Investigating the dynamics and function of Arc intercellular transfer in memory

About This Grant

PROJECT SUMMARY / ABSTRACT Memory formation is thought to involve long-lasting changes in the synaptic connections between neurons to form memory circuits, but the precise molecular mechanisms remain poorly understood. One key player in memory is the immediate early gene Arc, which is critical for memory consolidation. The Shepherd lab discovered that Arc self-assembles into virus-like capsids that can traffic RNA and protein between cells in extracellular vesicles. We recently found that when Arc is transferred between primary cultured neurons, recipient neurons exhibit changes in synaptic neurotransmitter receptors. This suggests a novel form of intercellular synaptic plasticity, where Arc transfer modulates the activity of surrounding neurons. However, the significance of this mechanism in memory formation is unknown. My preliminary data suggest 1) Arc intercellular transfer occurs in vivo and 2) the fear memory deficit in Arc knockout (KO) mice can be rescued by expression of wildtype Arc in adulthood. This proposal will test whether Arc intercellular transfer facilitates memory consolidation in vivo. To investigate the role of Arc intercellular transfer in memory, I will evaluate its dynamics and necessity in vivo. In Aim 1, I will directly characterize intercellular Arc transfer in the brain using a novel molecular reporter to visualize Arc donor and recipient cells. I will determine the spatiotemporal dynamics of intercellular Arc transfer during memory consolidation. I will also evaluate the cell-type specificity of recipient cells and determine whether Arc intercellular transfer captured with our tool is behaviorally induced. In Aim 2, I will express Arc mutants that either disrupt intercellular signaling or Arc-dependent regulation of synaptic receptors in Arc KO mice, using a “rescue” approach to restore memory deficits. This experiment will inform which of Arc’s molecular functions are necessary for fear memory. These experiments may reveal a novel form of brain plasticity that uses viral-like intercellular signaling, shedding light on how memories are formed, stabilized, and stored in the brain. Elucidating the molecular mechanisms of Arc in normal memory stands to inform potential points of failure in neurological disorders.