BBB Seminar: Clive Bramham
The Arc of synaptic memory
Clive Bramham, Department of Biomedicine and Bergen Mental Health Research Center, University of Bergen
The immense complexity and specificity of memory storage in the mammalian central nervous system is thought to depend on the modifiability (or plasticity) of neuronal communication at synapses. Dysfunction of synaptic plasticity is implicated in a range of disorders from Alzheimer’s disease to major depression and chronic pain states. Stable changes in synaptic connectivity require activity-dependent changes in gene expression, yet causal roles for specific activity-regulated RNAs have been hard to define. This talk will present recent evidence implicating the immediate early gene, Arc, in consolidation of long-term synaptic plasticity.
The mRNA encoded by the immediate early gene Arc traffics to dendrites and specifically accumulates at sites of synaptic activity. Arc protein also accumulates in dendrites and becomes enriched at the site of local synaptic activity suggesting that Arc protein is locally synthesized. Using local infusion of Arc antisense, we have identified a casual role for Arc synthesis in the consolidation of long-term potentiation (LTP) in the dentate gyrus of anesthetized rats. Sustained Arc synthesis during a critical time-window is required for dephosphorylation and inactivation of the actin-binding protein cofilin, coupled with expansion of the F-actin network and probably stable enlargement of dendritic spines. The secretory neuropeptide, brain-derived neurotrophic factor (BDNF), has multiple functions in sculpting the structure and function of adult neural networks. Our recent evidence suggests that BDNF-induced LTP is completely dependent on Arc synthesis. Recent efforts are focused on elucidating the mechanisms controlling Arc synthesis during the critical time-window of LTP consolidation. Arc synthesis is associated with sustained phosphorylation of translation initiation factor 4E (eIF4E) through a mechanism that appears to require stable F-actin formation. Candidate microRNA regulators of Arc synthesis have been identified. In addition, recent work has revealed an important role for post-translational modification of Arc in regulating its subcellular localization in neurons. Taken together with findings from other laboratories, these data shed significant light on Arc function in adult neurons. Interestingly, newborn neuronal precursors express Arc spontaneously, prior to synapse formation, suggesting a novel role for Arc in neurogenesis.
Messaoudi E, Kanhema T, Soule J, Tiron A, Dagyte G, DaSilva B, Bramham CR (2007) Sustained Arc/Arg3.1 synthesis controls long-term potentiation consolidation through regulation of local actin polymerization in the dentate gyrus in vivo. J Neurosci 27: 10445-10455.
Bramham CR, Wells DG (2007) Dendritic mRNA: transport, translation, and function. Nat Rev Neurosci 8: 776-789.
Bramham CR (2008) Local protein synthesis, actin dynamics, and LTP consolidation. Curr Opin Neurobiol 18: 524-531.
Kuipers SD, Tiron A, Soule J, Messaoudi E, Trentani A, and Bramham CR Selective survival and maturation of adult-born dentate granule cells expressing the immediate early gene Arc/Arg3.1. PLoS One, in press.
Chair: Arne Tjølsen, Department of Biomedicine