The AMPA receptor-associated protein Shisa7 regulates hippocampal synaptic function and contextual memory
- Vrije Universiteit, Netherlands
Abstract
Glutamatergic synapses rely on AMPA receptors (AMPARs) for fast synaptic transmission and plasticity. AMPAR auxiliary proteins regulate receptor trafficking, and modulate receptor mobility and its biophysical properties. The AMPAR auxiliary protein Shisa7 (CKAMP59) has been shown to interact with AMPARs in artificial expression systems, but it is unknown whether Shisa7 has a functional role in glutamatergic synapses. We show that Shisa7 physically interacts with synaptic AMPARs in mouse hippocampus. Shisa7 gene deletion resulted in faster AMPAR currents in CA1 synapses, without affecting its synaptic expression. Shisa7 KO mice showed reduced initiation and maintenance of long-term potentiation of glutamatergic synapses. In line with this, Shisa7 KO mice showed a specific deficit in contextual fear memory, both short-term and long-term after conditioning, whereas auditory fear memory and anxiety-related behavior were normal. Thus, Shisa7 is a bona-fide AMPAR modulatory protein affecting channel kinetics of AMPARs, necessary for synaptic hippocampal plasticity, and memory recall.
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Author details
Funding
HEALTH-2009-2.1.2.1 EU-FP7 SynSys (SynSys)
- Marta Ruiperez-Alonso
- Jasper Stroeder
- Huib D Mansvelder
- August B Smit
- Sabine Spijker
Erasmus Mundus (159302-1-2009-1-NL-ERA MUNDUS-EMJD)
- Azra Elia Zamri
NWO-ALW #822.02.020 (#822.02.020)
- Remco V Klaassen
NBSIK PharmaPhenomics FES0908 (FES0908)
- Leanne J M Schmitz
- Rolinka J van der Loo
- August B Smit
NBSIK Mouse Phenomics Consortium BSIK03053 (BSIK03053)
- Priyanka Rao-Ruiz
- Rolinka J van der Loo
- August B Smit
MEST-CT-2005-020919 Neuromics (20919)
- Priyanka Rao-Ruiz
MEST-ITN-2008-238686 CerebNet (238686)
- Jasper Stroeder
NWO-ALW Vici 865.13.002 (865.13.002)
- Huib D Mansvelder
ERC BrainSignals 281443 (281443)
- Huib D Mansvelder
NWO-ALW Vici 016.150.673 / 865.14.002 (016.150.673 / 865.14.002)
- Leanne J M Schmitz
- Sabine Spijker
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
Ethics
Animal experimentation: All experiments were performed in accordance to Dutch law and licensing agreements using a protocol approved by the Animal Ethics Committee of the VU University Amsterdam.
Copyright
© 2017, Schmitz 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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The AMPA receptor-associated protein Shisa7 regulates hippocampal synaptic function and contextual memory
eLife 6:e24192.
https://doi.org/10.7554/eLife.24192
Further reading
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- Neuroscience
The relation between neural activity and behaviorally relevant variables is at the heart of neuroscience research. When strong, this relation is termed a neural representation. There is increasing evidence, however, for partial dissociations between activity in an area and relevant external variables. While many explanations have been proposed, a theoretical framework for the relationship between external and internal variables is lacking. Here, we utilize recurrent neural networks (RNNs) to explore the question of when and how neural dynamics and the network’s output are related from a geometrical point of view. We find that training RNNs can lead to two dynamical regimes: dynamics can either be aligned with the directions that generate output variables, or oblique to them. We show that the choice of readout weight magnitude before training can serve as a control knob between the regimes, similar to recent findings in feedforward networks. These regimes are functionally distinct. Oblique networks are more heterogeneous and suppress noise in their output directions. They are furthermore more robust to perturbations along the output directions. Crucially, the oblique regime is specific to recurrent (but not feedforward) networks, arising from dynamical stability considerations. Finally, we show that tendencies toward the aligned or the oblique regime can be dissociated in neural recordings. Altogether, our results open a new perspective for interpreting neural activity by relating network dynamics and their output.
