TY - JOUR
T1 - KV7/M channels mediate osmotic modulation of intrinsic neuronal excitability
AU - Caspi, Anna
AU - Benninger, Felix
AU - Yaari, Yoel
PY - 2009/9/9
Y1 - 2009/9/9
N2 - 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 KV7 (KCNQ) channels underlying neuronal M-type K+ currents (KV7/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 KV7/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.
AB - 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 KV7 (KCNQ) channels underlying neuronal M-type K+ currents (KV7/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 KV7/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.
UR - http://www.scopus.com/inward/record.url?scp=70349104762&partnerID=8YFLogxK
U2 - 10.1523/JNEUROSCI.0942-09.2009
DO - 10.1523/JNEUROSCI.0942-09.2009
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C2 - 19741116
AN - SCOPUS:70349104762
SN - 0270-6474
VL - 29
SP - 11098
EP - 11111
JO - Journal of Neuroscience
JF - Journal of Neuroscience
IS - 36
ER -