ORIGINAL RESEARCH article
Front. Pharmacol.
Sec. Pharmacology of Ion Channels and Channelopathies
Volume 16 - 2025 | doi: 10.3389/fphar.2025.1568908
This article is part of the Research TopicNew Insights into Ionotropic Glutamate Receptor Structure and Function in Health and DiseaseView all 3 articles
Loss of SynDIG4/PRRT1 alters distribution of AMPA receptors in Rab4- and Rab11-positive endosomes and impairs basal AMPA receptor recycling
Provisionally accepted
- Pharmacology/ School of Medicine, University of California, Davis, Davis, CA, United States
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The transmembrane protein Synapse Differentiation Induced Gene 4 (SynDIG4) functions as an auxiliary factor of AMPA receptors (AMPARs) and plays a critical role in excitatory synaptic plasticity as well as hippocampal-dependent learning and memory. Mice lacking SynDIG4 have reduced surface expression of GluA1 and GluA2 and are impaired in single tetanus-induced long-term potentiation and NMDA receptor (NMDAR)-dependent long-term depression. These findings suggest that SynDIG4 may play an important role in regulating AMPAR distribution through intracellular trafficking mechanisms; however, the precise roles by which SynDIG4 governs AMPAR distribution remain unclear. Here, we characterized the endocytosis and recycling of GluA1-containing AMPARs under basal conditions. We did not observe any change in baseline endocytosis; however, we did observe a significant decrease in recycling of GluA1-containing AMPARs in cultured hippocampal neurons from mice lacking SynDIG4. This resulted in a significant increase in the levels of internal GluA1 and GluA2, along with greater colocalization of these subunits with Rab4-positive recycling endosomes. Notably, the overlap between Rab4- and Rab11-positive vesicles was elevated in hippocampal neurons lacking SynDIG4, suggesting an impairment in the trafficking between these compartments. Furthermore, our findings revealed a reduction in surface GluA1 within synaptic regions of hippocampal neurons lacking SynDIG4. Collectively, these results indicate that SynDIG4 regulates the distribution of GluA1-containing AMPARs via the Rab4-dependent endosomal recycling pathway, thereby maintaining AMPAR levels at synaptic regions under baseline conditions. This regulatory function of SynDIG4 may contribute to the deficits in GluA1-dependent synaptic plasticity and impairment of hippocampal-dependent behaviors observed in SynDIG4 deficient mice.
Keywords: SynDIG4, Prrt1, AMPA receptor, Endosomes, Recycling, Rab4, Rab11
Received: 30 Jan 2025; Accepted: 29 Apr 2025.
Copyright: © 2025 He and Diaz. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
* Correspondence: Elva Diaz, Pharmacology/ School of Medicine, University of California, Davis, Davis, 95616, CA, United States
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