Regulation of synaptic stability by AMPA receptor reverse signaling

Abstract

The establishment of neuronal circuits relies on the stabilization of functionally appropriate connections and the elimination of inappropriate ones. Here we report that postsynaptic AMPA receptors play a critical role in regulating the stability of glutamatergic synapses. Removal of surface AMPA receptors leads to a decrease in the number and stability of excitatory presynaptic inputs, whereas overexpression increases synapse number and stability. Furthermore, overexpression of AMPA receptors along with Neuroligin-1 in 293T cells is sufficient to stabilize presynaptic inputs from cortical neurons onto heterologous cells. The stabilization of presynaptic inputs by AMPA receptors is not dependent on receptor-mediated current and instead relies on structural interactions mediated by the N-terminal domain of the glutamate receptor 2 (GluR2) subunit. These observations indicate that transsynaptic signaling mediated by the extracellular domain of GluR2 regulates the stability of presynaptic terminals.GluR2 N-terminal domain | Presynaptic stabilization | Presynaptic input dynamics T he development of neural circuits is characterized by exuberant synapse formation followed by elimination of inappropriate connections (1-4). Although there is considerable evidence that activity-dependent mechanisms are involved in synapse elimination, the mechanisms responsible for regulating and maintaining stable synapses are largely unknown.Synapse formation is a dynamic process and involves the rapid recruitment of several synaptic proteins to sites of axo-dendritic contact. Transport packets containing essential components of the presynaptic active zone are highly motile before they reach synaptic sites (5). Likewise, synaptic vesicles traffic rapidly along axons before stabilizing at dendritic contact sites (6), suggesting that a dendrite-associated signal regulates presynaptic stability. At glutamatergic synapses, AMPA and NMDA receptors are recruited to the postsynaptic density in 1 h or less (7,8), raising the possibility that they may play an important role in regulating synapse stability.Electrophysiological and immunohistochemical experiments suggest that a large percentage of young synapses contain NMDA receptors but lack AMPA receptors (9, 10). AMPA receptors are recruited gradually to postsynaptic sites, resulting in an increase in the AMPA/NMDA ratio at these synapses (11-13). The increase in the AMPA/NMDA ratio correlates with the stabilization of dendritic spines.Synapse formation requires the precise apposition of presynaptic and postsynaptic elements underlying the need for bidirectional signaling. Key postsynaptic proteins such as neuroligins, synaptic cell-adhesion molecules (SynCAMs), Ephrin type B (EphB) receptors, netrin G ligands, and leucine-rich repeat transmembrane (LRRTM) proteins signal transsynaptically to induce recruitment of presynaptic components (14)(15)(16)(17)(18)(19)(20). Postsynaptic adhesion molecules also are involved in the functional maturation of presynaptic inputs (21-23). Recent work demons...

Nonassociative Learning in Invertebrates

“…Postsynaptic Ca 2þ is, in turn, necessary for LTF, perhaps through retrograde signaling to presynaptic ApCAM, neurexin, or Trk receptors (Purcell et al 2003;Ormond et al 2004;Sharma et al 2006;Cai et al 2008;Hu et al 2010;Choi et al 2011;Kassabov et al 2013). The new postsynaptic clusters of AMPA-like receptors may also participate in retrograde signaling, and recruit presynaptic clusters of synaptophysin during a later stage of ITF and growth of presynaptic varicosities during LTF (Kim et al 2003;Ripley et al 2011;Lee et al 2012). These ideas are similar to theoretical "cascade" models of memory storage that can show plasticity as well as long-term stability (Fusi et al 2005), which would seem to be mutually exclusive but are both essential features of memory.…”

Structural plasticity upon learning: regulation and functions

“…Finally, one important mechanism through which synapse stability could be improved is by changes in the organization of the postsynaptic density (PSD) that promote trans-synaptic adhesion and contact. Expression of PSD95 and/or AMPA receptors enhances synaptic strength and synapse stability 28,29 . Several adhesion molecule systems have also been linked to spine stability, including neuroligin 1 (REFS 29,30) and N-cadherin.…”

Determinants of synaptic strength vary across an axon arbor

“…The observation that the amount of GluR1 does not correlate with presynaptic strength, whereas the amount of NMDA receptors and PSD-95 does, suggests that not all postsynaptic proteins are affected by retrograde signaling that matches preand postsynaptic properties. Recent studies showed that the amount of AMPA receptors does not correlate with presynaptic strength with baseline activity (Tokuoka and Goda 2008), and AMPA receptor subunits retrogradely stabilize presynaptic terminals when neuroligin-1 is present (Ripley et al 2010). Our work suggests that the amount of two postsynaptic proteins, NMDA receptors and PSD-95, is an indirect indicator of presynaptic strength, regardless of the spatial configuration or the identity of postsynaptic neuron targets.…”