PROJECT SUMMARY The ability to remember and the capacity to forget are both required for a functional memory system, whereas their dysfunction is a common feature of cognitive disorders such as Alzheimer’s Disease (AD). It is unclear, however, how these opposing memory processes are balanced. Memory formation is driven by activity- dependent synaptic changes in neurons involved in the memory trace. Rho GTPases regulate this synaptic plasticity by controlling actin dynamics. Although Rac1 and RhoA can promote learning and memory, Rac1 also plays a key role in forgetting. To function properly, Rho GTPases require precise spatiotemporal regulation that is mediated by guanine nucleotide exchange factors (GEFs) and GTPase-activating proteins (GAPs), which not only control Rho GTPase activity, but also provide signaling specificity via interactions with upstream receptors and downstream effectors. We previously identified the Rac1-GEF Tiam1 as a critical regulator of spine/synapse development that couples synaptic receptors like NMDAR and EphB2 to localized Rac1-dependent actin remodeling. Tiam1 forms a GEF/GAP complex with the Rac1-GAP/RhoA-GEF Bcr, which bidirectionally regulates excitatory synapse development by dynamically controlling synaptic Rac1 activity. Following Bcr loss, excessive EphB-induced Tiam1-Rac1 signaling drives EphB internalization and spine retraction rather than synaptogenesis. However, the role of this GEF/GAP complex in the adult brain remains unclear. Using Tiam1 conditional knockout mice, we recently found that Tiam1 restricts NMDAR function and synaptic plasticity in the dentate gyrus of adult mice and limits learning and memory, in contrast to Bcr. Thus, we hypothesize that Tiam1 and Bcr cooperate in the adult brain to provide spatiotemporal control and signaling specificity to Rho GTPases, enabling dynamic regulation of synaptic plasticity critical for learning, memory, and forgetting. Moreover, Ab- induced Tiam1-Rac1 dysregulation likely drives aberrant synaptic plasticity that contributes to AD-associated memory impairments, and targeting this pathway will alleviate these deficits. To test this hypothesis, we aim to: (1) uncover the mechanisms by which Tiam1/Bcr dynamically regulate Rho GTPase signaling and synaptic plasticity important for learning and memory; (2) determine how Tiam1/Bcr regulates hippocampal-dependent learning, memory, and forgetting in adult mice; and (3) elucidate the role of Tiam1-Rac1 in Ab-induced EphB/NMDAR internalization and synapse loss, and determine how targeting this pathway affects synaptic plasticity and learning and memory deficits in an AD mouse model. We will accomplish this using a combination of mouse genetics, viral injections, confocal imaging, biochemistry, pharmacology, electrophysiology, and behavioral analyses. Our study should provide critical insight into Rho GTPase-dependent mechanisms that control normal synaptic plasticity underlying learning, memory, and forgetting as wel...