KCNQ/Kv7 Channel Regulation of Hippocampal Gamma-Frequency Firing in the Absence of Synaptic Transmission

Abstract

Piccinin, S., A. D. Randall, and J. T. Brown. KCNQ/Kv7 channel regulation of hippocampal gamma-frequency firing in the absence of synaptic transmission. J Neurophysiol 95: 3105-3112, 2006. First published February 8, 2006 doi:10.1152/jn.01083.2005. Synchronous neuronal firing can be induced in hippocampal slices in the absence of synaptic transmission by lowering extracellular Ca 2ϩ and raising extracellular K ϩ . However, the ionic mechanisms underlying this nonsynaptic synchronous firing are not well understood. In this study we have investigated the role of KCNQ/Kv7 channels in regulating this form of nonsynaptic bursting activity. Incubation of rat hippocampal slices in reduced (Ͻ0.2 mM) [Ca 2ϩ ] o and increased (6.3 mM) [K ϩ ] o , blocked synaptic transmission, increased neuronal firing, and led to the development of spontaneous periodic nonsynaptic epileptiform activity. This activity was recorded extracellularly as large (4.7 Ϯ 1.9 mV) depolarizing envelopes with superimposed highfrequency synchronous population spikes. These intraburst population spikes initially occurred at a high frequency (about 120 Hz), which decayed throughout the burst stabilizing in the gamma-frequency band (30 -80 Hz). Further increasing [K ϩ ] o resulted in an increase in the interburst frequency without altering the intraburst population spike frequency. Application of retigabine (10 M), a Kv7 channel modulator, completely abolished the bursts, in an XE-991-sensitive manner. Furthermore, application of the Kv7 channel blockers, linopirdine (10 M) or XE-991 (10 M) alone, abolished the gamma frequency, but not the higher-frequency population spike firing observed during low Ca 2ϩ /high K ϩ bursts. These data suggest that Kv7 channels are likely to play a role in the regulation of synchronous population firing activity.

Involvement of inward rectifier and M-type currents in carbachol-induced epileptiform synchronization

“…However, retigabine completely suppressed these long-lasting events whenever present. The fact that retigabine failed to fully suppress all types of CCh-induced events is in apparent contrast with the ability of this drug to abolish both ictal-and interictallike events induced in vitro by 4-aminopyridine (Armand et al, 1999), or by perfusion with low Mg 2+ - (Qiu et al, 2007) or low Ca 2+ /high K + - (Piccinin et al, 2006) containing medium. It should be, however, mentioned that distinct levels of K M activity could be recruited by different epileptogenic stimuli; in particular, in the present model of ictogenesis triggered by muscarinic stimulation, K M contribution would be less pronounced since CCh induces a profound depletion in plasma membrane PIP2, thus leading to a substantial suppression of K M .…”

Kv7 channels: interaction with dopaminergic and serotonergic neurotransmission in the CNS

“…This greatly increases open channel probability at resting membrane potentials (Tatulian & Brown, 2003). In the hippocampus, retigabine inhibits action potential generation (Piccinin et al 2006; Hu et al 2007). Conversely, inhibition of Kv7 channel function by application of the Kv7 channel blockers XE991 or linopirdine produces hyperexcitability and triggers burst firing in various hippocampal neurons (Yue & Yaari, 2004; Lawrence et al 2006).…”

A schizophrenia-linked mutation in PIP5K2A fails to activate neuronal M channels

“…Except KCNQ1, all KCNQ subunits are expressed in the brain controlling axonal excitability, synaptic transmission, spike afterpotentials, spike frequency adaptation, and theta resonance, leading to neuronal hyperpolarization and stabilizing the membrane potential (Hu et al 2007;Jentsch et al 2000;Vervaeke et al 2006). KCNQ channels regulate nonsynaptic bursting activity, block synaptic transmission, increase neuronal firing, and control synchronous population firing activity in the brain (Piccinin et al 2006). Mutations of KCNQ channels have been linked to several brain disorders accompanied with increased neuronal excitability, such as epilepsy, anxiety, and migraine (Korsgaard et al 2005;Lerche et al 2005).…”