Kv1.1 channels mediate network excitability and feed-forward inhibition in local amygdala circuits

Samrat Thouta,Terrance P Snutch,Yiming Zhang,Esperanza Garcia

doi:10.1038/s41598-021-94633-3

Abstract

Kv1.1 containing potassium channels play crucial roles towards dampening neuronal excitability. Mice lacking Kv1.1 subunits (Kcna1−/−) display recurrent spontaneous seizures and often exhibit sudden unexpected death. Seizures in Kcna1−/− mice resemble those in well-characterized models of temporal lobe epilepsy known to involve limbic brain regions and spontaneous seizures result in enhanced cFos expression and neuronal death in the amygdala. Yet, the functional alterations leading to amygdala hyperexcitability have not been identified. In this study, we used Kcna1−/− mice to examine the contributions of Kv1.1 subunits to excitability in neuronal subtypes from basolateral (BLA) and central lateral (CeL) amygdala known to exhibit distinct firing patterns. We also analyzed synaptic transmission properties in an amygdala local circuit predicted to be involved in epilepsy-related comorbidities. Our data implicate Kv1.1 subunits in controlling spontaneous excitatory synaptic activity in BLA pyramidal neurons. In the CeL, Kv1.1 loss enhances intrinsic excitability and impairs inhibitory synaptic transmission, notably resulting in dysfunction of feed-forward inhibition, a critical mechanism for controlling spike timing. Overall, we find inhibitory control of CeL interneurons is reduced in Kcna1−/− mice suggesting that basal inhibitory network functioning is less able to prevent recurrent hyperexcitation related to seizures.

Highlights

Kv1.1 containing potassium channels play crucial roles towards dampening neuronal excitability
Seizure related neuronal cell loss, gliosis and enhanced Fos immunostaining have been observed in the BLA of Kcna1−/− mice[19,20], experimental evidence showing functional alterations associated to BLA in this animal model remain lacking
Employing whole-cell current clamp recordings of BLA pyramidal neurons from Kcna1+/+ and Kcna1−/− mice, we initially examined whether the loss of K v1.1 subunits in BLA pyramidal neurons affects their intrinsic excitability and synaptic activity (Figs. 1 and 2)

Summary

Introduction

Kv1.1 containing potassium channels play crucial roles towards dampening neuronal excitability. Seizures in Kcna1−/− mice resemble those in well-characterized models of temporal lobe epilepsy known to involve limbic brain regions and spontaneous seizures result in enhanced cFos expression and neuronal death in the amygdala. In support of an epileptogenic role for Kcna[1] mutations, a Kcna[1] knock out mouse model (Kcna1−/−) exhibits phenotypes similar to patients with severe epilepsy as characterized by recurrent spontaneous seizures including myoclonic and generalized tonic–clonic seizures beginning at 3–4 weeks p ostnatally[13,14]. Kcna1−/− mice resemble well-characterized kainate-and kindling-induced seizure models of temporal lobe epilepsy (TLE), suggesting Kcna[1] channel involvement in limbic brain circuits towards the generation and propagation of s eizures[13,14,19,20]. Given the role of the hippocampus in cognitive function e.g., learning and memory, deficits in hippocampal function are proposed to contribute to cognitive impairments associated with e pilepsy[23]

Methods

Results

Conclusion