Activity Patterns Govern Synapse-Specific AMPA Receptor Trafficking between Deliverable and Synaptic Pools

Abstract

In single neurons, glutamatergic synapses receiving distinct afferent inputs may contain AMPA receptors (-Rs) with unique subunit compositions. However, the cellular mechanisms by which differential receptor transport achieves this synaptic diversity remain poorly understood. In lateral geniculate neurons, we show that retinogeniculate and corticogeniculate synapses have distinct AMPA-R subunit compositions. Under basal conditions at both synapses, GluR1-containing AMPA-Rs are transported from an anatomically defined reserve pool to a deliverable pool near the postsynaptic density (PSD), but further incorporate into the PSD or functional synaptic pool only at retinogeniculate synapses. Vision-dependent activity, stimulation mimicking retinal input, or activation of CaMKII or Ras signaling regulated forward GluR1 trafficking from the deliverable pool to the synaptic pool at both synapses, whereas Rap2 signals reverse GluR1 transport at retinogeniculate synapses. These findings suggest that synapse-specific AMPA-R delivery involves constitutive and activity-regulated transport steps between morphological pools, a mechanism that may extend to the site-specific delivery of other membrane protein complexes.

Immobilized Pool of NCAM180 in the Postsynaptic Membrane Is Homeostatically Replenished by the Flux of NCAM180 from Extrasynaptic Regions

“…It is likely that NCAM180 is delivered to the activated synapses in intracellular organelles as it has been shown for neuroligins (13) and AMPA receptors (37,50,51). In addition, our data suggest that an increase in the homophilic interactions of NCAM180 or its binding to the spectrin cytoskeleton can also promote immobilization of NCAM180 in activated synapses.…”

Pharmacological rescue of Ras signaling, GluA1-dependent synaptic plasticity, and learning deficits in a fragile X model

“…S1), indicating synaptic delivery of rectified GluA1-GFP in wild-type neurons but not Fmr1 knockout neurons. To confirm the synaptic delivery of endogenous GluA1, we expressed in CA1 neurons the GFP-tagged cytoplasmic termini of GluA1 (GluA1ct-GFP) that functions as a dominant-negative construct and can selectively block synaptic trafficking of endogenous GluA1-containing AMPA-Rs (Qin et al 2005;Kielland et al 2009). GluA1ct-GFP-expressing neurons of wild-type mice, but not Fmr1 knockout mice, had depressed AMPA responses (Supplemental Fig.…”

“…To understand how 5HT and DA modulators, particularly the low-dose 5HT and DA drug cocktail, may stimulate synaptic GluA1 trafficking in Fmr1 knockout mice, we examined the effects of those modulators on Ras-PI3K/ PKB signal transduction, which is essential for synaptic GluA1 trafficking (Qin et al 2005;Hu et al 2008;Kielland et al 2009). We first measured the levels of the active form of Ras (GTP-bound Ras) in CA1 cells prepared from both sleeping and awake wild-type and Fmr1 knockout mice, since the dynamic Ras activity depends on the behavioral state of animals (Qin et al 2005;Hu et al 2008).…”

Plk2 Raps up Ras to subdue synapses

“…5,6 In terms of synaptic plasticity, Ras often favors postsynaptic strengthening or growth; its activity is required for and stimulated by LTP. 7,8 Ras also drives synaptic delivery of AMPARs [8][9][10][11] as well as production of dendritic protrusions/ spines. 12,13 In contrast, Rap typically favors However, a deeper analysis suggests another reason Plk2 may target multiple GAPs and GEFs, beyond the requirements of simple efficacy.…”

“…On the other end of the spectrum, postsynaptic weakening and is implicated in LTD or depotentiation, processes involving AMPAR internalization and loss of dendritic spines. [8][9][10][14][15][16][17] However, this picture is somewhat muddled by observations that Rap1 mutant mice also display deficits in LTP, 18,19 and LTP can be increased by H-Ras ablation or decreased by H-Ras overexpression. 20,21 Possible explanations for some of these discrepancies are differences in the exact experimental paradigm used, memory task involved or brain area examined.…”