Insulin and Insulin-like Growth Factor-I Receptors in Astrocytes Exert Different Effects on Behavior and Alzheimer´s-like Pathology

Overview

Journal F1000Res

Specialties Biomedical Engineering
Science

Date 2023 Jan 16

PMID 36636477

Authors

Jonathan Zegarra-Valdivia

Ana M Fernandez

Laura Martinez-Rachadell

Raquel Herrero-Labrador

Jansen Fernandes

Ignacio Torres Aleman

Affiliations

Soon will be listed here.

Abstract

Pleiotropic actions of insulin and insulin-like growth factor I (IGF-I) in the brain are context- and cell-dependent, but whether this holds for their receptors (insulin receptor (IR) and IGF-I receptor (IGF-IR), respectively), is less clear. We compared mice lacking IR or IGF-IR in glial fibrillary astrocytic protein (GFAP)-expressing astrocytes in a tamoxifen-regulated manner, to clarify their role in this type of glial cells, as the majority of data of their actions in brain have been obtained in neurons. We observed that mice lacking IR in GFAP astrocytes (GFAP IR KO mice) develop mood disturbances and maintained intact cognition, while at the same time show greater pathology when cross-bred with APP/PS1 mice, a model of familial Alzheimer´s disease (AD). Conversely, mice lacking IGF-IR in GFAP astrocytes (GFAP-IGF-IR KO mice) show cognitive disturbances, maintained mood tone, and show control-dependent changes in AD-like pathology. These observations confirm that the role of IR and IGF-IR in the brain is cell-specific and context-dependent.

Citing Articles

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References

Gontier G, George C, Chaker Z, Holzenberger M, Aid S . Blocking IGF Signaling in Adult Neurons Alleviates Alzheimer's Disease Pathology through Amyloid-β Clearance. J Neurosci. 2015; 35(33):11500-13. PMC: 6605240. DOI: 10.1523/JNEUROSCI.0343-15.2015. View

Ortiz O, Delgado-Garcia J, Espadas I, Bahi A, Trullas R, Dreyer J . Associative learning and CA3-CA1 synaptic plasticity are impaired in D1R null, Drd1a-/- mice and in hippocampal siRNA silenced Drd1a mice. J Neurosci. 2010; 30(37):12288-300. PMC: 6633447. DOI: 10.1523/JNEUROSCI.2655-10.2010. View

Noriega-Prieto J, Maglio L, Zegarra-Valdivia J, Pignatelli J, Fernandez A, Martinez-Rachadell L . Astrocytic IGF-IRs Induce Adenosine-Mediated Inhibitory Downregulation and Improve Sensory Discrimination. J Neurosci. 2021; 41(22):4768-4781. PMC: 8260162. DOI: 10.1523/JNEUROSCI.0005-21.2021. View

Fernandez de Sevilla M, Pignatelli J, Zegarra-Valdivia J, Mendez P, Nunez A, Torres Aleman I . Insulin-like growth factor I mitigates post-traumatic stress by inhibiting AMP-kinase in orexin neurons. Mol Psychiatry. 2022; 27(4):2182-2196. PMC: 9126821. DOI: 10.1038/s41380-022-01442-9. View

Cohen E, Bieschke J, Perciavalle R, Kelly J, Dillin A . Opposing activities protect against age-onset proteotoxicity. Science. 2006; 313(5793):1604-10. DOI: 10.1126/science.1124646. View

Pfaffl M . A new mathematical model for relative quantification in real-time RT-PCR. Nucleic Acids Res. 2001; 29(9):e45. PMC: 55695. DOI: 10.1093/nar/29.9.e45. View

Logan S, Pharaoh G, Marlin M, Masser D, Matsuzaki S, Wronowski B . Insulin-like growth factor receptor signaling regulates working memory, mitochondrial metabolism, and amyloid-β uptake in astrocytes. Mol Metab. 2018; 9:141-155. PMC: 5870102. DOI: 10.1016/j.molmet.2018.01.013. View

Garcia-Caceres C, Quarta C, Varela L, Gao Y, Gruber T, Legutko B . Astrocytic Insulin Signaling Couples Brain Glucose Uptake with Nutrient Availability. Cell. 2016; 166(4):867-880. PMC: 8961449. DOI: 10.1016/j.cell.2016.07.028. View

Soto M, Cai W, Konishi M, Kahn C . Insulin signaling in the hippocampus and amygdala regulates metabolism and neurobehavior. Proc Natl Acad Sci U S A. 2019; 116(13):6379-6384. PMC: 6442573. DOI: 10.1073/pnas.1817391116. View

10.

Fernandes De Abreu D, Caballero A, Fardel P, Stroustrup N, Chen Z, Lee K . An insulin-to-insulin regulatory network orchestrates phenotypic specificity in development and physiology. PLoS Genet. 2014; 10(3):e1004225. PMC: 3967928. DOI: 10.1371/journal.pgen.1004225. View

11.

Munive V, Zegarra-Valdivia J, Herrero-Labrador R, Fernandez A, Torres Aleman I . Loss of the interaction between estradiol and insulin-like growth factor I in brain endothelial cells associates to changes in mood homeostasis during peri-menopause in mice. Aging (Albany NY). 2019; 11(1):174-184. PMC: 6339786. DOI: 10.18632/aging.101739. View

12.

Cohen E, Paulsson J, Blinder P, Burstyn-Cohen T, Du D, Estepa G . Reduced IGF-1 signaling delays age-associated proteotoxicity in mice. Cell. 2009; 139(6):1157-69. PMC: 3017511. DOI: 10.1016/j.cell.2009.11.014. View

13.

Hausrat T, Muhia M, Gerrow K, Thomas P, Hirdes W, Tsukita S . Radixin regulates synaptic GABAA receptor density and is essential for reversal learning and short-term memory. Nat Commun. 2015; 6:6872. PMC: 4411296. DOI: 10.1038/ncomms7872. View

14.

Freude S, Schilbach K, Schubert M . The role of IGF-1 receptor and insulin receptor signaling for the pathogenesis of Alzheimer's disease: from model organisms to human disease. Curr Alzheimer Res. 2009; 6(3):213-23. DOI: 10.2174/156720509788486527. View

15.

Hirrlinger P, Scheller A, Braun C, Hirrlinger J, Kirchhoff F . Temporal control of gene recombination in astrocytes by transgenic expression of the tamoxifen-inducible DNA recombinase variant CreERT2. Glia. 2006; 54(1):11-20. DOI: 10.1002/glia.20342. View

16.

Biundo F, Prete D, Zhang H, Arancio O, DAdamio L . A role for tau in learning, memory and synaptic plasticity. Sci Rep. 2018; 8(1):3184. PMC: 5816660. DOI: 10.1038/s41598-018-21596-3. View

17.

Santi A, Genis L, Torres Aleman I . A Coordinated Action of Blood-Borne and Brain Insulin-Like Growth Factor I in the Response to Traumatic Brain Injury. Cereb Cortex. 2017; 28(6):2007-2014. DOI: 10.1093/cercor/bhx106. View

18.

Cai W, Xue C, Sakaguchi M, Konishi M, Shirazian A, Ferris H . Insulin regulates astrocyte gliotransmission and modulates behavior. J Clin Invest. 2018; 128(7):2914-2926. PMC: 6025980. DOI: 10.1172/JCI99366. View

19.

McGaugh S, Bronikowski A, Kuo C, Reding D, Addis E, Flagel L . Rapid molecular evolution across amniotes of the IIS/TOR network. Proc Natl Acad Sci U S A. 2015; 112(22):7055-60. PMC: 4460498. DOI: 10.1073/pnas.1419659112. View

20.

Recinto P, Samant A, Chavez G, Kim A, Yuan C, Soleiman M . Levels of neural progenitors in the hippocampus predict memory impairment and relapse to drug seeking as a function of excessive methamphetamine self-administration. Neuropsychopharmacology. 2011; 37(5):1275-87. PMC: 3306889. DOI: 10.1038/npp.2011.315. View