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

Authors

Francisco A Blanco
Md Ali Bin Saifullah
Jinxuan X Cheng
Carlota Abella
Federico Scala
Karen Firozi
Sanyong Niu
Jin Park
Jeannie Chin
Kimberley F Tolias

Language

English

Publication Date

2-5-2025

Journal

The Journal of Neuroscience

DOI

10.1523/JNEUROSCI.0298-24.2024

PMID

39725519

PMCID

PMC11800756

PubMedCentral® Posted Date

12-26-2024

PubMedCentral® Full Text Version

Post-print

Abstract

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 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.

Keywords

Animals, T-Lymphoma Invasion and Metastasis-inducing Protein 1, Receptors, N-Methyl-D-Aspartate, Mice, Male, Neuronal Plasticity, Female, Mice, Knockout, Hippocampus, Memory, Mice, Inbred C57BL, Fear, Learning, Synapses, Dendritic Spines, actin cytoskeleton, dendritic spines, hippocampus, learning and memory, NMDAR, Tiam1

Published Open-Access

yes

Recommended Citation

Blanco, Francisco A; Saifullah, Md Ali Bin; Cheng, Jinxuan X; et al., "Targeting Tiam1 Enhances Hippocampal-Dependent Learning and Memory in the Adult Brain and Promotes NMDA Receptor-Mediated Synaptic Plasticity and Function" (2025). Faculty and Staff Publications. 5295.
https://digitalcommons.library.tmc.edu/baylor_docs/5295