Fine-Tuning the PI3K/Akt Signaling Pathway Intensity by Sex and Genotype-Load: Sex-Dependent Homozygotic Threshold for Somatic Growth but Feminization of Anxious Phenotype in Middle-Aged PDK1 K465E Knock-In and Heterozygous Mice

Overview

Journal Biomedicines

Specialty Biomedical Engineering

Date 2021 Jul 2

PMID 34203450

Citations 12

Authors

Mikel Santana-Santana

Jose-Ramon Bayascas

Lydia Gimenez-Llort

Affiliations

Soon will be listed here.

Abstract

According to the Research Domain Criteria (RDoC), phenotypic differences among disorders may be explained by variations in the nature and degree of neural circuitry disruptions and/or dysfunctions modulated by several biological and environmental factors. We recently demonstrated the in vivo behavioral translation of tweaking the PI3K/Akt signaling, an essential pathway for regulating cellular processes and physiology, and its modulation through aging. Here we describe, for the first time, the in vivo behavioral impact of the sex and genetic-load tweaking this pathway. The anxiety-like phenotypes of 61 mature (11-14-month-old) male and female PDK1 K465E knock-in, heterozygous, and WT mice were studied. Forced (open-field) anxiogenic environmental conditions were sensitive to detect sex and genetic-load differences at middle age. Despite similar neophobia and horizontal activity among the six groups, females exhibited faster ethograms than males, with increased thigmotaxis, increased wall and bizarre rearing. Genotype-load unveiled increased anxiety in males, resembling female performances. The performance of mutants in naturalistic conditions (marble test) was normal. Homozygotic-load was needed for reduced somatic growth only in males. Factor interactions indicated the complex interplay in the elicitation of different negative valence system's items and the fine-tuning of PI3K/Akt signaling pathway intensity by genotype-load and sex.

Citing Articles

Combination of Haloperidol With UNC9994, β-arrestin-Biased Analog of Aripiprazole, Ameliorates Schizophrenia-Related Phenotypes Induced by NMDAR Deficit in Mice.

Lipina T, Giang H, Thacker J, Wetsel W, Caron M, Beaulieu J Int J Neuropsychopharmacol. 2024; 27(12).

PMID: 39612588 PMC: 11656026. DOI: 10.1093/ijnp/pyae060.

The Impact of C-3 Side Chain Modifications on Kynurenic Acid: A Behavioral Analysis of Its Analogs in the Motor Domain.

Martos D, Lorinczi B, Szatmari I, Vecsei L, Tanaka M Int J Mol Sci. 2024; 25(6).

PMID: 38542368 PMC: 10970565. DOI: 10.3390/ijms25063394.

Neural Correlates and Molecular Mechanisms of Memory and Learning.

Battaglia S, Avenanti A, Vecsei L, Tanaka M Int J Mol Sci. 2024; 25(5).

PMID: 38473973 PMC: 10931689. DOI: 10.3390/ijms25052724.

From CGRP to PACAP, VIP, and Beyond: Unraveling the Next Chapters in Migraine Treatment.

Tanaka M, Szabo A, Kortesi T, Szok D, Tajti J, Vecsei L Cells. 2023; 12(22).

PMID: 37998384 PMC: 10670698. DOI: 10.3390/cells12222649.

Emerging Translational Research in Neurological and Psychiatric Diseases: From In Vitro to In Vivo Models.

Tanaka M, Szabo A, Vecsei L, Gimenez-Llort L Int J Mol Sci. 2023; 24(21).

PMID: 37958722 PMC: 10649796. DOI: 10.3390/ijms242115739.

References

Baeta-Corral R, Gimenez-Llort L . Bizarre behaviors and risk assessment in 3xTg-AD mice at early stages of the disease. Behav Brain Res. 2013; 258:97-105. DOI: 10.1016/j.bbr.2013.10.017. View

Gimenez-Llort L, Santana-Santana M, Bayascas J . The Impact of the PI3K/Akt Signaling Pathway in Anxiety and Working Memory in Young and Middle-Aged PDK1 K465E Knock-In Mice. Front Behav Neurosci. 2020; 14:61. PMC: 7225327. DOI: 10.3389/fnbeh.2020.00061. View

Greene-Schloesser D, van der Zee E, Sheppard D, Castillo M, Gregg K, Burrow T . Predictive validity of a non-induced mouse model of compulsive-like behavior. Behav Brain Res. 2011; 221(1):55-62. PMC: 3097060. DOI: 10.1016/j.bbr.2011.02.010. View

Bayascas J . PDK1: the major transducer of PI 3-kinase actions. Curr Top Microbiol Immunol. 2010; 346:9-29. DOI: 10.1007/82_2010_43. View

Gyertyan I . Analysis of the marble burying response: marbles serve to measure digging rather than evoke burying. Behav Pharmacol. 1995; 6(1):24-31. View

Singh K . An emerging role for Wnt and GSK3 signaling pathways in schizophrenia. Clin Genet. 2013; 83(6):511-7. DOI: 10.1111/cge.12111. View

Torres-Lista V, Lopez-Pousa S, Gimenez-Llort L . Marble-burying is enhanced in 3xTg-AD mice, can be reversed by risperidone and it is modulable by handling. Behav Processes. 2015; 116:69-74. DOI: 10.1016/j.beproc.2015.05.001. View

Lenze E, Wetherell J . A lifespan view of anxiety disorders. Dialogues Clin Neurosci. 2012; 13(4):381-99. PMC: 3263387. View

Beery A, Zucker I . Sex bias in neuroscience and biomedical research. Neurosci Biobehav Rev. 2010; 35(3):565-72. PMC: 3008499. DOI: 10.1016/j.neubiorev.2010.07.002. View

10.

Sun L, Cui K, Xing F, Liu X . Akt dependent adult hippocampal neurogenesis regulates the behavioral improvement of treadmill running to mice model of post-traumatic stress disorder. Behav Brain Res. 2019; 379:112375. DOI: 10.1016/j.bbr.2019.112375. View

11.

Dwivedi Y, Rizavi H, Zhang H, Roberts R, Conley R, Pandey G . Modulation in activation and expression of phosphatase and tensin homolog on chromosome ten, Akt1, and 3-phosphoinositide-dependent kinase 1: further evidence demonstrating altered phosphoinositide 3-kinase signaling in postmortem brain of suicide.... Biol Psychiatry. 2010; 67(11):1017-25. PMC: 2868089. DOI: 10.1016/j.biopsych.2009.12.031. View

12.

Yang S, Pascual-Guiral S, Ponce R, Gimenez-Llort L, Baltrons M, Arancio O . Reducing the Levels of Akt Activation by PDK1 Knock-in Mutation Protects Neuronal Cultures against Synthetic Amyloid-Beta Peptides. Front Aging Neurosci. 2018; 9:435. PMC: 5766684. DOI: 10.3389/fnagi.2017.00435. View

13.

Wang W, Lu Y, Xue Z, Li C, Wang C, Zhao X . Rapid-acting antidepressant-like effects of acetyl-l-carnitine mediated by PI3K/AKT/BDNF/VGF signaling pathway in mice. Neuroscience. 2014; 285:281-91. DOI: 10.1016/j.neuroscience.2014.11.025. View

14.

Bayascas J, Wullschleger S, Sakamoto K, Garcia-Martinez J, Clacher C, Komander D . Mutation of the PDK1 PH domain inhibits protein kinase B/Akt, leading to small size and insulin resistance. Mol Cell Biol. 2008; 28(10):3258-72. PMC: 2423167. DOI: 10.1128/MCB.02032-07. View

15.

Muntsant A, Gimenez-Llort L . Impact of Social Isolation on the Behavioral, Functional Profiles, and Hippocampal Atrophy Asymmetry in Dementia in Times of Coronavirus Pandemic (COVID-19): A Translational Neuroscience Approach. Front Psychiatry. 2020; 11:572583. PMC: 7732415. DOI: 10.3389/fpsyt.2020.572583. View

16.

Sachs B, Rodriguiz R, Siesser W, Kenan A, Royer E, Jacobsen J . The effects of brain serotonin deficiency on behavioural disinhibition and anxiety-like behaviour following mild early life stress. Int J Neuropsychopharmacol. 2013; 16(9):2081-94. PMC: 3931011. DOI: 10.1017/S1461145713000321. View

17.

Pearce L, Komander D, Alessi D . The nuts and bolts of AGC protein kinases. Nat Rev Mol Cell Biol. 2009; 11(1):9-22. DOI: 10.1038/nrm2822. View

18.

Huang H, Wang Q, Guan X, Zhang X, Zhang Y, Cao J . Effects of enriched environment on depression and anxiety-like behavior induced by early life stress: A comparison between different periods. Behav Brain Res. 2021; 411:113389. DOI: 10.1016/j.bbr.2021.113389. View

19.

Beurel E, Grieco S, Jope R . Glycogen synthase kinase-3 (GSK3): regulation, actions, and diseases. Pharmacol Ther. 2014; 148:114-31. PMC: 4340754. DOI: 10.1016/j.pharmthera.2014.11.016. View

20.

Ackermann T, Hortnagl H, Wolfer D, Colacicco G, Sohr R, Lang F . Phosphatidylinositide dependent kinase deficiency increases anxiety and decreases GABA and serotonin abundance in the amygdala. Cell Physiol Biochem. 2008; 22(5-6):735-44. DOI: 10.1159/000185557. View