Effects of adolescent intermittent ethanol on hippocampal expression of glutamate homeostasis and astrocyte‐neuronal tethering proteins in male and female rats
Open accessAbstract
Adolescent alcohol drinking is widely recognized as a significant public health problem, and evidence is accumulating that sufficient levels of consumption during this critical period of brain development have an enduring impact on neural and behavioral function. Recent studies have indicated that adolescent intermittent ethanol (AIE) exposure alters astrocyte function, astrocyte–neuronal interactions, and related synaptic regulation and activity. However, few of those studies have included female animals, and a broader assessment of AIE effects on the proteins mediating astrocyte‐mediated glutamate dynamics and synaptic function is needed. We measured synaptic membrane expression of several such proteins in the dorsal and ventral regions of the hippocampal formation (DH, VH) from male and female rats exposed to AIE or adolescent intermittent water. In the DH, AIE caused elevated expression of glutamate transporter 1 (GLT‐1) in both males and females, elevated postsynaptic density 95 expression in females only, and diminished NMDA receptor subunit 2A expression in males only. AIE and sex interactively altered ephrin receptor A4 (EphA4) expression in the DH. In the VH, AIE elevated expression of the cystine/glutamate antiporter and the glutamate aspartate transporter 1 (GLAST) in males only. Compared to males, female animals expressed lower levels of GLT‐1 in the DH and greater levels of ephrin receptor B6 (EphB6) in the VH, in the absence of AIE effects. These results support the growing literature indicating that adolescent alcohol exposure produces long‐lasting effects on astrocyte function and astrocyte‐neuronal interactions. The sex and subregion specificity of these effects have mechanistic implications for our understanding of AIE effects generally.
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Potential mechanisms underlying the long-lasting effects of adolescent alcohol exposure include glial functioning and morphology.
“Potential mechanisms underlying the long-lasting effects of AAE have begun to emerge, one of which is glial functioning and morphology [67, 68].”
From Consequences of adolescent drug use (2023) · cites this paper as [68]
The Discussion (page unavailable) identifies enduring changes in glially mediated glutamate homeostasis as a possible mechanism of adolescent ethanol exposure’s effects. The Introduction (page unavailable) also describes altered astrocyte–neuron proximity in adulthood, but our copy does not establish that ethanol exposure changes glial morphology itself. (LLM, conf=0.81)
Experimental — accuracy not yet measuredAdolescent alcohol exposure elevates levels of astrocytic glutamate transporter GLT-1 in the dorsal hippocampus and ventral hippocampus in both male and female rats.
“Furthermore, AAE elevates levels of astrocytic glutamate transporter (GLT)-1 in the dorsal hippocampus (DH), as well as the ventral hippocampus (VH), in both male and female rats [68].”
From Consequences of adolescent drug use (2023) · cites this paper as [68]
The Results section reports that adolescent intermittent ethanol increased synaptic GLT-1 in the dorsal hippocampus of both male and female rats. It explicitly reports no ethanol effect on GLT-1 in the ventral hippocampus, so the claim's extension to that region is unsupported. (LLM, conf=0.93)
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Functional organization of the hippocampal longitudinal axis
Strange, B. A., Witter, M. P., Lein, E. S., & Moser, E. I. (2014) · Nature reviews. Neuroscience · doi:10.1038/nrn3785 · Cited by 1,738 · see citing works
Eroglu, Ç., Allen, N. J., Susman, M. W., O'Rourke, N. A., Park, C. Y., Özkan, E., Chakraborty, C., Mulinyawe, S. B., Annis, D. S., Huberman, A. D., et al. (2009) · Cell · doi:10.1016/j.cell.2009.09.025 · Cited by 893 · see citing works
Pandey, S. C., Sakharkar, A. J., Tang, L., & Zhang, H. (2015) · Neurobiology of Disease · doi:10.1016/j.nbd.2015.03.019 · Cited by 191 · see citing works
Risher, M., Fleming, R. L., Risher, W. C., Miller, K. M., Klein, R. C., Wills, T., Acheson, S. K., Moore, S. D., Wilson, W. A., Eroglu, C., et al. (2015) · Alcoholism: Clinical and Experimental Research · doi:10.1111/acer.12725 · Cited by 104 · see citing works
Self-citationSwartzwelder, H. S., Park, M.-H., & Acheson, S. (2017) · Scientific Reports · doi:10.1038/s41598-017-12956-6 · Cited by 38 · see citing works
Self-citationHealey, K. L., Kibble, S., Hodges, S., Reissner, K. J., Testen, A., Wills, T. A., Acheson, S. K., Siemsen, B. M., McFaddin, J. A., Scofield, M. D., et al. (2020) · Neural Regeneration Research · doi:10.4103/1673-5374.274339 · Cited by 27 · see citing works
Self-citation
Flagged first, then by citations
Research works printed but not linked: 31
- Allen NJ, & Eroglu C (2017). Cell biology of astrocyte-synapse interactions. Neuron, 96(3), 697– 708. 10.1016/j.neuron.2017.09.056 29096081 PMC5687890 · DOI
- Bjørnsen LP, Hadera MG, Zhou Y, Danbolt NC, & Sonnewald U (2014). The GLT-1 (EAAT2; slcla2) glutamate transporter is essential for glutamate homeostasis in the neocortex of the mouse. Journal of Neurochemistry, 128(5), 641– 649. 10.1111/jnc.12509 24224925 · DOI
- Bragdon AC, Taylor DM, & Wilson WA (1986). Potassium-induced epileptiform activity in area CAS varies markedly along the septo-temporal axis of the rat hippocampus. Brain Research, 378(1), 169– 173. 10.1016/0006-8993(86)90300-8 3742197 · DOI
- Carmona MA, Murai KK, Wang L, Roberts AJ, & Pasquale EB (2009). Glial ephrin-A3 regulates hippocampal dendritic spine morphology and glutamate transport. Proceedings of the National Academy of Sciences of the United States of America, 106(30), 12524– 12529. 19592509 PMC2718351
- Carrara-Nascimento PF, Griffin WC, Pastrello DM, Olive MF, & Camarini R (2011). Changes in extracellular levels of glutamate in the nucleus accumbens after ethanol-induced behavioral sensitization in adolescent and adult mice. Alcohol, 45(5), 451– 460. 10.1016/j.alcohol.2011.01.002 21570797 PMC3310207 · DOI
- Choudhury S, Blakemore SJ, & Charman T (2006). Social cognitive development during adolescence. Social Cognitive and Affective Neuroscience, 1(3), 165– 174. 10.1093/scan/nsl024 18985103 PMC2555426 · DOI · Paper page
- Colombo E, & Farina C (2016). Astrocytes: Key regulators of neuroinflammation. Trends in Immunology, 37(9), 608– 620. 10.1016/j.it.2016.06.006 27443914 · DOI
- Crews FT, Robinson DL, Chandler LJ, Ehlers CL, Mulholland PJ, Pandey SC, Rodd ZA, Spear LP, Swartzwelder HS, & Vetreno RP (2019). Mechanisms of persistent neurobiological changes following adolescent alcohol exposure: NADIA consortium findings. Alcoholism, Clinical and Experimental Research, 43(9), 1806– 1822. 10.1111/acer.14154 PMC6758927 31335972 · DOI
- Fanselow MS, & Dong HW (2010). Are the dorsal and ventral hippocampus functionally distinct structures? Neuron, 65(1), 7– 19. 20152109 PMC2822727
- Healey KL, Landin JD, Dubester K, Kibble S, Marquardt K, Brutman JN, Davis JF, Swartzwelder HS, & Chandler LJ (2020). Effects of ethanol on plasma ghrelin levels in the rat during early and late adolescence. Alcohol, 85, 111– 118. 10.1016/j.alcohol.2019.12.006 31923560 PMC7238721 · DOI
- Huttner WB, Schiebler W, Greengard P, & De Camilli P (1983). Synapsin I (protein I), a nerve terminal-specific phosphoprotein. III. Its association with synaptic vesicles studied in a highly purified synaptic vesicle preparation. Journal of Cell Biology, 96(5), 1374– 1388. 10.1083/jcb.96.5.1374 PMC2112660 6404912 · DOI
- Jimenez JC, Su K, Goldberg AR, Luna VM, Biane JS, Ordek G, Zhou P, Ong SK, Wright MA, Zweifel L, Paninski L, Hen R, & Kheirbek MA (2018). Anxiety cells in a hippocampai-hypotha-lamic circuit. Neuron, 97(3), 670– 683.e6. 10.1016/j.neuron.2018.01.016 29397273 PMC5877404 · DOI
- Kalivas PW (2009). The glutamate homeostasis hypothesis of addiction. Nature Reviews Neuroscience, 10(8), 561– 572. 19571793
- Kasten CR, Carzoli KL, Sharfman NM, Henderson T, Holmgren EB, Lerner MR, Miller MC, & Wills TA (2020). Adolescent alcohol exposure produces sex differences in negative affect-like behavior and group I mGluR BNST plasticity. Neuropsychopharmacology, 45(8), 1306– 1315. 10.1038/s41386-020-0670-7 32268346 PMC7297734 · DOI
- Kilb W (2012). Development of the GABAergic system from birth to adolescence. Neuroscientist, 18(6), 613– 630. 10.1177/1073858411422114 21952258 · DOI · Paper page
- Kim R, Healey KL, Sepulveda-Orengo MT, & Reissner KJ (2018). Astroglial correlates of neuropsychiatric disease: From astrocytopathy to astrogliosis. Progress in Neuro-Psychopharmacology and Biological Psychiatry, 87(Pt A), 126– 146. 10.1016/j.pnpbp.2017.10.002 28989099 PMC5889368 · DOI
- Koss WA, Sadowski RN, Sherrill LK, Gulley JM, & Juraska JM (2012). Effects of ethanol during adolescence on the number of neurons and glia in the medial prefrontal cortex and basolateral amygdala of adult male and female rats. Brain Research, 1466, 24– 32. 22627163 PMC3389213
- Mulholland PJ, Teppen TL, Miller KM, Sexton HG, Pandey SC, & Swartzwelder HS (2018). Donepezil reverses dendritic spine morphology adaptations and Fmrl epigenetic modifications in hippocampus of adult rats after adolescent alcohol exposure. Alcoholism, Clinical and Experimental Research, 42(4), 706– 717. PMC5903436 29336496
- Pajarillo E, Rizor A, Lee J, Aschner M, & Lee E (2019). The role of astrocytic glutamate transporters GLT-1 and GLAST in neurological disorders: Potential targets for neurotherapeutics. Neuropharmacology, 161, 107559. 30851309 PMC6731169
- Paus T (2005). Mapping brain maturation and cognitive development during adolescence. Trends in Cognitive Sciences, 9(2), 60– 68. 10.1016/j.tics.2004.12.008 15668098 · DOI · Paper page
- Risher ML, Sexton HG, Risher WC, Wilson WA, Fleming RL, Madison RD, Moore SD, Eroglu C, & Swartzwelder HS (2015). Adolescent intermittent alcohol exposure: Dysregulation of thrombospondins and synapse formation are associated with decreased neuronal density in the adult hippocampus. Alcoholism, Clinical and Experimental Research, 39(12), 2403– 2413. PMC4712076 26537975
- Snedecor GW, & Cochran WG (1989). Statistical methods (8th ed.). lowa State University Press.
- Spear LP, & Swartzwelder HS (2014). Adolescent alcohol exposure and persistence of adolescent-typical phenotypes into adulthood: A mini-review. Neuroscience and Biobehavioral Reviews, 45, 1– 8. 10.1016/j.neubiorev.2014.04.012 24813805 PMC4134704 · DOI
- Suto T, Severino AL, Eisenach JC, & Hayashida K (2014). Gabapentin increases extracellular glutamatergic level in the locus coeruleus via astroglial glutamate transporter-dependent mechanisms. Neuropharmacology, 81, 95– 100. 10.1016/j.neuropharm.2014.01.040 24495399 PMC3992194 · DOI
- Swartzwelder HS, Acheson SK, Miller KM, Sexton HG, Liu W, Crews FT, & Risher M-L (2015). Adolescent intermittent alcohol exposure: Deficits in object recognition memory and forebrain cholinergic markers. PLoS ONE, 20(11), e0140042. 10.1371/journal.pone.0140042 PMC4631346 26529506 · DOI
- Swartzwelder HS, Risher ML, Miller KM, Colbran RJ, Winder DG, & Wills TA (2016). Changes in the adult GluN2B associated proteome following adolescent intermittent ethanol exposure. PLoS ONE, 11(5), e0155951. 27213757 PMC4877005
- Swartzwelder HS, Healey KL, Liu W, Dubester K, Miller KM, & Crews FT (2019). Changes in neuroimmune and neuronal death markers after adolescent alcohol exposure in rats are reversed by donepezil. Scientific Reports, 9(1), 12110. 31431637 PMC6702347
- Takahashi K, Foster JB, & Lin C-L-G (2015). Glutamate transporter EAAT2: Regulation, function, and potential as a therapeutic target for neurological and psychiatric disease. Cellular and Molecular Life Sciences, 72(18), 3489– 3506. 10.1007/s00018-015-1937-8 26033496 PMC11113985 · DOI
- Testen A, Ali M, Sexton HG, Hodges S, Dubester K, Reissner KJ, Swartzwelder HS, & Risher ML (2019). Region-specific differences in morphometric features and synaptic colocalization of astrocytes during development. Neuroscience, 400, 98– 109. 30599266 PMC6361709
- Walker CD, Risher WC, & Risher ML (2020). Regulation of synaptic development by astrocyte signaling factors and their emerging roles in substance abuse. Cells, 9(2), 297. PMC7072591 31991879
- White AM, Ghia AJ, Levin ED, & Swartzwelder HS (2000). Binge pattern ethanol exposure in adolescent and adult rats: Differential impact on subsequent responsiveness to ethanol. Alcoholism, Clinical and Experimental Research, 24(8), 1251– 1256. 10.1111/j.1530-0277.2000.tb02091.x 10968665 · DOI
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Sorted by citations
Consequences of adolescent drug use
Steinfeld, M. R., & Torregrossa, M. M. (2023) · Translational Psychiatry · doi:10.1038/s41398-023-02590-4 · Cited by 237 · see citing works
“Furthermore, AAE elevates levels of astrocytic glutamate transporter (GLT)-1 in the dorsal hippocampus (DH), as well as the ventral hippocampus (VH), in both male and female rats [68].”
Background
- Authors
- Healey, K. L., Kibble, S., Bell, A., Hodges, S., & Swartzwelder, H. S.
- Affiliations
- Duke University (US)
- Corresponding author
- Healey, Kati L.
- Venue
- Journal of Neuroscience Research
- Publisher
- Wiley
- Published
- 2020-11-20
- Volume
- 99
- Issue
- 8
- Pages
- 1908-1921
- ISSN
- 0360-4012 (ISSN-L)
- 1097-4547
- PMC
- PMC8340080
- OpenAlex
- W3099717989
- Cited by
- 18
- References
- 6
- Citations by year
- 2026: 2 · 2024: 1 · 2023: 6 · 2022: 5 · 2021: 4
- FWCI
- 1.72
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Journal of Neuroscience Research (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Institute on Alcohol Abuse and Alcoholism (3U01AA019925 (NADIA))
- Topics
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
- Health Sciences › Medicine › Pediatrics, Perinatology and Child Health › Prenatal Substance Exposure Effects
- Health Sciences › Medicine › Epidemiology › Substance Abuse Treatment and Outcomes
- Keywords
- adolescent alcohol exposure, hippocampus, glutamate homeostasis, GLT-1, PSD-95, SLC7A11, sex differences, dorsal hippocampus, ventral hippocampus, synaptic proteins
- MeSH terms
- Disks Large Homolog 4 Protein, Ethanol, Animals, Astrocytes, Female, Hippocampus, Homeostasis, Humans, Male, Neurons, Receptors, N-Methyl-D-Aspartate, Rats, Sprague-Dawley, Receptor, EphB6, Glutamate Plasma Membrane Transport Proteins, Rats
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