Role of extracellular sialic acid in regulation of neuronal and network excitability in the rat hippocampus.
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.
Isaev
Dmytro
D
Neuroscience Center at Dartmouth, Dartmouth Medical School, Lebanon, New Hampshire 03756, USA. dmytro.isaev@gmail.com
Isaeva
Elena
E
Shatskih
Tatiana
T
Zhao
Qian
Q
Smits
Nicole C
NC
Shworak
Nicholas W
NW
Khazipov
Rustem
R
Holmes
Gregory L
GL
D000200:Action Potentials / Q000502:physiology*; D000818:Animals; D045604:Extracellular Fluid / Q000502:physiology*; D006624:Hippocampus / Q000502:physiology*; D008564:Membrane Potentials / Q000502:physiology; D019158:N-Acetylneuraminic Acid / Q000502:physiology*; D009415:Nerve Net / Q000502:physiology*; D009474:Neurons / Q000502:physiology*; D051381:Rats; D017207:Rats, Sprague-Dawley
D019158:N-Acetylneuraminic Acid