Targeting Tiam1 Enhances Hippocampal-Dependent Learning and Memory in the Adult Brain and Promotes NMDA Receptor-Mediated Synaptic Plasticity and Function

Dec 26, 2024The Journal of neuroscience : the official journal of the Society for Neuroscience

Reducing Tiam1 Improves Adult Learning and Memory by Boosting NMDA Receptor-Related Brain Plasticity

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Abstract

Deletion of Tiam1 from adult forebrain excitatory neurons resulted in enhanced contextual fear memory and spatial discrimination in mice.

Adult male and female mice with Tiam1 deletion displayed improved performance in hippocampal-dependent behaviors.
Dentate granule cells exhibited increased synaptic plasticity and heightened function of N-methyl-D-aspartate-type glutamate receptors (NMDARs).
Loss of Tiam1 in neurons prevented the internalization of NMDARs and reduced levels of filamentous actin.
Activity-dependent degradation of Tiam1 may relieve constraints on synaptic plasticity in the hippocampus.
Tiam1 appears to play a role in limiting NMDAR-mediated synaptic plasticity and spine stabilization in the adult brain.

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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 () and assessed the effects on hippocampal-dependent behaviors. Adult male and femalemice displayed enhanced contextual fear memory, fear extinction, and spatial discrimination. Investigation into underlying mechanisms revealed that dentate granule cells frombrain slices exhibited augmented synaptic plasticity and N-methyl-D-aspartate-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. Tiam1fKO Tiam1fKO Tiam1fKO

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Targeting Tiam1 Enhances Hippocampal-Dependent Learning and Memory in the Adult Brain and Promotes NMDA Receptor-Mediated Synaptic Plasticity and Function

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