Control of synaptic consolidation in the dentate gyrus: mechanisms, functions, and therapeutic implications

Synaptic consolidation refers to the development and stabilization of protein synthesis-dependent modifications of synaptic strength as observed during long-term potentiation (LTP) and long-term depression (LTD). Activity-dependent changes in synaptic strength are thought to underlie memory storage and other adaptive responses of the nervous systems of importance in mood stability, reward behavior, and pain control. This chapter focuses on the mechanisms and functions of synaptic consolidation in the dentate gyrus, a critical structure not only in hippocampal memory function, but also in regulation of stress responses and cognitive aspects of depression. Recent evidence suggests that synaptic consolidation at excitatory medial perforant path-granule cell synapses requires brain-derived neurotrophic factor (BDNF) signaling and induction of the immediate early gene activity-regulated cytoskeleton-associated protein (Arc). Arc mRNA is strongly induced and transported to dendritic processes following high-frequency stimulation (HFS) that induces LTP in the rat dentate gyrus in vivo. Sustained synthesis of Arc during a surprisingly protracted time-window is required for hyperphosphorylation of actin depolymerizing factor/cofilin and local expansion of the actin cytoskeleton in vivo. Furthermore, this process of Arc-dependent synaptic consolidation is activated in response to brief infusion of BDNF. Microarray expression profiling has revealed a panel of BDNF-regulated genes that may cooperate with Arc during synaptic consolidation. In addition to regulating gene expression, BDNF signaling modulates the fine localization and biochemical activation of the translation machinery. By modulating the spatial and temporal translation of newly induced (Arc) and constitutively-expressed mRNA in dendrites, BDNF may effectively control the window of synaptic consolidation. Dysregulation of BDNF synthesis and Arc function, specifically within the dentate gyrus, is linked to behavioral symptoms and cognitive deficits in animal models of depression and Alzheimer's disease. Therapeutics strategies targeting synaptic consolidation hold promise for the future.