MAPK signaling and a mobile scaffold complex regulate AMPA receptor transport to modulate synaptic strength

• Published in: Cell reports (Cambridge) Vol. 38; no. 13; p. 110577
• Main Authors: Hoerndli, Frédéric J., Brockie, Penelope J., Wang, Rui, Mellem, Jerry E., Kallarackal, Angy, Doser, Rachel L., Pierce, Dayton M., Madsen, David M., Maricq, Andres V.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 29.03.2022
• Subjects: AMPA receptor; Animals; C. elegans; Caenorhabditis elegans; Calcium-Calmodulin-Dependent Protein Kinase Type 2; CaMKII signaling; cargo adaptor; kinesin; MAPK signaling; Mitogen-Activated Protein Kinases - metabolism; Neuronal Plasticity - physiology; Receptors, AMPA - metabolism; scaffold protein; Signal Transduction; synapse; Synapses - metabolism; synaptic plasticity; transport; AMPA receptor; CP: Neuroscience; kinesin; C. elegans; scaffold protein; CaMKII signaling; synaptic plasticity; transport; synapse; cargo adaptor; CP: Cell Biology; MAPK signaling
• ISSN: 2211-1247; 2211-1247
• DOI: 10.1016/j.celrep.2022.110577

Synaptic plasticity depends on rapid experience-dependent changes in the number of neurotransmitter receptors. Previously, we demonstrated that motor-mediated transport of AMPA receptors (AMPARs) to and from synapses is a critical determinant of synaptic strength. Here, we describe two convergent signaling pathways that coordinate the loading of synaptic AMPARs onto scaffolds, and scaffolds onto motors, thus providing a mechanism for experience-dependent changes in synaptic strength. We find that an evolutionarily conserved JIP-protein scaffold complex and two classes of mitogen-activated protein kinase (MAPK) proteins mediate AMPAR transport by kinesin-1 motors. Genetic analysis combined with in vivo, real-time imaging in Caenorhabditis elegans revealed that CaMKII is required for loading AMPARs onto the scaffold, and MAPK signaling is required for loading the scaffold complex onto motors. Our data support a model where CaMKII signaling and a MAPK-signaling pathway cooperate to facilitate the rapid exchange of AMPARs required for early stages of synaptic plasticity. [Display omitted] •Mobile MAPK-associated scaffold proteins are required for AMPAR transport•MAPKKs and MAPKs are required for loading scaffold proteins onto kinesin motors•CaMKII is required for loading AMPARs onto scaffold proteins•CaMKII and MAPK signaling contribute to the rapid exchange of synaptic AMPARs Regulated trafficking of AMPA receptors (AMPARs) contributes to glutamate-mediated neurotransmission and synaptic plasticity. Hoerndli et al. demonstrate that MAPK-associated scaffold proteins and MAPK signaling are essential for kinesin-mediated delivery and removal of synaptic AMPARs. Coordinated MAPK and CaMKII signaling regulates a mobile complex that contributes to the rapid exchange of synaptic AMPARs.