Arhgap22 Disruption Leads to RAC1 Hyperactivity Affecting Hippocampal Glutamatergic Synapses and Cognition in Mice.

Publisher: Humana Press Country of Publication: United States NLM ID: 8900963 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1559-1182 (Electronic) Linking ISSN: 08937648 NLM ISO Abbreviation: Mol Neurobiol Subsets: MEDLINE

Original Publication: Clifton, NJ : Humana Press, c1987-

Cognition/*physiology ; GTPase-Activating Proteins/*metabolism ; Glutamic Acid/*metabolism ; Hippocampus/*metabolism ; Neurons/*metabolism ; Neuropeptides/*metabolism ; Synapses/*metabolism ; rac1 GTP-Binding Protein/*metabolism; Animals ; Anxiety/genetics ; Anxiety/metabolism ; Behavior, Animal/physiology ; Dendritic Spines/metabolism ; GTPase-Activating Proteins/genetics ; Maze Learning/physiology ; Mice ; Mice, Knockout ; Motor Activity/physiology ; Neuronal Plasticity/genetics ; Neuropeptides/genetics ; Synapses/genetics ; Synaptosomes/metabolism ; rac1 GTP-Binding Protein/genetics

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.
(© 2021. The Author(s).)

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GGP17283 Fondazione Telethon; GR-2016-02361366 Ministero della Salute; 227333 Regione Lombardia

Keywords: ARHGAP22; Dendritic spines; Hippocampus; Learning and memory; Synaptic plasticity

0 (GTPase-Activating Proteins)
0 (Neuropeptides)
0 (Rac1 protein, mouse)
3KX376GY7L (Glutamic Acid)
EC 3.6.5.2 (rac1 GTP-Binding Protein)

Date Created: 20210829 Date Completed: 20220317 Latest Revision: 20240701

20240702

PMC8639580

10.1007/s12035-021-02502-x

34455539