Dysfunction of voltage-gated K + Channels Kv1.1 in sciatic nerve causes spontaneous and stress-induced neuromuscular hyperexcitability

Abstract

Episodic ataxia type 1 (EA1) is an autosomal dominant neurological disorder characterized by myokymia and attacks of ataxic gait precipitated by stress events. Several genetic mutations have been identified in the Shaker-like K+

channel Kv1.1 (KCNA1) of EA1 individuals, including the V408A which results in remarkable channel dysfunction. By inserting heterozygous V408A mutation in one Kv1.1 allele, a mouse model of EA1 has been generated (Kv1.1

V408A/+). Here, we hypothesized that dysfunction of Kv1.1 channels in sciatic nerve of Kv1.1V408A/+ ataxia mice leads to neuromuscular hyperexcitability and to abnormal susceptibility to different stressors. By using in vivo preparations of lateral gastrocnemius (LG) nerve–muscle from Kv1.1+/+ and Kv1.1V408A/+ mice, we show that the mutant animals exhibit spontaneous myokymic discharges consisting of repeated singlets, duplets or multiplets, despite sciatic nerve axotomy. Two-photon laser scanning microscopy from the sciatic nerve, ex vivo, revealed spontaneous Ca2+ signals that occurred abnormally only in preparations dissected from Kv1.1V408A/+ mice. The spontaneous bursting activity, as well as that evoked by motor nerve stimulation, was exacerbated by muscle fatigue, ischemia and low temperatures. These stressors also increased the amplitude of muscle compound action potential. Such abnormal neuromuscular transmission did not alter fiber type composition neuromuscular junction and vascularization of LG muscle analyzed by light and electron microscopy. These findings indicate that dysfunction of Kv1.1 channels results in sciatic nerve hyperexcitability and myokymia/neuromyotonia in Kv1.1V408A/+ ataxia mice. Moreover, this study sheds new light on the functional role played by K + channels segregated under the myelin sheath,

which becomes crucial in certain situations of physiological stress.