Arc protein: a flexible hub for synaptic plasticity and cognition

10 OCTOBER 2017 - 12:30 PM

Clive R. BramhamUniversity of Bergen, Bergen, Norway.

Summary: The adaptive capacity of the brain depends on synaptic plasticity – the ability of a synapse to change in strength in response to use or disuse. Plasticity in neural circuits shapes emotional responses, cognitive flexibility, and underlies memory formation. Aberrant synaptic plasticity impacts human cognition in brain disorders such as autism, schizophrenia, and Alzheimer’s disease. Thus, a major challenge in basic and clinical neuroscience is to elucidate the molecular control of synaptic plasticity. The neuronal activity-induced protein, Arc, has emerged as a potential master regulator of synaptic plasticity. Arc synthesis is required for long-term increase and decreases in synaptic strength (LTP, LTD, scaling), and the mechanisms of rapid Arc mRNA synthesis, protein expression and turnover are well known. However, the molecular basis of Arc protein is a master regulator remains a puzzle. Recent work has provided novel insight into the structural properties of Arc, its protein-protein interactions and post-translational modifications. The evidence suggest that Arc protein is a functionally versatile hub, capable of engaging distinct effector proteins within dendritic spines and nuclear subdomains. In sum, Arc is an organizer of long-term synaptic plasticity, made for encoding information in neural circuits.

About the speaker: Our research aims to elucidate the cell biological and molecular mechanisms that control synaptic plasticity, and the dysregulation of these mechanisms in cognitive disorders. Our team has made seminal contributions to the discovery of BDNF as a trigger for transcription and translation-dependent synaptic plasticity in the adult brain (Bramham 2005; Messaoudi 1998, 2002, 2007, Ying 2002). My lab has pioneered research on Arc as a “master regulator” of synaptic plasticity (Ying 2002, Messaoudi 2007, Bramham 2008, 2010; Soulé 2012), and we have identified mechanisms by which BDNF-TrkB regulates synthesis of Arc and other proteins in dendrites (Kanhema 2006; Messaoudi 2007, Panja 2009, 2014a,b). Recent work provided the first insight into the biophysical, biochemical and structural properties of Arc (Myrum 2015). In a parallel line, my lab has provided the first insights into the regulation and function of non-coding RNAs (miRNAs, lncRNAs, repeat elements) in synaptic plasticity (Wibrand 2010, 2012, Pai 2014, Maag, 2015).

Methods: The Bramham lab combines in vivo electrophysiological studies of synaptic transmission with genetic and pharmacological manipulations, analysis of signal transduction mechanisms, protein-protein interactions, post-translational modification, and function. Methods such as proximity ligation assay, 2-photon microscopy, FRET and quantum dot imaging enable analysis of protein localization and function in living neurons in culture and brain tissue. Protein biochemical and biophysical methods used include expression of recombinant protein, various forms of affinity-purification, surface plasmon resonance, dynamic light scattering, and signal transduction assays.

Location: Amphi Herpin, Esclangon building, Jussieu Campus.

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