GRASP-1 regulates endocytic receptor recycling and synaptic plasticity

Abstract

Remodeling of synapses is a fundamental mechanism for information storage and processing in the brain. Previous studies showed that the endosomal pathway play a central role in synapse formation and plasticity. A popular model holds that recycling endosomes in dendrites provide the local intracellular pool of postsynaptic receptors for long-term potentiation (LTP), a widely studied cellular model for learning and memory formation. However, we are far from a complete understanding how endocytic receptor sorting and recycling is organized and coordinated in dendrites. Especially, the molecular mechanisms that couple specific endosomal trafficking routes during LTP are poorly understood. In a recent paper we discovered that the coiled-coil protein GRIP-associated protein-1 (GRASP-1) is a neuron-specific effector of the small GTPase Rab4 and key component of AMPA receptor recycling machinery in dendrites.1 GRASP-1 is essential for maintenance of spine morphology and important for LTP. GRASP-1 connects Rab4 and Rab11 recycling endosomal domains through the interaction with target (t)-SNARE syntaxin 13, which constitutes a new principle for regulating endosomal recycling. Here, we summarize our recently reported observations and further discuss their possible implications.

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Acknowledgements

C.C.H. and P.v.d.S. are supported through grants from the Netherlands Organization for Scientific Research (NWO-ALW and NWO-CW). P.v.d.S. is supported by Netherlands Proteomics Center. CCH is supported by the Netherlands Organization for Health Research and Development (ZonMW-TOP), European Science Foundation (European Young Investigators (EURYI) Award), EMBO Young investigators programme (YIP), and Human Frontier Science Program Career Development Award (HFSP-CDA).

Figures and Tables

Figure 1 Synaptic receptor trafficking pathways in neuronal dendrites. (A) Schematic representation of the secretory and endosomal trafficking pathway of postsynaptic receptors. Glutamate receptor subunits are assembled in the endoplasmic reticulcum (ER) and are transported via the Golgi apparatus to the synaptic plasma membrane. The interaction between receptor and motor proteins often occurs through motor adaptor/synaptic scaffolding proteins. (B) Model for the endosomal membrane trafficking machinery in dendrites. The internalization of AMPA receptors into endocytic vesicles is mediated by clathrin acting on the lateral membrane within the spine. Rab5 controls transport to early endosomes (also called sorting endosomes) whereas Rab4 and Rab11 are involved in the regulation of endosomal recycling back to the plasma membrane. Re-entry of internalized AMPAR into the Rab4-Rab11 endosomal recycling route requires GRASP-1.

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