Functional Compartmentalization of Endosomal Trafficking for the Synaptic Delivery of AMPA Receptors during Long-Term Potentiation

Endosomal membrane trafficking in dendritic spines is important for proper synaptic function and plasticity. However, little is known about the molecular identity and functional compartmentalization of the membrane trafficking machinery operating at the postsynaptic terminal. Here we report that the transport of AMPA-type glutamate receptors into synapses occurs in two discrete steps, and we identify the specific endosomal functions that control this process during long-term potentiation. We found that Rab11-dependent endosomes translocate AMPA receptors from the dendritic shaft into spines. Subsequently, an additional endosomal trafficking step, controlled by Rab8, drives receptor insertion into the synaptic membrane. Separate from this receptor delivery route, we show that Rab4 mediates a constitutive endosomal recycling within the spine. This Rab4-dependent cycling is critical for maintaining spine size but does not influence receptor transport. Therefore, our data reveal a highly compartmentalized endosomal network within the spine and identify the molecular components and functional organization of the membrane organelles that mediate AMPA receptor synaptic delivery during plasticity.This work was supported by National Institute of Mental Health Grants MH070417 (J.A.E.) and F31-MH070205 (T.C.B.). We thank Ronald Holz, Jeffrey Martens, Maria Soengas, and members of the Esteban laboratory for critical reading of this manuscript.Peer reviewe

Role of PTEN on AMPAR mediated transmission on CA1 hippocampal neurons

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PI(3,4,5)P3-dependent regulation of AMPA receptor synaptic function.

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The phosphoinositide PI(3,4,5)P3 is a regulator of postsynaptic AMPA receptor trafficking.

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PTEN is recruited to the postsynaptic terminal for NMDA receptor-dependent long-term depression

Esteban and coworkers describe a novel role for the lipid phosphatase PTEN in synaptic physiology through regulation of AMPA receptors. Interestingly, this appears to be connected to an NMDAR-induced, PDZ-mediated PTEN recruitment to PSD-95

PIP3 controls synaptic function by maintaining AMPA receptor clustering at the postsynaptic membrane

Supplementary information is available on the Nature Neuroscience website.Despite their low abundance, phosphoinositides are critical regulators of intracellular signaling and membrane compartmentalization. However, little is known of phosphoinositide function at the postsynaptic membrane. Here we show that continuous synthesis and availability of phosphatidylinositol-(3,4,5)-trisphosphate (PIP3) at the postsynaptic terminal is necessary for sustaining synaptic function in rat hippocampal neurons. This requirement was specific for synaptic, but not extrasynaptic, AMPA receptors, nor for NMDA receptors. PIP3 downregulation impaired PSD-95 accumulation in spines. Concomitantly, AMPA receptors became more mobile and migrated from the postsynaptic density toward the perisynaptic membrane within the spine, leading to synaptic depression. Notably, these effects were only revealed after prolonged inhibition of PIP3 synthesis or by direct quenching of this phosphoinositide at the postsynaptic cell. Therefore, we conclude that a slow, but constant, turnover of PIP3 at synapses is required for maintaining AMPA receptor clustering and synaptic strength under basal conditions.This work was supported by grants from the US National Institute of Mental Health (J.A.E. and J.R.M.), the Dana Foundation (J.A.E.) and the Spanish Ministry of Science and Innovation (J.A.E.). M.F.-M. and S.K. are supported by postdoctoral contracts, and M.R. by a predoctoral fellowship, from the Spanish Ministry of Science and Innovation.Peer reviewe