Glutamate toxicity in immature cortical neurons precedes development of glutamate receptor currents
Abstract
Cationic fluxes resulting from glutamate receptor activity have recently been implicated in neurotoxicity. Immature cortical neurons are insensitive to the toxic effects of glutamate receptor stimulation. However, these neurons are killed by glutamate via a non-receptor-mediated mechanism thought to stem from glutamate's ability to inhibit cystine uptake. To examine the basis for their resistance to receptor-mediated toxicity, we have studied the development of glutamate receptor-mediated inward currents in cortical neurons in culture using the whole-cell voltage-clamp technique. We report that in immature cortical neurons (prepared from day-17 fetal brain and cultured for 1-3 days), N-methyl-D-aspartate, quisqualate, and glutamate are able to evoke only very small inward currents in a low percentage of neurons. After 7 days of culture, greater than 80% of neurons examined exhibited currents activated by these glutamate receptor agonists. Although most neurons expressed glutamate agonist-evoked currents after 7 days in culture, the amplitude of these currents was less than 10% of that observed after 15 days in culture. In contrast to currents activated by glutamate receptor agonists, those activated by gamma-aminobutyric acid reached maximal levels after only 2 days of culture. These results indicate that the delayed development of glutamate receptor-mediated currents accounts for the resistance of immature cortical neurons to glutamate receptor-mediated toxicity.
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At 2-DIV, mouse cortical neurons do not express glutamate receptors and are not synaptically active.
“At 2-DIV, mouse cortical neurons do not express glutamate receptors and are not synaptically active.”
From 2-Deoxyglucose drives plasticity via an adaptive ER stress-ATF4 pathway and elicits stroke recovery and Alzheimer’s resilience (2023) · cites this paper as [30]
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“LDH activity was measured spectrophotometrically (U-2000 spectrophotometer; Hitachi, Tokyo, Japan) in the culture medium and in the cellular lysates, at 340 nm by analyzing NADH reduction during pyruvate-lactate transformation (Murphy and Baraban, 1990).”
MethodResch, J., Albano, R., Liu, X., Hjelmhaug, J., Lobner, D., Baker, D. A., & Choi, S. (2014) · Synapse · doi:10.1002/syn.21772 · Cited by 11 · see citing works
Wee, X.-K., Ng, K.-S., Leung, H.-W., Cheong, Y., Kong, K.-H., Ng, F., Soh, W., Lam, Y., & Low, C. (2010) · British Journal of Pharmacology · doi:10.1111/j.1476-5381.2009.00549.x · Cited by 10
“In addition, increased glutamate-induced currents over time in cultures of E17-19 DIV7-15 rat cortical and hippocampal neurones has been demonstrated by the patch electrode voltage-clamp technique (Ozawa et al., 1988; Murphy and Baraban, 1990).”
MethodXu, L., Zhao, Y., Zhan, S., Tang, X., Guo, Y., Wang, H.-Q., & Yang, C. (2007) · Neuroscience · doi:10.1016/j.neuroscience.2006.12.029 · Cited by 10 · see citing works
ET‐18‐OCH3‐induced cytotoxicity and DNA damage in rat astrocytes
Renis, M., Cardile, V., Palumbo, M., & Russo, A. (2000) · International Journal of Developmental Neuroscience · doi:10.1016/s0736-5748(00)00020-4 · Cited by 10
“The lactic dehydrogenase (LDH) activity was measured spectrophotometrically [25] in the culture medium and in the cell lysates and expressed as a percentage of total LDH released in the medium.”
MethodAmplification of calcium signals at dendritic spines provides a method for CNS quantal analysis.
Wang, S., Prange, O., & Murphy, T. H. (1999) · Canadian Journal of Physiology and Pharmacology · doi:10.1139/y99-073 · Cited by 10
“Embryonic cortical neurons and glial cells (from day-18 rat fetuses ) were grown 3–4 weeks in vitro on polylysine-coated Aclar 33C (a nonfluorescent plastic substrate 0.127 mm thick) or glass cover slips before use in imaging experiments (as in Murphy and Baraban 1990).”
InfluentialSelf-citationAMPA receptor-mediated miniature synaptic calcium transients in GluR2 null mice.
Wang, S., Jia, Z.-P., Roder, J., & Murphy, T. (2002) · Journal of Neurophysiology · doi:10.1152/jn.2002.88.1.29 · Cited by 8 · see citing works
Self-citationNon-competitive NMDA antagonists, FR115427 and MK801, enhance neuronal survival in primary culture.
Ueda, Y., Katsuta, K., Nakanishi, H., & Yoshida, K. (1995) · Neuroscience Letters · doi:10.1016/0304-3940(94)11236-c · Cited by 8
A free-radical hypothesis for the instability and evolution of genotype and phenotypein vitro
Parchment, R., & Natarajan, K. (2004) · Cytotechnology (Dordrecht) · doi:10.1007/bf00570888 · Cited by 8 · see citing works
Thomas, G. D., O'Rourke, B. P., Sikkink, R. A., Rusnak, F. M., Marbán, E., & Victor, R. G. (1997) · Brain Research · doi:10.1016/s0006-8993(96)01305-4 · Cited by 8 · see citing works
Quantitative neurotoxic effects of heavy metals and glutamate in mouse hippocampal neuronal cells
Jamsranjav, A., Gil, J., Kim, D., Choi, S.-B., Park, H., Shin, Y., & Bae, O. (2025) · Environmental Analysis Health and Toxicology · doi:10.5620/eaht.2025s08 · Cited by 6
“The HT-22 cell line, derived from mouse hippocampal neurons, is widely used as an in vitro model to study oxidative glutamate toxicity independent of ionotropic glutamate receptors [14].”
7 Sulfur-Containing Amino Acids
McBean, G. (2007) · doi:10.1007/978-0-387-30373-4_7 · Cited by 6
Developmental dissociation of pharmacological and neurotoxic effects of excitatory amino acids.
Cai, N., & Erdö, S. L. (1992) · Brain research. Developmental brain research · doi:10.1016/0165-3806(92)90089-f · Cited by 5
Tran, H. D., Huynh, H. M., Beckers, P., Desmet, N., Lamrani, M., Massie, A., Hermans, E., & Vanommeslaeghe, K. (2022) · Frontiers in Molecular Biosciences · doi:10.3389/fmolb.2022.1064199 · Cited by 4 · see citing works
Cardioprotective Potential of Qusqualis indica Leaves; An in silico Docking Study
Kulshreshtha, M., Sharma, A. K., Pathak, D., Pandey, P., Snehi, V., Shukla, K., Ved, A., Singh, A., Verma, N., Singh, A., et al. (2023) · Free Radicals and Antioxidants · doi:10.5530/fra.2023.1.7 · Cited by 3
Matsumoto, M., Sasaki, T., Nagashima, H., Ahn, E. S., Young, W., & Kodama, N. (2005) · Neurologia medico-chirurgica · doi:10.2176/nmc.45.73 · Cited by 3
Deciphering the role of novel kinase cascades in neuronal signalling
Murphy, T. H., & Baraban, J. M. (1995) · Neurobiology of Aging · doi:10.1016/0197-4580(94)00188-7 · Cited by 2 · see citing works
Self-citationBlack, A. M. (2010) · ERA: Education and Research Archive (University of Alberta) · doi:10.7939/r32g8b · Cited by 1 · see citing works
de Freitas, R. D. (2012) · InTech eBooks · doi:10.5772/26965
“Depending on neuronal maturity, the glutamate may induce either apoptotic or necrotic types of death (Ferrer et al, 1995) by impairing the Ca2+ homeostasis and inducting the oxidative stress (Leite et al, 1990; Murphy and Baraban, 1990).”
BackgroundShayan, H., & Murphy, T. H. (1999) · Neuroscience · doi:10.1016/s0306-4522(98)00323-6
Self-citationCharacterization of Novel Neuroprotective Lipid Analogues for the Treatment of Stroke
Maher, P., Biraboneye, A. C., & Kraus, J. (2012) · doi:10.1007/978-1-4419-9530-8_19
“Experimentally, this mechanism can be investigated in isolation from excitotoxicity in neuronal cell lines [ 15– 18 ] or immature primary cultured neurons still devoid of NMDA receptors [ 18, 19 ] .”
Background
- Authors
- Murphy, T. H., & Baraban, J. M.
- Affiliations
- Johns Hopkins University (US)
- Corresponding author
- Murphy, Timothy H.
- Venue
- Developmental Brain Research
- Publisher
- Elsevier BV
- Published
- 1990-12
- Volume
- 57
- Issue
- 1
- Pages
- 146-150
- ISSN
- 0165-3806 (ISSN-L)
- OpenAlex
- W2064789374
- Cited by
- 99
- References
- 21
- Citations by year
- 2025: 1 · 2024: 1 · 2023: 2 · 2022: 2 · 2020: 2 · 2019: 1 · 2015: 1 · 2014: 3 · 2013: 3 · 2012: 4
- FWCI
- 0.99
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Developmental Brain Research (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Institute of Mental Health (5T32 MH15330-11, T32MH015330)
- National Institute on Drug Abuse (DA.00266)
- Topics
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Biochemistry › Amino Acid Enzymes and Metabolism
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Nicotinic Acetylcholine Receptors Study
- Keywords
- glutamate excitotoxicity, NMDA receptor, kainate receptors, neurotoxicity, GABA-evoked currents, cystine uptake, neuronal maturation, excitatory amino acid toxicity
- MeSH terms
- Animals, Cerebral Cortex, Electrophysiology, Female, gamma-Aminobutyric Acid, Glutamates, Neurons, Pregnancy, Rats, Inbred Strains, N-Methylaspartate, Quisqualic Acid, Receptors, Glutamate, Receptors, Neurotransmitter, Glutamic Acid, Rats
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