Hippocampal LTP and contextual learning require surface diffusion of AMPA receptors

Abstract

Long-term potentiation (LTP) of excitatory synaptic transmission has long been considered a cellular correlate for learning and memory1,2. Early LTP (eLTP, <1 hour) had initially been explained either by presynaptic increases in glutamate release3–5 or by direct modification of post-synaptic α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (AMPAR) function6,7. Compelling models have more recently proposed that synaptic potentiation can occur by the recruitment of additional post-synaptic AMPARs8, sourced either from an intracellular reserve pool by exocytosis or from nearby extra synaptic receptors pre-existing on the neuronal surface9–12. However, the exact mechanism through which synapses can rapidly recruit new AMPARs during eLTP is still unknown. In particular, direct evidence for a pivotal role of AMPAR surface diffusion as a trafficking mechanism in synaptic plasticity is still lacking. Using AMPAR immobilization approaches, we show that interfering with AMPAR surface diffusion dramatically impaired synaptic potentiation of Schaffer collateral/commissural inputs to cornu ammonis area 1 (CA1) in cultured slices, acute slices and in vivo. Our data also identifies distinct contributions of various AMPAR trafficking routes to the temporal profile of synaptic potentiation. In addition, AMPAR immobilization in vivo in the dorsal hippocampus (DH) before fear conditioning, indicated that AMPAR diffusion is important for the early phase of contextual learning. Therefore, our results provide a direct demonstration that the recruitment of new receptors to synapses by surface diffusion is a critical mechanism for the expression of LTP and hippocampal learning. Since AMPAR surface diffusion is dictated by weak Brownian forces that are readily perturbed by protein-protein interactions, we anticipate that this fundamental trafficking mechanism will be a key target for modulating synaptic potentiation and learning.

L-Type Voltage-Gated Ca2+ Channels Regulate Synaptic Activity-Triggered Recycling Endosome Fusion in Neuronal Dendrites

“…Using this approach, we detected reliable NMDA receptor-dependent GluA1 surface delivery following cLTP (Figures 2E and 2F; no cLTP 100.0% ± 3.2%, cLTP 118.2% ± 3.2% [p = 0.011 versus no stimulation], and cLTP + D-2-amino-5-posphonovalerate (AP5) 99.4% ± 3.4% [p = 0.0006 versus cLTP]). While this increase is modest, we note that the size of the effect that we identified is consistent with the degree of synaptic potentiation that requires postsynaptic insertion of GluA1-containing AMPA receptors (Penn et al, 2017). Consistent with our previous results demonstrating a critical role for L-VGCCs in regulating RE cargo delivery to the PM, we found that pharmacologically blocking L-VGCCs with either nimodipine (10 μM) or verapamil (25 μM) also prevented activity-triggered membrane insertion of GluA1-containing AMPA receptors (Figures 2E and 2F; cLTP 118.2 ± 3.2%, cLTP + nimodipine [Nim] 99.24 ± 1.6 [p = 0.0003 versus cLTP], and cLTP + verapamil [Verap] 95.8 ± 2.2 [p < 0.0001 versus cLTP]).…”

CaMKII Metaplasticity Drives Aβ Oligomer-Mediated Synaptotoxicity

“…Banker cultures of hippocampal neurons from E18 Sprague-Dawley rat embryos of either sex were prepared as described previously (Penn et al, 2017). Neurons (10–12 days in vitro [DIV]) were transfected using Effectene as per the manufacturer’s instructions.…”

“…Western blots and cLTP experiments were prepared as described previously (Penn et al, 2017). Cultured hippocampal neurons at DIV 14 were treated either with vehicle or 1 μM oAβ diluted in Tyrode’s buffer during 30 min.…”

Glutamatergic signaling between neurons and oligodendrocyte lineage cells: Is it synaptic or non‐synaptic?

“…Submillimolar to millimolar concentrations of glutamate are reached within the synaptic cleft upon vesicular release, and therefore, AMPARs are usually placed in direct opposition to the active zone where they mediate synaptic signaling. AMPARs can also be found extrasynaptically, but those are required for efficient trafficking in and out of the synapse underlying rapid changes in the synaptic strength (Penn et al, ; Wu et al, ). NMDARs, KARs, and mGluRs may be placed extrasynaptically on postsynaptic neurons, and/or on glial cells; mGluRs are also often found on the presynaptic terminals where they regulate neurotransmitter release.…”