BBB seminar: Steven Finkbeiner

Steven Finkbeiner
Gladstone Institute of Neurological Disease, University of California, San Francisco, CA, USA

Long-term adaptive responses such as learning and memory are believed to require activity-dependent changes in new gene expression. However, the basis for synaptic signal transduction specificity and the mechanisms by which newly synthesized genes regulate selected synapses are areas of ongoing research. The N -methyl-D-aspartate (NMDA) receptor is critically involved in activity-dependent synaptic plasticity at many synapses and potently regulates new gene expression. We find that the C-terminus of the NR1 subunit plays an essential role in coupling Ca ²⁺ influx through the NMDA receptor to downstream signaling pathways and new gene expression. We have discovered a novel pathway that is dually controlled by NMDA and metabotropic glutamate receptors and, in turn, regulates AMPA receptor trafficking and gene expression. In parallel work, we have studied the role of transcription, translation, trafficking, and stability in activity-dependent mechanisms, which regulate the plasticity-related gene Arc . We have found two DNA elements within the Arc promoter, a serum-response element and a novel Zeste-like element, which mediates activity-dependent Arc transcription. We also uncovered an unexpected G-protein dependent pathway by which AMPA receptors suppress new transcription of Arc . Recently, we have found that the Arc protein interacts with a molecule that regulates actin assembly and that Arc regulates spine morphology. The results suggest a model in which Arc transcription may integrate opposing signals from the NMDA and AMPA receptor. We speculate that Arc may play dual roles in synaptic homeostasis and in the consolidation of synaptic plasticity.

Host : Clive Bramham <clive.bramham@biomed.uib.no> , Department of Biomedicine