DOI: 10.1523/jneurosci.23-05-01840.2003. Excitatory Actions of Endogenously Released GABA Contribute to Initiation of Ictal Epileptiform Activity in the Developing Hippocampus

Excitatory Actions of Endogenously Released GABA Contribute to Initiation of Ictal Epileptiform Activity in the Developing Hippocampus

10.1523/jneurosci.23-05-01840.2003

Crossref journal-article

Society for Neuroscience

The Journal of Neuroscience (393)

Abstract

In the developing rat hippocampus, ictal epileptiform activity can be elicited easilyin vitroduring the first three postnatal weeks. Changes in neuronal ion transport during this time cause the effects of GABAAreceptor (GABAA-R) activation to shift gradually from strongly depolarizing to hyperpolarizing. It is not known whether the depolarizing effects of GABA and the propensity for ictal activity are causally linked. A key question is whether the GABA-mediated depolarization is excitatory, which we defined operationally as being sufficient to trigger action potentials. We assessed the effect of endogenous GABA on ictal activity and neuronal firing rate in hippocampal slices from postnatal day 1 (P1) to P30. In extracellular recordings, there was a strong correlation between the postnatal age at which GABAA-R antagonists decreased action potential frequency (P23) and the age at which ictal activity could be induced by elevated potassium (P23). In addition, there was a strong correlation between the fraction of slices in which ictal activity was induced by elevated potassium concentrations and the fractional decrease in action potential firing when GABAA-Rs were blocked in the presence of ionotropic glutamate receptor antagonists. Finally, ictal activity induced by elevated potassium was blocked by the GABAA-R antagonists bicuculline and SR-95531 (gabazine) and increased in frequency and duration by GABAA-R agonists isoguvacine and muscimol. Thus, the propensity of the developing hippocampus for ictal activity is highly correlated with the effect of GABA on action potential probability and reversed by GABAAantagonists, indicating that GABA-mediated excitation is causally linked to ictal activity in this developmental window.

Bibliography

Dzhala, V. I., & Staley, K. J. (2003). Excitatory Actions of Endogenously Released GABA Contribute to Initiation of Ictal Epileptiform Activity in the Developing Hippocampus. The Journal of Neuroscience, 23(5), 1840â1846.

Authors 2

Volodymyr I. Dzhala (first)
Kevin J. Staley (additional)

References 48 Referenced 155

10.1113/jphysiol.1982.sp014255
10.1002/cne.901900108
10.1113/jphysiol.1989.sp017762
10.1016/S0166-2236(97)01147-8
10.1002/(SICI)1098-1063(1999)9:2<137::AID-HIPO5>3.0.CO;2-0
10.1111/j.1528-1157.1999.tb00849.x
10.1113/jphysiol.1996.sp021505
10.1016/0166-2236(91)90003-D
10.1080/08990229870691
10.1111/j.1469-7793.2000.00485.x
10.1113/jphysiol.1988.sp017390
10.1111/j.1528-1157.1992.tb06223.x / Epilepsia / Status epilepticus in children, adults, and the elderly. by DeLorenzo (1992)
10.1111/j.1469-7793.2001.0521c.xd
10.1002/(SICI)1098-1063(1996)6:4<347::AID-HIPO1>3.0.CO;2-I
10.1111/j.1469-7793.1998.219bu.x
10.1002/(SICI)1096-9861(19970728)384:2<165::AID-CNE1>3.0.CO;2-#
10.1111/j.1528-1157.1997.tb01074.x
10.1002/ana.410240502
10.1152/jn.1997.77.3.1224 / J Neurophysiol / Role of intrinsic burst firing, potassium accumulation, and electrical coupling in the elevated potassium model of hippocampal epilepsy. by Jensen (1997)
10.1016/S0896-6273(00)80956-3
10.1159/000017380
10.1073/pnas.80.9.2799
10.1152/jn.1987.57.1.325 / J Neurophysiol / Epileptiform burst activity induced by potassium in the hippocampus and its regulation by GABA-mediated inhibition. by Korn (1987)
10.1152/jn.2000.83.1.359 / J Neurophysiol / Synaptic GABAA activation inhibits AMPA-kainate receptor-mediated bursting in the newborn (P0–P2) rat hippocampus. by Lamsa (2000)
10.1113/jphysiol.1995.sp020882
10.1126/science.1071111
10.1016/0168-0102(94)90025-6
10.1016/0896-6273(95)90008-X
10.1113/jphysiol.1987.sp016634
10.1016/0165-3806(96)00064-8
10.1523/JNEUROSCI.16-20-06414.1996
10.1080/00029238.1980.11080014 / Am J EEG Technol / Interictal epileptiform discharges: discriminating characteristics and clinical correlations. by Pedley (1980)
10.1038/16697
10.1152/jn.1985.54.5.1363 / J Neurophysiol / Epileptiform activity induced by changes in extracellular potassium in hippocampus. by Rutecki (1985)
10.1113/jphysiol.1995.sp020973
10.1038/89439
10.1002/syn.890090308
10.1152/jn.1992.68.1.197 / J Neurophysiol / Shunting of excitatory input to dentate gyrus granule cells by a depolarizing GABAA receptor-mediated postsynaptic conductance. by Staley (1992)
10.1111/j.1469-7793.1999.0693n.x
10.1002/1098-2779(2000)6:4<258::AID-MRDD5>3.0.CO;2-H
10.1152/jn.1989.61.3.501 / J Neurophysiol / Activity-dependent disinhibition. I. Repetitive stimulation reduces IPSP driving force and conductance in the hippocampus in vitro. by Thompson (1989)
10.1152/jn.1989.61.3.512 / J Neurophysiol / Activity-dependent disinhibition. II. Effects of extracellular potassium, furosemide, and membrane potential on ECl− in hippocampal CA3 neurons. by Thompson (1989)
10.1111/j.1749-6632.1991.tb25931.x
10.1152/jn.1988.59.1.259 / J Neurophysiol / Potassium-induced spontaneous electrographic seizures in the rat hippocampal slice. by Traynelis (1988)
10.1523/JNEUROSCI.19-23-10372.1999
10.1523/JNEUROSCI.17-01-00277.1997
10.1523/JNEUROSCI.20-23-08822.2000
10.1016/0896-6273(91)90243-S

Dates

Type	When
Created	7 years, 4 months ago (April 4, 2018, 4:45 p.m.)
Deposited	2 years, 6 months ago (Feb. 23, 2023, 11 a.m.)
Indexed	6 days, 21 hours ago (Aug. 23, 2025, 9:42 p.m.)
Issued	22 years, 5 months ago (March 1, 2003)
Published	22 years, 5 months ago (March 1, 2003)
Published Online	22 years, 5 months ago (March 1, 2003)
Published Print	22 years, 5 months ago (March 1, 2003)

Funders 0

None

BibTeX

@article{Dzhala_2003, title={Excitatory Actions of Endogenously Released GABA Contribute to Initiation of Ictal Epileptiform Activity in the Developing Hippocampus}, volume={23}, ISSN={1529-2401}, url={http://dx.doi.org/10.1523/jneurosci.23-05-01840.2003}, DOI={10.1523/jneurosci.23-05-01840.2003}, number={5}, journal={The Journal of Neuroscience}, publisher={Society for Neuroscience}, author={Dzhala, Volodymyr I. and Staley, Kevin J.}, year={2003}, month=mar, pages={1840–1846} }

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    "1529-2401"
  ],
  "subject": [],
  "container-title-short": "J. Neurosci.",
  "published": {
    "date-parts": [
      [
        2003,
        3,
        1
      ]
    ]
  }
}