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The Journal of Neuroscience, October 24, 2007, 27(43):11587-11594; doi:10.1523/JNEUROSCI.2033-07.2007

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Cellular/Molecular
Role of Extracellular Sialic Acid in Regulation of Neuronal and Network Excitability in the Rat Hippocampus

Dmytro Isaev,^1,2,3,4 Elena Isaeva,^1,2,3,4 Tatiana Shatskih,^1,2,3 Qian Zhao,^1,2,3 Nicole C. Smits,² Nicholas W. Shworak,² Rustem Khazipov,^1,2,3,5 and Gregory L. Holmes^1,2,3

¹Neuroscience Center at Dartmouth, ²Department of Medicine, and ³Section of Neurology, Dartmouth Medical School, Lebanon, New Hampshire 03756, ⁴Bogomoletz Institute of Physiology, Kiev, Ukraine 01024, and ⁵Institute de Neurobiologie de la Méditeranée, Inserm-U29, 13273 Marseille, France

Correspondence should be addressed to Dr. Dmytro Isaev, Department of Physiology of Nervous System, Bogomoletz Institute of Physiology, Bogomoletz Street 4, Kiev, Ukraine 01024. Email: dmytro.isaev{at}gmail.com

The extracellular membrane surface contains a substantial amount of negatively charged sialic acid residues. Some of the sialic acids are located close to the pore of voltage-gated channel, substantially influencing their gating properties. However, the role of sialylation of the extracellular membrane in modulation of neuronal and network activity remains primarily unknown. The level of sialylation is controlled by neuraminidase (NEU), the key enzyme that cleaves sialic acids. Here we show that NEU treatment causes a large depolarizing shift of voltage-gated sodium channel activation/inactivation and action potential (AP) threshold without any change in the resting membrane potential of hippocampal CA3 pyramidal neurons. Cleavage of sialic acids by NEU also reduced sensitivity of sodium channel gating and AP threshold to extracellular calcium. At the network level, exogenous NEU exerted powerful anticonvulsive action both in vitro and in acute and chronic in vivo models of epilepsy. In contrast, a NEU blocker (N-acetyl-2,3-dehydro-2-deoxyneuraminic acid) dramatically reduced seizure threshold and aggravated hippocampal seizures. Thus, sialylation appears to be a powerful mechanism to control neuronal and network excitability. We propose that decreasing the amount of extracellular sialic acid residues can be a useful approach to reduce neuronal excitability and serve as a novel therapeutic approach in the treatment of seizures.

Key words: sialic acid; neuraminidase; seizure; surface charge; hippocampus; sodium channels

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Received July 17, 2006; revised Aug. 25, 2007; accepted Sept. 3, 2007.

Correspondence should be addressed to Dr. Dmytro Isaev, Department of Physiology of Nervous System, Bogomoletz Institute of Physiology, Bogomoletz Street 4, Kiev, Ukraine 01024. Email: dmytro.isaev{at}gmail.com

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