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

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

doi:10.1016/j.neuron.2016.11.046

Abstract

SummaryAccumulating evidence indicates that cerebellar long-term potentiation (LTP) is necessary for procedural learning. However, little is known about its underlying molecular mechanisms. Whereas AMPA receptor (AMPAR) subunit rules for synaptic plasticity have been extensively studied in relation to declarative learning, it is unclear whether these rules apply to cerebellum-dependent motor learning. Here we show that LTP at the parallel-fiber-to-Purkinje-cell synapse and adaptation of the vestibulo-ocular reflex depend not on GluA1- but on GluA3-containing AMPARs. In contrast to the classic form of LTP implicated in declarative memory formation, this form of LTP does not require GluA1-AMPAR trafficking but rather requires changes in open-channel probability of GluA3-AMPARs mediated by cAMP signaling and activation of the protein directly activated by cAMP (Epac). We conclude that vestibulo-cerebellar motor learning is the first form of memory acquisition shown to depend on GluA3-dependent synaptic potentiation by increasing single-channel conductance.

Highlights

Plasticity mediated by synaptic trafficking of a-amino-3-hydroxy-5-methyl-4-isoxazolepropionic-acid-type glutamate receptors (AMPARs) plays an important role in the acquisition of declarative memories (Kessels and Malinow, 2009)
Cerebellar Motor Learning Depends on GluA3, but Not on GluA1 Unlike GluA2 global knockout (KO) mice, which suffer from severe motor performance deficits including ataxia (Gerlai et al, Neuron 93, 409–424, January 18, 2017 a 2017 The Author(s)
We examined whether cAMP-driven synaptic potentiation is a result of synaptic trafficking of GluA3-containing AMPARs

Summary

Introduction

Plasticity mediated by synaptic trafficking of a-amino-3-hydroxy-5-methyl-4-isoxazolepropionic-acid-type glutamate receptors (AMPARs) plays an important role in the acquisition of declarative memories (Kessels and Malinow, 2009). Cortex, and amygdala, both long-term potentiation (LTP) and learning depend on the trafficking of GluA1-containing AMPARs to synapses (Makino and Malinow, 2011; Nedelescu et al, 2010; Rumpel et al, 2005; Mitsushima et al, 2011), whereas GluA3-containing AMPARs contribute relatively little to synaptic currents, synaptic plasticity, or learning (Adamczyk et al, 2012; Meng et al, 2003; Humeau et al, 2007). The roles of GluA1- and/or GluA3-containing AMPARs in the plasticity of Purkinje cells (PCs) have hardly been studied (Bats et al, 2013; Douyard et al, 2007; Kakegawa and Yuzaki, 2005)

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