LTP requires postsynaptic PDZ-domain interactions with glutamate receptor/auxiliary protein complexes

Abstract

Long-term potentiation (LTP) is a persistent strengthening of synaptic transmission in the brain and is arguably the most compelling cellular and molecular model for learning and memory. Previous work found that both AMPA receptors and exogenously expressed kainate receptors are equally capable of expressing LTP, despite their limited homology and their association with distinct auxiliary subunits, indicating that LTP is far more promiscuous than previously thought. What might these two subtypes of glutamate receptor have in common? Using a single-cell molecular replacement strategy, we demonstrate that the AMPA receptor auxiliary subunit TARP γ-8, via its PDZ-binding motif, is indispensable for both basal synaptic transmission and LTP. Remarkably, kainate receptors and their auxiliary subunits Neto proteins share the same requirement of PDZ-binding domains for synaptic trafficking and LTP. Together, these results suggest that a minimal postsynaptic requirement for LTP is the PDZ binding of glutamate receptors/auxiliary subunits to PSD scaffolding proteins.

Postsynaptic localization and regulation of AMPA receptors and Cav1.2 by β2 adrenergic receptor/PKA and Ca 2+ /CaMKII signaling

“…However, the apparent contradictions between findings that specifically implicate CaMKII‐mediated phosphorylation of γ2 (Tomita et al, ) versus γ8 (Park et al, ) in LTP have to be addressed. There is also a disagreement between recent studies that suggest either phosphorylation of γ8 on S277 and S281 but not PDZ anchoring (Park et al, ) or PDZ anchoring of γ8 but not S277 and S281 phosphorylation (Sheng et al, ) is critical for LTP. The work by Park et al () is based on KI mice in which the CaMKII phosphorylation sites had been eliminated and the work by Sheng et al () on replacement of all endogenous AMPARs with a GluA1–γ8 fusion protein.…”

“…There is also a disagreement between recent studies that suggest either phosphorylation of γ8 on S277 and S281 but not PDZ anchoring (Park et al, ) or PDZ anchoring of γ8 but not S277 and S281 phosphorylation (Sheng et al, ) is critical for LTP. The work by Park et al () is based on KI mice in which the CaMKII phosphorylation sites had been eliminated and the work by Sheng et al () on replacement of all endogenous AMPARs with a GluA1–γ8 fusion protein. Perhaps fusing γ8 to GluA1 leads to a conformation of the γ8 C‐terminus that augments PSD‐95 binding similar to the conformation that is induced by CaMKII‐mediated phosphorylation as shown for γ2 (Sumioka et al, ; Hafner et al, ).…”

“…In fact, phosphorylation of stargazin/γ 2 at its C‐terminus by CaMKII at multiple sites, which had been implicated earlier by Tomita et al () in LTP, detaches the otherwise positively charged C‐terminus from the plasma membrane for increased binding to PSD‐95 and postsynaptic AMPAR localization (Opazo et al, ; Sumioka et al, ; Hafner et al, ). However, more recent work by Tomita and co‐workers suggests a role of CaMKII‐mediated phosphorylation of γ 8 and not of γ 2 in LTP, leaving open the question of whether and which TARPs are truly the relevant CaMKII targets (Sumioka et al, ; Park et al, ; Sheng et al, ).…”

Visualizing synaptic plasticity in vivo by large-scale imaging of endogenous AMPA receptors

“…When coupled to the extracellular N-terminal domain of the AMPAR, this SEP tag reports the concentration of functional receptors at the cell surface, as the fluorescence of receptors localized in acidic compartments such as endosomes and Golgi is quenched. Our genetic labeling strategy also avoids confounds arising from manipulation of the AMPAR c-terminus, a region important for proper function and trafficking to the postsynaptic membrane (Sheng et al, 2018;Zhou et al, 2018). Many groups have used overexpression of SEP-tagged AMPARs in neuronal culture to study AMPAR trafficking in vitro (Araki et al, 2015;Ashby et al, 2004;Kopec et al, 2006;Makino and Malinow, 2009;Patterson et al, 2010;Roth et al, 2017).…”

Neto-α controls synapse organization and homeostasis at the Drosophila neuromuscular junction

“…A role for Neto in the biology of KARs in vivo has been more difficult to assess because of the low levels of KARs and Neto proteins (Lerma and Marques, 2013). Nevertheless, vertebrate Netos could modulate the synaptic recruitment of selective KARs by association with synaptic scaffolds such as GRIP and PSD-95; in fact, the PDZ-binding domains of vertebrate KAR/Neto complexes are essential for basal synaptic transmission and LTP (Sheng et al, 2018;Tang et al, 2012). Post-translational modifications regulate Neto activities in vitro, but the in vivo relevance of many of these observations remains unknown (Lomash et al, 2017).…”