Arhgap22 Disruption Leads to RAC1 Hyperactivity Affecting Hippocampal Glutamatergic Synapses and Cognition in Mice.
Animals
Anxiety
/ genetics
Behavior, Animal
/ physiology
Cognition
/ physiology
Dendritic Spines
/ metabolism
GTPase-Activating Proteins
/ genetics
Glutamic Acid
/ metabolism
Hippocampus
/ metabolism
Maze Learning
/ physiology
Mice
Mice, Knockout
Motor Activity
/ physiology
Neuronal Plasticity
/ genetics
Neurons
/ metabolism
Neuropeptides
/ genetics
Synapses
/ genetics
Synaptosomes
/ metabolism
rac1 GTP-Binding Protein
/ genetics
ARHGAP22
Dendritic spines
Hippocampus
Learning and memory
Synaptic plasticity
Journal
Molecular neurobiology
ISSN: 1559-1182
Titre abrégé: Mol Neurobiol
Pays: United States
ID NLM: 8900963
Informations de publication
Date de publication:
Dec 2021
Dec 2021
Historique:
received:
07
10
2020
accepted:
15
07
2021
pubmed:
30
8
2021
medline:
18
3
2022
entrez:
29
8
2021
Statut:
ppublish
Résumé
Rho GTPases are a class of G-proteins involved in several aspects of cellular biology, including the regulation of actin cytoskeleton. The most studied members of this family are RHOA and RAC1 that act in concert to regulate actin dynamics. Recently, Rho GTPases gained much attention as synaptic regulators in the mammalian central nervous system (CNS). In this context, ARHGAP22 protein has been previously shown to specifically inhibit RAC1 activity thus standing as critical cytoskeleton regulator in cancer cell models; however, whether this function is maintained in neurons in the CNS is unknown. Here, we generated a knockout animal model for arhgap22 and provided evidence of its role in the hippocampus. Specifically, we found that ARHGAP22 absence leads to RAC1 hyperactivity and to an increase in dendritic spine density with defects in synaptic structure, molecular composition, and plasticity. Furthermore, arhgap22 silencing causes impairment in cognition and a reduction in anxiety-like behavior in mice. We also found that inhibiting RAC1 restored synaptic plasticity in ARHGAP22 KO mice. All together, these results shed light on the specific role of ARHGAP22 in hippocampal excitatory synapse formation and function as well as in learning and memory behaviors.
Identifiants
pubmed: 34455539
doi: 10.1007/s12035-021-02502-x
pii: 10.1007/s12035-021-02502-x
pmc: PMC8639580
doi:
Substances chimiques
GTPase-Activating Proteins
0
Neuropeptides
0
Rac1 protein, mouse
0
Glutamic Acid
3KX376GY7L
rac1 GTP-Binding Protein
EC 3.6.5.2
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
6092-6110Subventions
Organisme : Fondazione Telethon
ID : GGP17283
Organisme : Ministero della Salute
ID : GR-2016-02361366
Organisme : Regione Lombardia
ID : 227333
Informations de copyright
© 2021. The Author(s).
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pmcid: 6345483