Gutierrez‐Castellanos et al . ). Interestingly, although 1 Hz‐LTP does not rely on NMDARs (Wang et al .…”

Section: Introductionmentioning

confidence: 97%

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

Interneuronal NMDA receptors regulate long‐term depression and motor learning in the cerebellum

Kono

Kakegawa

Yoshida

et al. 2018

The Journal of Physiology

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“…S5), and, consequently, increased the number of patterns the PC could store with an s/n ratio >4 (from ~200 with simple LTD to more than 800 with combined LTP and nsLTD). This importance of LTP-induced weight homeostasis may explain the observed need for LTP in motor learning424344.…”

Section: Resultsmentioning

confidence: 98%

Nonspecific synaptic plasticity improves the recognition of sparse patterns degraded by local noise

Safaryan

Maex

Davey

et al. 2017

Sci Rep

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Many forms of synaptic plasticity require the local production of volatile or rapidly diffusing substances such as nitric oxide. The nonspecific plasticity these neuromodulators may induce at neighboring non-active synapses is thought to be detrimental for the specificity of memory storage. We show here that memory retrieval may benefit from this non-specific plasticity when the applied sparse binary input patterns are degraded by local noise. Simulations of a biophysically realistic model of a cerebellar Purkinje cell in a pattern recognition task show that, in the absence of noise, leakage of plasticity to adjacent synapses degrades the recognition of sparse static patterns. However, above a local noise level of 20%, the model with nonspecific plasticity outperforms the standard, specific model. The gain in performance is greatest when the spatial distribution of noise in the input matches the range of diffusion-induced plasticity. Hence non-specific plasticity may offer a benefit in noisy environments or when the pressure to generalize is strong.

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AMPA Receptors

Striessnig¹,

Watson²,

Greger³

2020

Encyclopedia of Life Sciences

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Neuronal communication relies on rapid signalling through chemical synapses. The majority of excitatory neurotransmission in the central nervous system is mediated by binding of glutamate to a family of postsynaptic glutamate receptors. Among these, α‐amino‐3‐hydroxy‐5‐methylisoxazole‐4‐propionic acid receptors (AMPARs) mediate fast excitatory synaptic transmission and play a critical role in the synaptic plasticity that underlies learning and memory. AMPAR function is influenced on multiple levels by a combination of transcriptional modifications, post‐translational regulation, and association with a multitude of auxiliary subunits. These processes give rise to a diverse array of receptors with unique properties for their specific role in brain function. Due to their central role in neuronal signalling, malfunction in AMPAR production or regulation can cause severe neurological and neuropsychiatric diseases. Since their cloning in the 1990s, much has been learned about AMPAR structure, assembly and trafficking, demonstrating the molecular complexity that underlies brain function. Key Concepts AMPA receptors mediate fast glutamatergic synaptic transmission. The receptor has a highly flexible, four‐layered, domain organisation. AMPARs associate with a diverse array of auxiliary subunits. Post‐transcriptional modifications and distinct combinations of core and auxiliary subunits generate structurally and functionally diverse AMPA receptors. The composition of AMPA receptor complexes varies between cell‐types and at different synapses. Regulation of synaptic AMPA receptors expression is highly dynamic. Synaptic AMPA receptor anchoring and accumulation is essential for neurotransmission. Modulation of AMPA receptor function and/or trafficking allows synaptic plasticity. AMPA receptor dysfunction is involved in various neurological diseases.

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Motor Learning Requires Purkinje Cell Synaptic Potentiation through Activation of AMPA-Receptor Subunit GluA3

Cited by 99 publications

References 68 publications

Interneuronal NMDA receptors regulate long‐term depression and motor learning in the cerebellum

Interneuronal NMDA receptors regulate long‐term depression and motor learning in the cerebellum

Nonspecific synaptic plasticity improves the recognition of sparse patterns degraded by local noise

AMPA Receptors

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