Astrocytic Glutamate Transport is Essential for the Memory-enhancing Effects of 17β-estradiol in Ovariectomized Mice

Overview

Journal Horm Behav

Specialties Endocrinology
Psychology
Social Sciences

Date 2024 Aug 24

PMID 39180889

Authors

Lisa R Taxier

Miriam Pillerova

Taylor E Branyan

Farida Sohrabji

Karyn M Frick

Affiliations

Soon will be listed here.

Abstract

Infusion of 17β-estradiol (E) into the dorsal hippocampus (DH) of ovariectomized (OVX) mice enhances memory consolidation, an effect that depends on rapid phosphorylation of extracellular signal-regulated kinase (ERK) and Akt. Astrocytic glutamate transporter 1 (GLT-1) modulates neurotransmission via glutamate uptake from the synaptic cleft. However, little is known about the contribution of DH astrocytes, and astrocytic glutamate transport, to the memory-enhancing effects of E. This study was designed to test whether DH astrocytes contribute to estrogenic modulation of memory consolidation by determining the extent to which DH GLT-1 is necessary for E to enhance memory in object recognition and object placement tasks and trigger rapid phosphorylation events in DH astrocytes. OVX female mice were bilaterally cannulated into the DH or the DH and dorsal third ventricle (ICV). Post-training DH infusion of the GLT-1 inhibitor dihydrokainic acid (DHK) dose-dependently impaired memory consolidation in both tasks. Moreover, the memory-enhancing effects of ICV-infused E in each task were blocked by DH DHK infusion. E increased p42 ERK and Akt phosphorylation in DH astrocytes, and these effects were blocked by DHK. Results suggest the necessity of DH GLT-1 activity for object and spatial memory consolidation, and for E to enhance consolidation of these memories and to rapidly activate cell signaling in DH astrocytes. Findings indicate that astrocytic function in the DH of OVX females is necessary for memory formation and is regulated by E and suggest an essential role for DH astrocytic GLT-1 activity in the memory-enhancing effects of E.

References

Liang Z, Valla J, Sefidvash-Hockley S, Rogers J, Li R . Effects of estrogen treatment on glutamate uptake in cultured human astrocytes derived from cortex of Alzheimer's disease patients. J Neurochem. 2002; 80(5):807-14. DOI: 10.1046/j.0022-3042.2002.00779.x. View

Gervais N, Jacob S, Brake W, Mumby D . Systemic and intra-rhinal-cortical 17-β estradiol administration modulate object-recognition memory in ovariectomized female rats. Horm Behav. 2013; 64(4):642-52. DOI: 10.1016/j.yhbeh.2013.08.010. View

Arevalo M, Santos-Galindo M, Bellini M, Azcoitia I, Garcia-Segura L . Actions of estrogens on glial cells: Implications for neuroprotection. Biochim Biophys Acta. 2009; 1800(10):1106-12. DOI: 10.1016/j.bbagen.2009.10.002. View

Fan L, Zhao Z, Orr P, Chambers C, Lewis M, Frick K . Estradiol-induced object memory consolidation in middle-aged female mice requires dorsal hippocampal extracellular signal-regulated kinase and phosphatidylinositol 3-kinase activation. J Neurosci. 2010; 30(12):4390-400. PMC: 2852263. DOI: 10.1523/JNEUROSCI.4333-09.2010. View

Luine V, Frankfurt M . Estrogenic regulation of memory: The first 50 years. Horm Behav. 2020; 121:104711. PMC: 7198346. DOI: 10.1016/j.yhbeh.2020.104711. View

Gibbs M, Shleper M, Mustafa T, Burnstock G, Bowser D . ATP derived from astrocytes modulates memory in the chick. Neuron Glia Biol. 2012; 7(2-4):177-86. DOI: 10.1017/S1740925X12000117. View

Woolley C, Weiland N, McEwen B, Schwartzkroin P . Estradiol increases the sensitivity of hippocampal CA1 pyramidal cells to NMDA receptor-mediated synaptic input: correlation with dendritic spine density. J Neurosci. 1997; 17(5):1848-59. PMC: 6573364. View

Pita-Almenar J, Zou S, Colbert C, Eskin A . Relationship between increase in astrocytic GLT-1 glutamate transport and late-LTP. Learn Mem. 2012; 19(12):615-26. PMC: 3506973. DOI: 10.1101/lm.023259.111. View

Gross K, Lincoln C, Anderson M, Geiger G, Frick K . Extracellular matrix metalloproteinase-9 (MMP-9) is required in female mice for 17β-estradiol enhancement of hippocampal memory consolidation. Psychoneuroendocrinology. 2022; 141:105773. PMC: 9173600. DOI: 10.1016/j.psyneuen.2022.105773. View

10.

Chaban V, Lakhter A, Micevych P . A membrane estrogen receptor mediates intracellular calcium release in astrocytes. Endocrinology. 2004; 145(8):3788-95. DOI: 10.1210/en.2004-0149. View

11.

Chisholm N, Henderson M, Selvamani A, Park M, Dindot S, Miranda R . Histone methylation patterns in astrocytes are influenced by age following ischemia. Epigenetics. 2015; 10(2):142-52. PMC: 4622874. DOI: 10.1080/15592294.2014.1001219. View

12.

Rothstein J, Pardo C, Bristol L, Jin L, Kuncl R, Kanai Y . Knockout of glutamate transporters reveals a major role for astroglial transport in excitotoxicity and clearance of glutamate. Neuron. 1996; 16(3):675-86. DOI: 10.1016/s0896-6273(00)80086-0. View

13.

Heo S, Jung G, Beuk T, Hoger H, Lubec G . Hippocampal glutamate transporter 1 (GLT-1) complex levels are paralleling memory training in the Multiple T-maze in C57BL/6J mice. Brain Struct Funct. 2011; 217(2):363-78. DOI: 10.1007/s00429-011-0362-5. View

14.

Bechtholt-Gompf A, Walther H, Adams M, Carlezon Jr W, Ongur D, Cohen B . Blockade of astrocytic glutamate uptake in rats induces signs of anhedonia and impaired spatial memory. Neuropsychopharmacology. 2010; 35(10):2049-59. PMC: 3055299. DOI: 10.1038/npp.2010.74. View

15.

Kim J, Szinte J, Boulware M, Frick K . 17β-Estradiol and Agonism of G-protein-Coupled Estrogen Receptor Enhance Hippocampal Memory via Different Cell-Signaling Mechanisms. J Neurosci. 2016; 36(11):3309-21. PMC: 4792941. DOI: 10.1523/JNEUROSCI.0257-15.2016. View

16.

Sheppard P, Koss W, Frick K, Choleris E . Rapid actions of oestrogens and their receptors on memory acquisition and consolidation in females. J Neuroendocrinol. 2017; 30(2). PMC: 6543823. DOI: 10.1111/jne.12485. View

17.

Luine V, Serrano P, Frankfurt M . Rapid effects on memory consolidation and spine morphology by estradiol in female and male rodents. Horm Behav. 2018; 104:111-118. PMC: 6274598. DOI: 10.1016/j.yhbeh.2018.04.007. View

18.

Gibbs M, Anderson D, Hertz L . Inhibition of glycogenolysis in astrocytes interrupts memory consolidation in young chickens. Glia. 2006; 54(3):214-22. DOI: 10.1002/glia.20377. View

19.

Weis S, Souza J, Hoppe J, Firmino M, Auer M, Ataii N . In-depth quantitative proteomic characterization of organotypic hippocampal slice culture reveals sex-specific differences in biochemical pathways. Sci Rep. 2021; 11(1):2560. PMC: 7844295. DOI: 10.1038/s41598-021-82016-7. View

20.

Kol A, Adamsky A, Groysman M, Kreisel T, London M, Goshen I . Astrocytes contribute to remote memory formation by modulating hippocampal-cortical communication during learning. Nat Neurosci. 2020; 23(10):1229-1239. PMC: 7611962. DOI: 10.1038/s41593-020-0679-6. View