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
At many vertebrate synapses, presynaptic functions are tuned by expression of different Cav2 channels. Most invertebrate genomes contain only one Cav2 gene. The Drosophila Cav2 homolog, cacophony (cac), induces synaptic vesicle release at presynaptic active zones (AZs). We hypothesize that Drosophila cac functional diversity is enhanced by two mutually exclusive exon pairs that are not conserved in vertebrates, one in the voltage sensor and one in the loop binding Caβ and Gβγ subunits. We find that alternative splicing in the voltage sensor affects channel activation voltage. Only the isoform with the higher activation voltage localizes to AZs at the glutamatergic Drosophila larval neuromuscular junction and is imperative for normal synapse function. By contrast, alternative splicing at the other alternative exon pair tunes multiple aspects of presynaptic function. While expression of one exon yields normal transmission, expression of the other reduces channel number in the AZ and thus release probability. This also abolishes presynaptic homeostatic plasticity. Moreover, reduced channel number affects short-term plasticity, which is rescued by increasing the external calcium concentration to match release probability to control. In sum, in Drosophila alternative splicing provides a mechanism to regulate different aspects of presynaptic functions with only one Cav2 gene.
