PROJECT SUMMARY Our ability to learn and form memories relies on the precise and dynamic regulation of excitatory synapses. The dysfunction of these specialized connections is strongly implicated as a causal factor of cognitive decline. Recent findings strongly suggest a connection between the gradual impairment of hippocampal synaptic plasticity and the cognitive decline that accompanies aging and the progression of neurodegenerative diseases. Thus, it is imperative to further elucidate the mechanisms of hippocampal synaptic plasticity to better understand learning and memory and to develop effective approaches to treat memory decline. Excitatory synapses are primarily located on actin-rich protrusions of neuronal dendrites known as dendritic spines. We previously established the Rac1-specific guanine nucleotide exchange factor (GEF) Tiam1 as an important regulator of spine morphogenesis that couple’s NMDA-type glutamate receptor (NMDAR) activity to Rac1 signaling in cultured hippocampal neurons. In both the human and rodent brains, Tiam1 is enriched in the dentate gyrus (DG) subregion of the hippocampus throughout life. However, its functional role in the mammalian brain, particularly in adults, is unclear. Our recent preliminary data suggests that Tiam1 plays an ongoing role in regulating synaptic plasticity within the DG. We found that the deletion of Tiam1 from excitatory neurons in the adult mouse forebrain enhanced NMDAR-mediated currents in DG granule neurons and synaptic plasticity in the DG. Surprisingly, Tiam1 null mice also demonstrated enhanced performance in hippocampal-dependent learning and memory. Based on our preliminary findings, we propose that the Rac1-GEF Tiam1 may serve as an ideal molecular tool for exploring the mechanisms responsible for maintaining proper synaptic plasticity within the hippocampus as well as a potential therapeutic target for the treatment of disorders involving memory impairments. Using cutting- edge techniques that include high-resolution microscopy, viral-mediated activity-dependent neuronal labeling, molecular and cellular biology, electrophysiology, and behavioral analyses, we propose to determine the role of Tiam1 in the control of proper synaptic plasticity and cognitive function in the adult brain. Specifically, we propose to (1) elucidate the mechanisms by which Tiam1 restricts synaptic plasticity and (2) determine Tiam1’s role in hippocampal-dependent learning and memory. The goals of the proposed study are to reveal key molecular and cellular mechanisms that limit hippocampal plasticity and learning and memory in the adult brain and help to identify new therapeutic targets to enhance cognitive function.