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J Physiol Volume 586, Number 2, 477-494, January 15, 2008 DOI: 10.1113/jphysiol.2007.143065
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NEUROSCIENCE

Transition to seizures in the isolated immature mouse hippocampus: a switch from dominant phasic inhibition to dominant phasic excitation

 M. Derchansky1,2, S. S. Jahromi1, M. Mamani1,2, D. S. Shin1, A. Sik3 and P. L. Carlen1,2,4,5,6

1 Division of Cellular and Molecular Biology, Toronto Western Research Institute, Toronto, Canada
2 Department of Physiology, University of Toronto, Toronto, Canada
3 Centre de Recherche Université Laval Robert-Giffard, Beauport, Canada
4 Krembil Neuroscience Center, Toronto Western Hospital, University of Toronto, Toronto, Canada
5 Institute of Biomaterials and Biomedical Engineering, University of Toronto, Toronto, Canada
6 Division of Neurology, Department of Medicine, University of Toronto, Toronto, Canada

The neural dynamics and mechanisms responsible for the transition from the interictal to the ictal state (seizures) are unresolved questions in epilepsy. It has been suggested that a shift from inhibitory to excitatory GABAergic drive can promote seizure generation. In this study, we utilized an experimental model of temporal lobe epilepsy which produces recurrent seizure-like events in the isolated immature mouse hippocampus (P8–16), perfused with low magnesium ACSF, to investigate the cellular dynamics of seizure transition. Whole-cell and perforated patch recordings from CA1 pyramidal cells and from fast- and non-fast-spiking interneurons in the CA1 stratum oriens hippocampal region showed a change in intracellular signal integration during the transition period, starting with dominant phasic inhibitory synaptic input, followed by dominant phasic excitation prior to a seizure. Efflux of bicarbonate ions through the GABAA receptor did not fully account for this excitation and GABAergic excitation via reversed IPSPs was also excluded as the prime mechanism generating the dominant excitation, since somatic and dendritic GABAA responses to externally applied muscimol remained hyperpolarizing throughout the transition period. In addition, abolishing EPSPs in a single neuron by intracellularly injected QX222, revealed that inhibitory synaptic drive was maintained throughout the entire transition period. We suggest that rather than a major shift from inhibitory to excitatory GABAergic drive prior to seizure onset, there is a change in the interaction between afferent synaptic inhibition, and afferent and intrinsic excitatory processes in pyramidal neurons and interneurons, with maintained inhibition and increasing, entrained ‘overpowering’ excitation during the transition to seizure.

(Received 14 August 2007; accepted after revision 31 October 2007; first published online 8 November 2007)
Corresponding author P. L. Carlen: Toronto Western Hospital, 399 Bathurst St, 12-413, Toronto, Ontario, Canada M5T2S8. Email: carlen{at}uhnres.utoronto.ca






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