The Probability of Neurotransmitter Release Governs AMPA Receptor Trafficking via Activity-Dependent Regulation of mGluR1 Surface Expression

Abstract

SummaryA major mechanism contributing to synaptic plasticity involves alterations in the number of AMPA receptors (AMPARs) expressed at synapses. Hippocampal CA1 synapses, where this process has been most extensively studied, are highly heterogeneous with respect to their probability of neurotransmitter release, P(r). It is unknown whether there is any relationship between the extent of plasticity-related AMPAR trafficking and the initial P(r) of a synapse. To address this question, we induced metabotropic glutamate receptor (mGluR) dependent long-term depression (mGluR-LTD) and assessed AMPAR trafficking and P(r) at individual synapses, using SEP-GluA2 and FM4-64, respectively. We found that either pharmacological or synaptic activation of mGluR1 reduced synaptic SEP-GluA2 in a manner that depends upon P(r); this process involved an activity-dependent reduction in surface mGluR1 that selectively protects high-P(r) synapses from synaptic weakening. Consequently, the extent of postsynaptic plasticity can be pre-tuned by presynaptic activity.

Illuminating Relationships Between the Pre- and Post-synapse

“…Circles indicate a SEP-GluA2 punctum at the synapse opposed to the FM4-64 labeling. Reproduced from Sanderson et al (2018) under CC BY-NC-ND license.…”

“…Dye in external membranes can then be washed out, leaving only those internalized vesicles that can be visualized as puncta by confocal or multiphoton microscopy and when photo converted can be visualized in synaptic vesicles by electron microscopy (Harata et al, 2001;Branco et al, 2008). The development of agents that reduce background FM staining (Kay et al, 1999;Pyle et al, 1999) have enabled the use of this technique in brain slice preparations (Johnstone and Raymond, 2013;Sanderson et al, 2018) as well as facilitating their use in dissociated culture (Tokuoka and Goda, 2008).…”

“…For example, one highly reproduced finding that mirrors the presynaptic structural diversity of synapses is that the probability of neurotransmitter release [P(r)] at central synapses is highly variable. The diversity of P(r) has been measured using a variety of methods including the progressive block by the use-dependent NMDA receptor (NMDAR) antagonist MK-801 (Hessler et al, 1993;Rosenmund et al, 1993), the activity-dependent uptake of styryl dye (Murthy et al, 1997;Sanderson et al, 2018), high affinity calcium indicators like Oregon Green BAPTA-1 (Emptage et al, 1999(Emptage et al, , 2003Ward et al, 2006;Enoki et al, 2009;Padamsey et al, 2017Padamsey et al, , 2019 or the glutamate sensor SF-iGluSnFR (Jensen et al, 2019;Soares et al, 2019). P(r) correlates with structural features of synapses such as the active zone area (Schikorski and Stevens, 1997;Holderith et al, 2012) and also with the readily releasable pool size (Dobrunz and Stevens, 1997) which is thought to consist of those vesicles docked at the active zone (Schikorski and Stevens, 1997;Murthy et al, 2001).…”

The Hippocampus Is the Place to Be: Opioid Receptors and LTP

“…This mechanism may involve activation of mGluR1, leading to inhibition of SK channels that ordinarily limit the synaptic activation of NMDARs (Tigaret et al, 2016). Recently, theta burst stimulation was shown to rapidly internalize mGluR1 and thereby protect high P(r) synapses from synaptic weakening (Sanderson et al, 2018). The findings reported in this study highlight an additional mechanism by which group I mGluRs might indirectly regulate LTP via modulation of the intrinsic excitability of axons.…”

Autism‐associated Shank3 mutations alter mGluR expression and mGluR‐dependent but not NMDA receptor‐dependent long‐term depression

“…Therefore, ASD‐associated mutations in Shank3 may induce an alteration in the presynaptic function in hippocampal neurons that can potentially occlude the presynaptic expression of mGluR‐LTD without affecting the expression of NMDAR‐LTD. Interestingly, a recent study has shown that surface expression of mGluR1 at CA1 synapses in organotypic hippocampal slices is dependent on neuronal activity, and DHPG‐induced mGluR‐LTD occurs exclusively via the activation of mGluR1 at these synapses (Sanderson et al, ). In our current work, the expression of ASD mutations in Shank3 led to a failure of increasing the synaptic density of surface mGluR1 puncta in cultured hippocampal neurons unlike that of wild‐type Shank3 overexpressing neurons.…”