Arc Oligomerization Is Regulated by CaMKII Phosphorylation of the GAG Domain: An Essential Mechanism for Plasticity and Memory Formation

Arc is a synaptic protein essential for memory consolidation. Recent studies indicate that Arc originates in evolution from a Ty3-Gypsy retrotransposon GAG domain. The N-lobe of Arc GAG domain acquired a hydrophobic binding pocket in higher vertebrates that is essential for Arc’s canonical function to weaken excitatory synapses. Here, we report that Arc GAG also acquired phosphorylation sites that can acutely regulate its synaptic function. CaMKII phosphorylates the N-lobe of the Arc GAG domain and disrupts an interaction surface essential for high-order oligomerization. In Purkinje neurons, CaMKII phosphorylation acutely reverses Arc’s synaptic action. Mutant Arc that cannot be phosphorylated by CaMKII enhances metabotropic receptor-dependent depression in the hippocampus but does not alter baseline synaptic transmission or long-term potentiation. Behavioral studies indicate that hippocampus- and amygdala-dependent learning requires Arc GAG domain phosphorylation. These studies provide an atomic model for dynamic and local control of Arc function underlying synaptic plasticity and memory. [Display omitted] •Arc GAG domain is phosphorylated by CaMKII, which prevents Arc oligomerization•Arc phosphorylation controls the magnitude of mGluR-dependent LTD•Arc regulation by CaMKII phosphorylation is required for adaptive learning Normal learning and memory require dynamic control of synaptic connections. Arc plays a critical role in modifying synaptic strengths. Zhang et al. reveal that Arc’s function is controlled by a novel regulatory mechanism that exploits its evolutionary origin as a retrotransposon GAG domain together with CaMKII that records activity history.