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Vervaeke K, Gu N, Agdestein C, Hu H, Storm JF: Kv7/KCNQ/M-channels in rat glutamatergic hippocampal axons and their role in regulation of excitability and transmitter release. J Physiol. 2006 Oct 1;576(Pt 1):235-56. Epub 2006 Jul 13.
M-current (I (M)) plays a key role in regulating neuronal excitability. Mutations in Kv7/KCNQ subunits, the molecular correlates of I (M), are associated with a familial human epilepsy syndrome. Kv7/KCNQ subunits are widely expressed, and I (M) has been recorded in somata of several types of neurons, but the subcellular distribution of M-channels remains elusive. By combining field-potential, whole-cell and intracellular recordings from area CA1 in rat hippocampal slices, and computational modelling, we provide evidence for functional M-channels in unmyelinated axons in the brain. Our data indicate that presynaptic M-channels can regulate axonal excitability and synaptic transmission, provided the axons are depolarized into the I (M) activation range (beyond approximately -65 mV). Here, such depolarization was achieved by increasing the extracellular K (+) concentration ([K (+)](o)). Extracellular recordings in the presence of moderately elevated [K (+)](o) (7-11 mm), showed that the specific M-channel blocker XE991 reduced the amplitude of the presynaptic fibre volley and the field EPSP in a [K (+)](o)-dependent manner, both in stratum radiatum and in stratum lacknosum moleculare. The M-channel opener, retigabine, had opposite effects. The higher the [K (+)](o), the greater the effects of XE991 and retigabine. Similar pharmacological modulation of EPSPs recorded intracellularly from CA1 pyramidal neurons, while blocking postsynaptic K (+) channels with intracellular Cs (+), confirmed that active M-channels are located presynaptically. Computational analysis with an axon model showed that presynaptic I (M) can control Na (+) channel inactivation and thereby affect the presynaptic action potential amplitude and Ca (2+) influx, provided the axonal membrane potential is sufficiently depolarized. Finally, we compared the effects of blocking I (M) on the spike after-depolarization and bursting in CA3 pyramidal neuron somata versus their axons. In standard [K (+)](o) (2.5 mm), XE991 increased the ADP and promoted burst firing at the soma, but not in the axons. However, I (M) contributed to the refractory period in the axons when spikes were broadened by a low dose 4-aminopyridine (200 microm). Our results indicate that functional Kv7/KCNQ/M-channels are present in unmyelinated axons in the brain, and that these channels may have contrasting effects on excitability depending on their subcellular localization. |
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