Key result
The ataxia-associated Kcna1V408A/+ mutation broadened presynaptic action potentials in cerebellar basket cells to 1.26 ms compared to 0.93 ms in wild-type mice, leading to increased GABA release.
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The study demonstrates that Kv1.1 channels are crucial for action potential repolarization at cerebellar basket cell terminals, and their dysfunction in a mouse model of episodic ataxia type 1 leads to spike broadening and increased GABA release without developmental compensation.
Brain development and interictal function are unaffected in many paroxysmal neurological channelopathies, possibly explained by homoeostatic plasticity of synaptic transmission. Episodic ataxia type 1 is caused by missense mutations of the potassium channel Kv1.1, which is abundantly expressed in the terminals of cerebellar basket cells. Presynaptic action potentials of small inhibitory terminals have not been characterized, and it is not known whether developmental plasticity compensates for the effects of Kv1.1 dysfunction. Here we use visually targeted patch-clamp recordings from basket cell terminals of mice harbouring an ataxia-associated mutation and their wild-type littermates. Presynaptic spikes are followed by a pronounced afterdepolarization, and are broadened by pharmacological blockade of Kv1.1 or by a dominant ataxia-associated mutation. Somatic recordings fail to detect such changes. Spike broadening leads to increased Ca(2+) influx and GABA release, and decreased spontaneous Purkinje cell firing. We find no evidence for developmental compensation for inherited Kv1.1 dysfunction.
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Begum et al. (2016) studied Episodic ataxia type 1. Kcna1V408A/+ mutation vs. Wild-type (Kcna1+/+) was evaluated on Presynaptic action potential width at -30 mV (ms) (p=<0.002). The ataxia-associated Kcna1V408A/+ mutation broadened presynaptic action potentials in cerebellar basket cells to 1.26 ms compared to 0.93 ms in wild-type mice, leading to increased GABA release.
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