Journal
TOXICOLOGICAL SCIENCES
Volume 130, Issue 2, Pages 362-372Publisher
OXFORD UNIV PRESS
DOI: 10.1093/toxsci/kfs244
Keywords
Ca2+ oscillations; GABA(A) receptors; microelectrode array; NMDA receptors; rapid throughput assay; tetramethylenedisulfotetramine
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Funding
- National Institute of Neurological Disorders and Stroke [1U54 NS079202-01, R21 NS072094]
- National Institute on Aging [1R01 AG032119]
- National Institute of Environmental Health Sciences [4P42 ES04699, 1R01 ES 002710, F32 ES007059]
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Tetramethylenedisulfotetramine (TETS) is a potent convulsant that is considered a chemical threat agent. We characterized TETS as an activator of spontaneous Ca2+ oscillations and electrical burst discharges in mouse hippocampal neuronal cultures at 1317 days in vitro using FLIPR Fluo-4 fluorescence measurements and extracellular microelectrode array recording. Acute exposure to TETS (>= 2 mu M) reversibly altered the pattern of spontaneous neuronal discharges, producing clustered burst firing and an overall increase in discharge frequency. TETS also dramatically affected Ca2+ dynamics causing an immediate but transient elevation of neuronal intracellular Ca2+ followed by decreased frequency of Ca2+ oscillations but greater peak amplitude. The effect on Ca2+ dynamics was similar to that elicited by picrotoxin and bicuculline, supporting the view that TETS acts by inhibiting type A gamma-aminobutyric acid (GABA(A)) receptor function. The effect of TETS on Ca2+ dynamics requires activation of N-methyl-d-aspartic acid (NMDA) receptors, because the changes induced by TETS were prevented by MK-801 block of NMDA receptors, but not nifedipine block of L-type Ca2+ channels. Pretreatment with the GABA(A) receptor-positive modulators diazepam and allopregnanolone partially mitigated TETS-induced changes in Ca2+ dynamics. Moreover, low, minimally effective concentrations of diazepam (0.1M) and allopregnanolone (0.1M), when administered together, were highly effective in suppressing TETS-induced alterations in Ca2+ dynamics, suggesting that the combination of positive modulators of synaptic and extrasynaptic GABA(A) receptors may have therapeutic potential. These rapid throughput in vitro assays may assist in the identification of single agents or combinations that have utility in the treatment of TETS intoxication.
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