Isoform-specific roles for AKT in affective behavior, spatial memory, and extinction related to psychiatric disorders

Wong, Helen; Levenga, Josien; LaPlante, Lauren; Keller, Bailey N.; Cooper-Sansone, Andrew; Borski, Curtis; Milstead, Ryan; Ehringer, Marissa A.; Hoeffer, Charles A.

doi:10.7554/elife.56630

Cited by 27 publications

(34 citation statements)

References 107 publications

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“…2017 ), and we demonstrated previously that Akt3 KO mice have normal synaptic plasticity in the hippocampus ( Levenga et al. 2017 ; Wong et al. 2020 ).…”

Section: Discussionmentioning

confidence: 63%

“…Indeed, we found that AKT1 can compensate for the loss of AKT3 activity to mediate normal expression of metabotropic glutamate receptor-dependent long-term depression in the hippocampus ( Levenga et al. 2017 ) and normal memory ( Wong et al. 2020 ).…”

Section: Discussionmentioning

confidence: 95%

“…Given the broad expression of AKT1 in neural cell types, AKT1 might be expected to exert the most significant effects on cognition and behavior. Supporting this idea, Akt1 KO mice display alterations in affective behavior, spatial memory, and fear extinction ( Wong et al. 2020 ).…”

Section: Discussionmentioning

confidence: 96%

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Immunohistological Examination of AKT Isoforms in the Brain: Cell-Type Specificity That May Underlie AKT’s Role in Complex Brain Disorders and Neurological Disease

Levenga

Wong

Milstead

et al. 2021

Cerebral Cortex Communications

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AKT/PKB is a central kinase involved in many neurobiological processes. AKT is expressed in the brain as three isoforms, AKT1, AKT2, and AKT3. Previous studies suggest isoform-specific roles in neural function, but very few studies have examined AKT isoform expression at the cellular level. In this study, we use a combination of histology, immunostaining, and genetics to characterize cell-type-specific expression of AKT isoforms in human and mouse brains. In mice, we find that AKT1 is the most broadly expressed isoform, with expression in excitatory neurons and the sole detectable AKT isoform in GABAergic interneurons and microglia. By contrast, we find that AKT2 is the sole isoform expressed in astroglia and not detected in other neural cell types. We find that AKT3 is expressed in excitatory neurons with AKT1 but shows greater expression levels in dendritic compartments than AKT1. We extend our analysis to human brain tissues and find similar results. Using genetic deletion approaches, we also find that the cellular determinants restricting AKT isoform expression to specific cell types remain intact under Akt deficiency conditions. Because AKT signaling is linked to numerous neurological disorders, a greater understanding of cell-specific isoform expression could improve treatment strategies involving AKT.

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“…2017 ), and we demonstrated previously that Akt3 KO mice have normal synaptic plasticity in the hippocampus ( Levenga et al. 2017 ; Wong et al. 2020 ).…”

Section: Discussionmentioning

confidence: 63%

Section: Discussionmentioning

confidence: 95%

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Immunohistological Examination of AKT Isoforms in the Brain: Cell-Type Specificity That May Underlie AKT’s Role in Complex Brain Disorders and Neurological Disease

Levenga

Wong

Milstead

et al. 2021

Cerebral Cortex Communications

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“…It is intriguing that females had higher levels of Akt phosphoproteins than males in the DG, which adds to the literature showing greater Akt phosphoproteins in the brain (26,48) and periphery (46) of females compared to males. The Akt pathway provides a mechanism through which extrinsic factors such as neurotrophic factors can activate transcription factors to affect the regulation of neural stem cells and neurogenesis in the DG (49).…”

Section: Sex Differences In Mapk and Akt Cell Signalling Pathways In The Dgmentioning

confidence: 59%

Sex differences and estradiol effects in MAPK and Akt cell signalling across subregions of the hippocampus

Sheppard

Puri

Galea

2021

Preprint

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Introduction: Rapid effects of estrogens within the hippocampus of rodents are dependent upon cell signaling cascades, and the activation of these cascades by estrogens varies by sex. Whether these pathways are rapidly activated within the dentate gyrus (DG) and CA1 by estrogens and across the longitudinal axis has been overlooked. Methods: Gonadally-intact female and male rats were given either vehicle or physiological systemic low (1.1μg/kg) or high (37.3μg/kg) doses of 17β-estradiol thirty minutes prior to tissue collection. To control for the effects of circulating estrogens, an additional group of female rats were ovariectomized (OVX) and administered 17β-estradiol. Brains were extracted and tissue punches of the CA1 and DG were taken along the longitudinal hippocampal axis (dorsal and ventral) and analyzed for key MAPK and Akt cascade phosphoproteins. Results: Intact females had higher Akt pathway phosphoproteins (pAkt, pGSK-3β, pp70S6K) than males in the DG (dorsal, ventral) and CA1 (dorsal), but lower MAPK phosphoproteins (pERK1/2, pp38) in the dorsal DG. Most of the effects of 17β-estradiol to influence cell signalling occurred in OVX animals and not in intact females or males. In OVX animals, 17β-estradiol increased cell signalling of MAPK and Akt phosphoproteins (pERK1/2, pJNK, pAkt, pGSK-3β) in both subregions but reduced MAPK phosphoproteins (pERK1/2, pp38)) in the ventral DG. Discussion/Conclusions: Systemic 17β-estradiol treatment rapidly alters phosphoprotein levels in the hippocampus dependent on reproductive status and intact females have greater expression of Akt phosphoproteins than intact males across the hippocampus. These findings shed light on the underlying mechanisms of sex differences in hippocampal function and response to interventions that affect MAPK or Akt signaling.

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“…AKT1 are one of them, and that lack of AKT1 increases the behavior of anxiety in mice. However, restoring the expression of AKT1 in the prefrontal cortex (PFC) can improve fear memory, behavior, where the GAGB pathway mediated this process (40). In addition to playing an important role in synaptic transmission, memory, and psychosis, AKT is also one of the most common highly activated protein kinases in human cancer.…”

Section: Figure 1 Depicts the Drug-component-target Relationshipsmentioning

confidence: 99%

Network pharmacology study on the mechanism of Qiangzhifang in the treatment of panic disorder

et al. 2021

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Background: Panic disorder (PD) is a kind of mental illness characterized by the symptom of recurring panic attacks. Qiangzhifang (QZF) is a novel decoction developed by Professor Zhaojun Yan based on a unique system of syndrome differentiation and clinical experience. It has achieved remarkable results after long-term clinical practice, but its mechanism of action is still unclear. This study aims to use network pharmacology and molecular docking to explore the mechanism of QZF in the treatment of PD. Methods: We used the Traditional Chinese Medicine Systems Pharmacology Database and Analysis Platform (TCMSP), a literature search, and Encyclopedia of Traditional Chinese Medicine (ETCM) to find active ingredients and targets of QZF. We searched for PD targets in GeneCards, Online Mendelian Inheritance in Man (OMIM), the Comparative Toxicogenomics Database (CTD), and DrugBank. We established a PD target database, constructed a protein-protein interaction (PPI) network, and performed Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analysis in order to screen possible pathways of action and analyze the mechanism.Results: This study identified 84 effective components of QZF, 691 potential targets, 357 PD targets, and 97 intersectional targets. Enrichment analysis using the Database for Annotation, Visualization, and Integrated Discovery (DAVID) showed that QZF was associated with 118 biological processes (BPs), 18 cellular components (CCs), 35 molecular functions (MFs) [false discovery rate (FDR) <0.01], and 62 pathways (FDR <0.01). QZF mainly acts on its targets AKT1, FOS, and APP through active ingredients such as quercetin, β-sitosterol, 4-(4'-hydroxybenzyloxy)benzyl methyl ether, harmine, 1,7-dimethoxyxanthone, and 1-hydroxy-3,7-dimethoxyxanthone to regulate serotonin, gamma-aminobutyric acid (GABA), cyclic adenosine monophosphate (cAMP), and other signal pathways to treat PD.Conclusions: Through network pharmacology and molecular docking technology, we predicted the possible mechanism of QZF in the treatment of PD, revealed the interaction targets and potential value of QZF, and provided a basis for its clinical application.

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Isoform-specific roles for AKT in affective behavior, spatial memory, and extinction related to psychiatric disorders

Cited by 27 publications

References 107 publications

Immunohistological Examination of AKT Isoforms in the Brain: Cell-Type Specificity That May Underlie AKT’s Role in Complex Brain Disorders and Neurological Disease

Immunohistological Examination of AKT Isoforms in the Brain: Cell-Type Specificity That May Underlie AKT’s Role in Complex Brain Disorders and Neurological Disease

Sex differences and estradiol effects in MAPK and Akt cell signalling across subregions of the hippocampus

Network pharmacology study on the mechanism of Qiangzhifang in the treatment of panic disorder

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