Time: 10:30-11:30 a.m. September. 19, 2013

Venue: Medical Science Building, B316

Reporter: Haruhiko Bito, Professor, Chairman, Department of Neurochemistry, University of Tokyo Graduate School of Medicine

Host: Professor Liu Guosong

Abstract

The nervous system adapts to a fluctuating environment through activity-dependent modulation of neuronal properties such as synaptic plasticity. The direction and extent of such sustainable modulation is determined by the stimulus parameters, suggesting that the biochemical machineries that operate at synapses can readily compute the input information. Furthermore, once induced, bistable plasticity is maintained over time through a mechanism that involves activity-dependent turning of a new gene expression and protein translation.

Over the past years, we have systematically investigated the molecular basis of the signaling from synapses to the nucleus that determines the persistence of synaptic plasticity. We thus uncovered an activity-dependent protein kinase cascade CaMKK-CaMKIV that critically controls the amplitude and time course of phosphorylation of a nuclear transcription factor CREB downstream of synaptic activity, thereby activating a plethora of adaptive transcriptional responses within a neuronal circuit. We further identified a potent synaptic activity-responsive element (SARE) on the promoter of one of the most prominent neuronal activity-induced genes, namely Arc/Arg3.1. Strikingly, the SARE of Arc gene consisted of a unique cluster of binding sites for CREB, MEF2 and SRF/TCF, each of which cooperatively contributed to converting synaptic responses into a transcriptional one. These mechanistic details were used to create a synthetic promoter E-SARE to map and record from activity-regulated neurons and circuits in various areas of the brain in vivo.

It remained, however, paradoxical why a memory trace-coding protein Arc, which was upregulated by strong synaptic activity that induced persistent forms of plasticity and learning, also critically contributed to weakening synapses by promoting AMPA-R endocytosis during various forms of synaptic and homeostatic plasticity. We therefore directly imaged plasticity-induced Arc/Arg3.1 trafficking to the dendrites and back to the synapses. Contrary to expectations, we found a preferred targeting of Arc/Arg3.1 to inactive synapses, and this was mediated via Arc’s high affinity interaction with an inactive form of CaMKIIβ. Consistently, the degree of synaptic Arc/Arg3.1 accumulation was more sustained during a period of inactivity following strong induction, and correlated with removal of surface GluA1 from individual synapses. A lack of CaMKIIβ either in vitro or in vivo resulted in loss of Arc/Arg3.1 up-regulation in the silenced synapses. These findings provide evidence for an “inverse” synaptic tagging mechanism that enables Arc to specifically target the un-potentiated synapses to promote the clearance of surface AMPA-R, thereby helping to maintain the contrast of synaptic weight between strengthened and weak synapses.