1. Neuroscience

GluA4 facilitates cerebellar expansion coding and enables associative memory formation

  1. Katarzyna Kita
  2. Catarina Albergaria
  3. Ana S Machado
  4. Megan R Carey
  5. Martin Mueller
  6. Igor Delvendahl  Is a corresponding author
  1. University of Zurich, Switzerland
  2. Champalimaud Centre for the Unknown, Portugal
  3. Champalimaud Foundation, Portugal
https://doi.org/10.7554/eLife.65152
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  1. Katarzyna Kita
  2. Catarina Albergaria
  3. Ana S Machado
  4. Megan R Carey
  5. Martin Mueller
  6. Igor Delvendahl
(2021)
GluA4 facilitates cerebellar expansion coding and enables associative memory formation
eLife 10:e65152.
https://doi.org/10.7554/eLife.65152
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Abstract

AMPA receptors (AMPARs) mediate excitatory neurotransmission in the CNS and their subunit composition determines synaptic efficacy. Whereas AMPAR subunits GluA1–GluA3 have been linked to particular forms of synaptic plasticity and learning, the functional role of GluA4 remains elusive. Here we demonstrate a crucial function of GluA4 for synaptic excitation and associative memory formation in the cerebellum. Notably, GluA4-knockout mice had ~80% reduced mossy fiber to granule cell synaptic transmission. The fidelity of granule cell spike output was markedly decreased despite attenuated tonic inhibition and increased NMDA receptor-mediated transmission. Computational network modeling incorporating these changes revealed that deletion of GluA4 impairs granule cell expansion coding, which is important for pattern separation and associative learning. On a behavioral level, while locomotor coordination was generally spared, GluA4-knockout mice failed to form associative memories during delay eyeblink conditioning. These results demonstrate an essential role for GluA4-containing AMPARs in cerebellar information processing and associative learning.

Data availability

All data generated or analyzed during this study are included in the manuscript and supporting files. Source data files have been provided for Figures 1-5; source code for simulations and modeling is available at https://github.com/delvendahl/GluA4_cerebellum_eLife.

Article and author information

Author details

  1. Katarzyna Kita

    Department of Molecular Life Sciences, University of Zurich, Zurich, Switzerland
    Competing interests
    No competing interests declared.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-8371-7941

  2. Catarina Albergaria

    Champalimaud Neuroscience Programme, Champalimaud Centre for the Unknown, Lisbon, Portugal
    Competing interests
    No competing interests declared.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-8257-3600

  3. Ana S Machado

    Champalimaud Neuroscience Programme, Champalimaud Centre for the Unknown, Champalimaud Foundation, Lisbon, Portugal
    Competing interests
    No competing interests declared.

  4. Megan R Carey

    Champalimaud Neuroscience Program, Champalimaud Centre for the Unknown, Champalimaud Foundation, Lisbon, Portugal
    Competing interests
    Megan R Carey, Reviewing editor, eLife.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-4499-1657

  5. Martin Mueller

    Institute of Molecular Life Sciences, University of Zurich, Zurich, Switzerland
    Competing interests
    No competing interests declared.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-1624-6761

  6. Igor Delvendahl

    Department of Molecular Life Sciences, University of Zurich, Zurich, Switzerland
    For correspondence
    igor.delvendahl@uzh.ch
    Competing interests
    No competing interests declared.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-6151-2363

Funding

European Research Council (640093)

  • Megan R Carey

Portuguese Fundação para a Ciência e a Tecnologia (PTDC/MED-NEU/30890/2017)

  • Megan R Carey

European Research Council (679881)

  • Martin Mueller

Swiss National Science Foundation (PP00P3_144816)

  • Martin Mueller

Swiss National Science Foundation (PZ00P3_174018)

  • Igor Delvendahl

The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.

Ethics

Animal experimentation: This study was performed in strict accordance with national and institutional guidelines. All experiments were approved by the Cantonal Veterinary Office of Zurich (authorization no. ZH206/2016 and ZH009/2020) or by the Portuguese Direcção Geral de Veterinária (Ref. No. 0421/000/000/2015).

Copyright

© 2021, Kita et al.

This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.

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  1. Katarzyna Kita
  2. Catarina Albergaria
  3. Ana S Machado
  4. Megan R Carey
  5. Martin Mueller
  6. Igor Delvendahl
(2021)
GluA4 facilitates cerebellar expansion coding and enables associative memory formation
eLife 10:e65152.
https://doi.org/10.7554/eLife.65152

Share this article

https://doi.org/10.7554/eLife.65152

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