The Journal of Neurophysiology Vol. 86 No. 5 November 2001, pp. 2520-2526
Copyright ©2001 by the American Physiological Society

Effect of Lamotrigine on the Ca²⁺-Sensing Cation Current in Cultured Hippocampal Neurons

 ¹Robert S. Dow Neurobiology Laboratories, Legacy Clinical Research and Technology Center, Portland, Oregon 97232; and  ²Department of Physiology, University of Toronto, Toronto, Ontario M5S 1A8, Canada

Xiong, Zhi-Gang, Xiang-Ping Chu, and J. F. MacDonald. Effect of Lamotrigine on the Ca²⁺-Sensing Cation Current in Cultured Hippocampal Neurons. J. Neurophysiol. 86: 2520-2526, 2001. Concentrations of extracellular calcium ([Ca²⁺]_e) in the CNS decrease substantially during seizure activity. We have demonstrated previously that decreases in [Ca²⁺]_e activate a novel calcium-sensing nonselective cation (csNSC) channel in hippocampal neurons. Activation of csNSC channels is responsible for a sustained membrane depolarization and increased neuronal excitability. Our study has suggested that the csNSC channel is likely involved in generating and maintaining seizure activities. In the present study, the effects of anti-epileptic agent lamotrigine (LTG) on csNSC channels were studied in cultured mouse hippocampal neurons using patch-clamp techniques. At a holding potential of 60 mV, a slow inward current through csNSC channels was activated by a step reduction of [Ca²⁺]_e from 1.5 to 0.2 mM. LTG decreased the amplitude of csNSC currents dose dependently with an IC₅₀ of 171 ± 25.8 (SE) µM. The effect of LTG was independent of membrane potential. In the presence of 300 µM LTG, the amplitude of csNSC current was decreased by 31 ± 3% at 60 mV and 29 ± 2.9% at +40 mV (P > 0.05). LTG depressed csNSC current without affecting the potency of Ca²⁺ block of the current (IC₅₀ for Ca²⁺ block of csNSC currents in the absence of LTG: 145 ± 18 µM; in the presence of 300 µM LTG: 136 ± 10 µM. n = 5, P > 0.05). In current-clamp recordings, activation of csNSC channel by reducing the [Ca²⁺]_e caused a sustained membrane depolarization and an increase in the frequency of spontaneous firing of action potentials. LTG (300 µM) significantly inhibited csNSC channel-mediated membrane depolarization and the excitation of neurons. Fura-2 ratiometric Ca²⁺ imaging experiment showed that LTG also inhibited the increase in intracellular Ca²⁺ concentration induced by csNSC channel activation. The effect of LTG on csNSC channels may partially contribute to its broad spectrum of anti-epileptic actions.