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The Journal of Neuroscience, September 9, 2009, 29(36):11098-11111; doi:10.1523/JNEUROSCI.0942-09.2009

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Cellular/Molecular
K_V7/M Channels Mediate Osmotic Modulation of Intrinsic Neuronal Excitability

Anna Caspi,¹ Felix Benninger,¹ and Yoel Yaari^1,2

¹Department of Medical Neurobiology, Institute for Medical Research Israel–Canada, The Hebrew University–Hadassah School of Medicine, Jerusalem 91120, Israel, and ²The Interdisciplinary Center for Neuronal Computation, The Hebrew University, Jerusalem 91904, Israel

Correspondence should be addressed to Dr. Yoel Yaari, Department of Medical Neurobiology, Institute for Medical Research Israel–Canada, Hebrew University–Hadassah School of Medicine, P.O. Box 12272, Jerusalem 91120, Israel. Email: yaari{at}md.huji.ac.il

Modest decreases in extracellular osmolarity induce brain hyperexcitability that may culminate in epileptic seizures. At the cellular level, moderate hyposmolarity markedly potentiates the intrinsic neuronal excitability of principal cortical neurons without significantly affecting their volume. The most conspicuous cellular effect of hyposmolarity is converting regular firing neurons to burst-firing mode. This effect is underlain by hyposmotic facilitation of the spike afterdepolarization (ADP), but its ionic mechanism is unknown. Because blockers of K_V7 (KCNQ) channels underlying neuronal M-type K⁺ currents (K_V7/M channels) also cause spike ADP facilitation and bursting, we hypothesized that lowering osmolarity inhibits these channels. Using current- and voltage-clamp recordings in CA1 pyramidal cells in situ, we have confirmed this hypothesis. Furthermore, we show that hyposmotic inhibition of K_V7/M channels is mediated by an increase in intracellular Ca²⁺ concentration via release from internal stores but not via influx of extracellular Ca²⁺. Finally, we show that interfering with internal Ca²⁺-mediated inhibition of K_V7/M channels entirely protects against hyposmotic ADP facilitation and bursting, indicating the exclusivity of this novel mechanism in producing intrinsic neuronal hyperexcitability in hyposmotic conditions.

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Received Feb. 25, 2009; revised June 18, 2009; accepted July 6, 2009.

Correspondence should be addressed to Dr. Yoel Yaari, Department of Medical Neurobiology, Institute for Medical Research Israel–Canada, Hebrew University–Hadassah School of Medicine, P.O. Box 12272, Jerusalem 91120, Israel. Email: yaari{at}md.huji.ac.il

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