Forebrain-specific deficiency of the GTPase CRAG/Centaurin-γ3 leads to immature dentate gyri and hyperactivity in mice

Nagashima, Shun; Ito, Naoki; Kobayashi, Reiki; Shiiba, Isshin; Shimura, Hiroki; Fukuda, Toshifumi; Hagihara, Hideo; Miyakawa, Tsuyoshi; Inatome, Ryoko; Yanagi, Shigeru

doi:10.1016/j.jbc.2021.100620

Cited by 4 publications

(1 citation statement)

References 38 publications

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“…Therefore, it is likely that Cn deficiency starting after 5 weeks of age may reverse the maturity of GCs, designated as dematuration [ 47 ]. A number of factors, including genetic [ 3 , 4 , 7 ] and non-genetic factors [ 5 , 47 , 82 ], have been suggested to postnatally induce dematuration of GCs. The iDG phenotype in Cn mutants could be another example of dematuration of GCs.…”

Section: Discussionmentioning

confidence: 99%

Forebrain-specific conditional calcineurin deficiency induces dentate gyrus immaturity and hyper-dopaminergic signaling in mice

et al. 2022

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Calcineurin (Cn), a phosphatase important for synaptic plasticity and neuronal development, has been implicated in the etiology and pathophysiology of neuropsychiatric disorders, including schizophrenia, intellectual disability, autism spectrum disorders, epilepsy, and Alzheimer’s disease. Forebrain-specific conditional Cn knockout mice have been known to exhibit multiple behavioral phenotypes related to these disorders. In this study, we investigated whether Cn mutant mice show pseudo-immaturity of the dentate gyrus (iDG) in the hippocampus, which we have proposed as an endophenotype shared by these disorders. Expression of calbindin and GluA1, typical markers for mature DG granule cells (GCs), was decreased and that of doublecortin, calretinin, phospho-CREB, and dopamine D1 receptor (Drd1), markers for immature GC, was increased in Cn mutants. Phosphorylation of cAMP-dependent protein kinase (PKA) substrates (GluA1, ERK2, DARPP-32, PDE4) was increased and showed higher sensitivity to SKF81297, a Drd1-like agonist, in Cn mutants than in controls. While cAMP/PKA signaling is increased in the iDG of Cn mutants, chronic treatment with rolipram, a selective PDE4 inhibitor that increases intracellular cAMP, ameliorated the iDG phenotype significantly and nesting behavior deficits with nominal significance. Chronic rolipram administration also decreased the phosphorylation of CREB, but not the other four PKA substrates examined, in Cn mutants. These results suggest that Cn deficiency induces pseudo-immaturity of GCs and that cAMP signaling increases to compensate for this maturation abnormality. This study further supports the idea that iDG is an endophenotype shared by certain neuropsychiatric disorders.

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Section: Discussionmentioning

confidence: 99%

Forebrain-specific conditional calcineurin deficiency induces dentate gyrus immaturity and hyper-dopaminergic signaling in mice

et al. 2022

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Novelty-induced memory consolidation is accompanied by increased Agap3 transcription: a cross-species study

Højgaard,

Szöllősi,

Henningsen

et al. 2023

Mol Brain

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Novelty-induced memory consolidation is a well-established phenomenon that depends on the activation of a locus coeruleus-hippocampal circuit. It is associated with the expression of activity-dependent genes that may mediate initial or cellular memory consolidation. Several genes have been identified to date, however, to fully understand the mechanisms of memory consolidation, additional candidates must be identified. In this cross-species study, we used a contextual novelty-exploration paradigm to identify changes in gene expression in the dorsal hippocampus of both mice and rats. We found that changes in gene expression following contextual novelty varied between the two species, with 9 genes being upregulated in mice and 3 genes in rats. Comparison across species revealed that ArfGAP with a GTPase domain, an ankyrin repeat and PH domain 3 (Agap3) was the only gene being upregulated in both, suggesting a potentially conserved role for Agap3. AGAP3 is known to regulate α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA)-type glutamate receptor trafficking in the synapse, which suggests that increased transcription of Agap3 may be involved in maintaining functional plasticity. While we identified several genes affected by contextual novelty exploration, we were unable to fully reverse these changes using SCH 23390, a dopamine D1/D5 receptor antagonist. Further research on the role of AGAP3 in novelty-induced memory consolidation could lead to better understanding of this process and guide future research.

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Forebrain-specific conditional calcineurin deficiency induces dentate gyrus immaturity and hyper-dopaminergic signaling in mice

Hagihara

Shoji

Kuroiwa

et al. 2022

Preprint

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Calcineurin (Cn), a phosphatase important for synaptic plasticity and neuronal development, has been implicated in the etiology and pathophysiology of neuropsychiatric disorders, including schizophrenia, intellectual disability, autism spectrum disorders, epilepsy, and Alzheimer’s disease. Forebrain-specific conditional Cn knockout mice have been known to exhibit multiple behavioral phenotypes related to these disorders. In this study, we investigated whether Cn mutant mice show pseudo-immaturity of the dentate gyrus (iDG) in the hippocampus, which we have proposed as an endophenotype shared by these disorders. Expression of calbindin and GluR1, typical markers for mature DG granule cells (GCs), was decreased and that of doublecortin, calretinin, phospho-CREB, and dopamine D1 receptor (Drd1), markers for immature GC, was increased in Cn mutants. Phosphorylation of cAMP-dependent protein kinase (PKA) substrates (GluR1, ERK2, DARPP-32, PDE4) was increased and showed higher sensitivity to SKF81297, a Drd1 agonist, in Cn mutants than in controls. While cAMP/PKA signaling is increased in the iDG of Cn mutants, chronic treatment with rolipram, a selective PDE4 inhibitor that increases intracellular cAMP, ameliorated the iDG phenotype significantly and nesting behavior deficits with nominal significance. Chronic rolipram administration also decreased the phosphorylation of CREB, but not the other four PKA substrates examined, in Cn mutants. These results suggest that Cn deficiency induces pseudo-immaturity of GCs and that cAMP signaling increases to compensate for this maturation abnormality. This study further supports the idea that iDG is an endophenotype shared by certain neuropsychiatric disorders.

show abstract

Forebrain-specific deficiency of the GTPase CRAG/Centaurin-γ3 leads to immature dentate gyri and hyperactivity in mice

Cited by 4 publications

References 38 publications

Forebrain-specific conditional calcineurin deficiency induces dentate gyrus immaturity and hyper-dopaminergic signaling in mice

Forebrain-specific conditional calcineurin deficiency induces dentate gyrus immaturity and hyper-dopaminergic signaling in mice

Novelty-induced memory consolidation is accompanied by increased Agap3 transcription: a cross-species study

Forebrain-specific conditional calcineurin deficiency induces dentate gyrus immaturity and hyper-dopaminergic signaling in mice

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