Abstract
Low threshold voltage activated Kv1 potassium channels play key roles in regulating action potential (AP) threshold, neural excitability, and synaptic transmission. Kv1 channels are highly expressed in the cerebellum and mutations of human Kv1 genes are associated to episodic forms of ataxia (EAT-1). Besides the well-established role of Kv1 channels in controlling the cerebellar basket-Purkinje cells synapses, Kv1 channels are expressed by the deep cerebellar nuclear neurons (DCNs) where they regulate the activity of principal DCNs carrying the cerebellar output. DCNs include as well GABAergic neurons serving important functions, such as those forming the inhibitory nucleo-olivary pathway, the nucleo-cortical DCNs providing feed-back inhibition to the cerebellar cortex, and those targeting principal DCNs, but whether their function is regulated by Kv1 channels remains unclear. Here, using cerebellar slices from mature GAD67-GFP mice to identify putative GABAergic-DCNs (GAD + DCN) we show that specific Kv1 channel blockers (dendrotoxin-alpha/I/K, DTXs) hyperpolarized the threshold of somatic action potentials, increased the spontaneous firing rate and hampered evoked high frequency repetitive responses of GAD + DCNs. Moreover, DTXs induced somatic depolarization and tonic firing in previously silent, putative nucleo-cortical DCNs. These results reveal a novel role of Kv1 channels in regulating GABAergic-DCNs activity and thereby, cerebellar function at multiple levels.
Highlights
Low threshold voltage activated Kv1 potassium channels play key roles in regulating action potential (AP) threshold, neural excitability, and synaptic transmission
To elucidate whether Kv1 channels control the activity of GABAergic deep cerebellar nuclear neurons (DCNs), we used cerebellar slices from the mature (>P21) GAD67-GFP mice[31], their wild type littermates, or mice with the same background to obtain whole cell current clamp recordings of DCNs from the lateral or interpositus nuclei, before and during application of pharmacological blockers of Kv1 channels, under conditions alike to those found in situ
We identified three classes of DCNs according to the presence of fluorescence, size, and electrophysiology: 1) putatively GABAergic DCNs31 (GAD + DCNs), 2) putatively glutamatergic principal DCNs31 and, 3) putative nucleo-cortical GABAergic/Glycinergic DCNs26,28
Summary
Low threshold voltage activated Kv1 potassium channels play key roles in regulating action potential (AP) threshold, neural excitability, and synaptic transmission. Besides the well-established role of Kv1 channels in controlling the cerebellar basket-Purkinje cells synapses, Kv1 channels are expressed by the deep cerebellar nuclear neurons (DCNs) where they regulate the activity of principal DCNs carrying the cerebellar output. DCNs include as well GABAergic neurons serving important functions, such as those forming the inhibitory nucleo-olivary pathway, the nucleo-cortical DCNs providing feed-back inhibition to the cerebellar cortex, and those targeting principal DCNs, but whether their function is regulated by Kv1 channels remains unclear. Since Kv1, heteromeric Kv1.1 and Kv1.2 channels are expressed at the output cerebellar stage by the deep cerebellar nuclei neurons (DCNs), it has been suggested that aberrant DCNs Kv1 channels could contribute to www.nature.com/scientificreports the EAT-1 cerebellar symptoms, supported by findings that glutamatergic principal DCNs activity is sensitive to specific Kv1 channel blockers[19]. Using cerebellar slices from GAD67-GFP mice line[30] to identify putative GABAergic-DCNs and a pharmacological approach we found evidence that the activity of GABAergic-DCNs is regulated by Kv1 channels and their alteration could contribute to the symptomatology of EAT-1
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