GluA4 facilitates cerebellar expansion coding and enables associative memory formation
- University of Zurich, Switzerland
- Champalimaud Centre for the Unknown, Portugal
- Champalimaud Foundation, Portugal
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
Catarina Albergaria
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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GluA4 facilitates cerebellar expansion coding and enables associative memory formation
eLife 10:e65152.
https://doi.org/10.7554/eLife.65152
