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
Synchronous neuronal activity is organized into neuronal oscillations with various frequency and time domains across different brain areas and brain states. For example, hippocampal theta, gamma, and sharp wave oscillations are critical for memory formation and communication between hippocampal subareas and the cortex. In this study, we investigated the neuronal activity of the dentate gyrus (DG) with optical imaging tools during sleep-wake cycles in mice. We found that the activity of major glutamatergic cell populations in the DG is organized into infraslow oscillations (0.01–0.03 Hz) during NREM sleep. Although the DG is considered a sparsely active network during wakefulness, we found that 50% of granule cells and about 25% of mossy cells exhibit increased activity during NREM sleep, compared to that during wakefulness. Further experiments revealed that the infraslow oscillation in the DG was correlated with rhythmic serotonin release during sleep, which oscillates at the same frequency but in an opposite phase. Genetic manipulation of 5-HT receptors revealed that this neuromodulatory regulation is mediated by Htr1a receptors and the knockdown of these receptors leads to memory impairment. Together, our results provide novel mechanistic insights into how the 5-HT system can influence hippocampal activity patterns during sleep.
