| Arc is an immediate early gene that is induced by neuronal activity associated with cognition. Similar gene induction occurs in long-term forms of synaptic plasticity such as long-term potentiation (LTP) and depression (LTD). Arc mRNA is exquisitely regulated, as the transcribed message is targeted to dendrites of neurons as they engage in information processing and storage, where it is locally translated at activated synapses. Despite these intriguing associations, Arc's synaptic function remains enigmatic. Here, we demonstrate that Arc protein interacts with dynamin and specific isoforms of endophilin to enhance receptor endocytosis. Arc selectively modulates trafficking of AMPA-type glutamate receptors (AMPARs) in neurons by accelerating endocytosis and reducing surface expression. The Arc-endocytosis pathway appears to regulate basal AMPAR levels since Arc KO neurons exhibit markedly reduced endocytosis and increased steady-state surface levels. These data suggests a model where in conditions of elevated activity, Arc expression increases, increasing AMPAR endocytosis, leading to decreases in surface AMPARs. In contrast, low neuronal activity decreases Arc expression, slowing the rate of AMPAR endocytosis, and increasing the steady-state surface expression of AMPARs. This form of homeostatic plasticity or synaptic scaling of AMPARs, is thought to be important for normal synaptic function as it maintains neuronal output without changing the relative strength of individual synapses. Indeed, we find that synaptic scaling of AMPARs is dependent on Arc. We also find that Arc interacts with presenilin 1, an integral part of the gamma-secretase complex that cleaves many type 1 transmembrane proteins such as the amyloid precursor protein (APP). In preliminary studies we find that Arc modulates the generation of beta-amyloid (Abeta) by recruiting PS1 to the Arc-dependent endocytic pathway, where optimal cleavage occurs. Thus Arc may play an integral role in dendritic processing of gamma-secretase targets.;These observations, together with evidence that Arc is required for late phase UP and memory consolidation, reveal the importance of Arc's dynamic expression as it exerts continuous and precise control over synaptic strength and cellular excitability. Arc thus provides a unique tool to bridge the gap between molecules and cognition in the brain. |
