Abstract
The role of Arc in synaptic plasticity and memory consolidation has been investigated for many years with recent evidence that defects in the expression or activity of this immediate-early gene may also contribute to the pathophysiology of brain disorders including schizophrenia and fragile X syndrome. These results bring forward the concept that reversing Arc abnormalities could provide an avenue to improve cognitive or neurological impairments in different disease contexts, but how to achieve this therapeutic objective has remained elusive. Here, we present results from a chemogenomic screen that probed a mechanistically diverse library of small molecules for modulators of BDNF-induced Arc expression in primary cortical neurons. This effort identified compounds with a range of influences on Arc, including promoting its acetylation—a previously uncharacterized post-translational modification of this protein. Together, our data provide insights into the control of Arc that could be targeted to harness neuroplasticity for clinical applications.
Highlights
The role of Arc in synaptic plasticity and memory consolidation has been investigated for many years with recent evidence that defects in the expression or activity of this immediateearly gene may contribute to the pathophysiology of brain disorders including schizophrenia and fragile X syndrome
As an initial step in the design of an assay that could assist with the discovery of pharmacological modulators of Arc, we tested whether recombinant brain-derived neurotrophic factor (BDNF) treatment or the combined application of 4-aminopyridine (4AP, a blocker of KV1 (Shaker, KCNA) family of voltage-activated K+ channels) and bicuculline (Bic, a GABA receptor antagonist) caused a more robust expression of Arc protein in dissociated cortical neurons
Difference between the two treatments could be attributed to the fact that BDNF, in comparison to 4AP/Bic, induced a significantly stronger phosphorylation of p44/42 mitogen-activated kinase (Mapk, known as Erk1/2) and ribosomal protein S6 (Fig. 1), which are two key molecular effectors in pathways known to play a role in activity-dependent expression of Arc[1,2]
Summary
The role of Arc in synaptic plasticity and memory consolidation has been investigated for many years with recent evidence that defects in the expression or activity of this immediateearly gene may contribute to the pathophysiology of brain disorders including schizophrenia and fragile X syndrome. Arc, whose expression is rapidly induced by signals coupled to neuronal activity, is a modular, “hub-like” protein[3] required for different forms of long-lasting synaptic plasticity including longterm potentiation (LTP)[4,5], long-term depression (LTD)[6], and homeostatic scaling[7]. At the synapse, it contributes to the endocytosis of 3-hydroxy-5-methyl-4-isoxazole receptors (AMPARs) by interacting with members of the endocytic vesicular machinery[8,9], influences the morphology of dendritic spines[10], as well as acts as a “tag” of inactive synapses[11]. Lower expression of Arc has been reported in the brain of Alzheimer’s disease
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