Targeting Tiam1 enhances hippocampal-dependent learning and memory in the adult brain and promotes NMDA receptor-mediated synaptic plasticity and function

Excitatory synapses and the actin-rich dendritic spines on which they reside are indispensable for information processing and storage in the brain. In the adult hippocampus, excitatory synapses must balance plasticity and stability to support learning and memory. However, the mechanisms governing this balance remain poorly understood. Tiam1 is an actin cytoskeleton regulator prominently expressed in the dentate gyrus (DG) throughout life. Previously, we showed that Tiam1 promotes dentate granule cell synapse and spine stabilization during development, but its role in the adult hippocampus remains unclear. Here, we deleted Tiam1 from adult forebrain excitatory neurons (Tiam1^fKO ) and assessed the effects on hippocampal-dependent behaviors. Adult male and female Tiam1^fKO mice displayed enhanced contextual fear memory, fear extinction, and spatial discrimination. Investigation into underlying mechanisms revealed that dentate granule cells from Tiam1^fKO brain slices exhibited augmented synaptic plasticity and NMDA-type glutamate receptor (NMDAR) function. Additionally, Tiam1 loss in primary hippocampal neurons blocked agonist-induced NMDAR internalization, reduced filamentous actin levels, and promoted activity-dependent spine remodeling. Notably, strong NMDAR activation in wild-type hippocampal neurons triggered Tiam1 loss from spines. Our results suggest that Tiam1 normally constrains hippocampal-dependent learning and memory in the adult brain by restricting NMDAR-mediated synaptic plasticity in the DG. We propose that Tiam1 achieves this by limiting NMDAR availability at synaptic membranes and stabilizing spine actin cytoskeleton, and that these constraints can be alleviated by activity-dependent degradation of Tiam1. These findings reveal a previously unknown mechanism restricting hippocampal synaptic plasticity and highlight Tiam1 as a therapeutic target for enhancing cognitive function.Significance statement The precise and dynamic regulation of excitatory synapses within hippocampal circuits is indispensable for learning and memory. These specialized connections must remain malleable to support the acquisition of relevant new information, but stable enough to protect the loss of previously stored memories. Dysregulation of this intricate balance drives cognitive decline following central nervous system injury and disease. Here, we establish the Rac1 guanine nucleotide exchange factor Tiam1 as an essential regulator of this balance that functions in the adult hippocampus to limit learning and memory. Our findings identify a previously unknown mechanism for restricting hippocampal synaptic plasticity that represents a potential therapeutic target for improving cognitive function.