Abstract
Agonist-induced internalization of transmembrane receptors is a widespread biological phenomenon that also may serve as a mechanism for synaptic plasticity. Here we show that the agonist AMPA causes a depression of AMPA receptor (AMPAR) signaling at glutamate synapses in the CA1 region of the hippocampus in slices from developing, but not from mature, rats. This developmentally restricted agonist-induced synaptic depression is expressed as a total loss of AMPAR signaling, without affecting NMDA receptor (NMDAR) signaling, in a large proportion of the developing synapses, thus creating AMPAR silent synapses. The AMPA-induced AMPAR silencing is induced independently of activation of mGluRs and NMDARs, and it mimics and occludes stimulus-induced depression, suggesting that this latter form of synaptic plasticity is expressed as agonist-induced removal of AMPARs. Induction of long-term potentiation (LTP) rendered the developing synapses resistant to the AMPA-induced depression, indicating that LTP contributes to the maturation-related increased stability of these synapses. Our study shows that agonist binding to AMPARs is a sufficient triggering stimulus for the creation of AMPAR silent synapses at developing glutamate synapses.
Highlights
Activity-dependent changes in synaptic strength, synaptic plasticity, is believed to be decisive both for formation of the basal synaptic organization during brain development, as well as for learning throughout life
Even synaptic activation at very low frequencies (0.05–0.2 Hz), and notably in the absence of NMDA receptor (NMDAR) or mGluR activation, is sufficient to induce AMPA receptor (AMPAR) silencing [21,26,27]. These results suggest that AMPAR activation per se may be a sufficient inducing stimulus for this form of plasticity. We tested this idea by activating AMPARs directly with the agonist AMPA and we found that AMPA itself induces removal of synaptic AMPAR signaling, leaving NMDAR signaling unaffected
Application (Fig 1F, G, ; 9569% of the initial level, n = 5, P = 0.68). These results demonstrate that agonist activation of AMPARs induces a depression of AMPAR-mediated transmission exclusively at developing synapses, leaving NMDARs unaffected, and that this AMPA-induced depression occludes subsequent stimulusinduced depression
Summary
Activity-dependent changes in synaptic strength, synaptic plasticity, is believed to be decisive both for formation of the basal synaptic organization during brain development, as well as for learning throughout life. Insertion or removal of synaptic alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic receptors (AMPARs) is a major mechanism underlying synaptic plasticity in learning as well as in development [1,2]. There are numerous differences between nascent and mature synapses, including the type of membrane receptor that triggers induction of synaptic plasticity, the intracellular pathways involved, as well as mechanisms for AMPAR trafficking. One form of LTD, which is likely important in initiating activity-dependent synaptic pruning during the developmental period, is expressed as removal of synaptic AMPARs [15]. This LTD can be induced by application of agonists to NMDARs and mGluRs [15]. Agonist-induced removal of AMPARs has been linked to the constitutive recycling of AMPARs [18,19,20]
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