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Recurrent neonatal seizures result in long-term increases in neuronal network excitability in the rat neocortex

Authors

  • Elena Isaeva,

    1. Department of Neurology, Neuroscience Center at Dartmouth, Dartmouth Medical School, One Medical Center Drive, Lebanon, NH 03756, USA
    2. Department of General Physiology of the Nervous System, Bogomoletz Institute of Physiology, Bogomoletz str. 4, Kiev, 01024, Ukraine
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  • Dmytro Isaev,

    1. Department of Neurology, Neuroscience Center at Dartmouth, Dartmouth Medical School, One Medical Center Drive, Lebanon, NH 03756, USA
    2. Department of General Physiology of the Nervous System, Bogomoletz Institute of Physiology, Bogomoletz str. 4, Kiev, 01024, Ukraine
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  • Alina Savrasova,

    1. Department of General Physiology of the Nervous System, Bogomoletz Institute of Physiology, Bogomoletz str. 4, Kiev, 01024, Ukraine
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  • Rustem Khazipov,

    1. Inmed/Inserm U901, Université de la Méditterranée, 163, Avenue du Luminy, 13273 Marseille, France
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  • Gregory L. Holmes

    1. Department of Neurology, Neuroscience Center at Dartmouth, Dartmouth Medical School, One Medical Center Drive, Lebanon, NH 03756, USA
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: Dr Gregory L. Holmes and Dr Elena Isaeva, as above.
E-mails: Gregory.L.Holmes@Dartmouth.Edu, olena.isaeva@gmail.com

Abstract

Neonatal seizures are associated with a high likelihood of adverse neurological outcomes, including mental retardation, behavioral disorders, and epilepsy. Early seizures typically involve the neocortex, and post-neonatal epilepsy is often of neocortical origin. However, our understanding of the consequences of neonatal seizures for neocortical function is limited. In the present study, we show that neonatal seizures induced by flurothyl result in markedly enhanced susceptibility of the neocortex to seizure-like activity. This change occurs in young rats studied weeks after the last induced seizure and in adult rats studied months after the initial seizures. Neonatal seizures resulted in reductions in the amplitude of spontaneous inhibitory postsynaptic currents and the frequency of miniature inhibitory postsynaptic currents, and significant increases in the amplitude and frequency of spontaneous excitatory postsynaptic currents (sEPSCs) and in the frequency of miniature excitatory postsynaptic currents (mEPSCs) in pyramidal cells of layer 2/3 of the somatosensory cortex. The selective N-methyl-d-aspartate (NMDA) receptor antagonist d-2-amino-5-phosphonovalerate eliminated the differences in amplitude and frequency of sEPSCs and mEPSCs in the control and flurothyl groups, suggesting that NMDA receptors contribute significantly to the enhanced excitability seen in slices from rats that experienced recurrent neonatal seizures. Taken together, our results suggest that recurrent seizures in infancy result in a persistent enhancement of neocortical excitability.

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