Pharmacological modulation of Kv3 voltage-gated potassium channels regulates fear discrimination and expression in a response-dependent manner

Stubbendorff, Christine; Hale, Ed; Day, Harriet Laura Lavinia; Smith, Jessica; Alvaro, Giuseppe; Large, Charles H.; Stevenson, Carl W.

doi:10.1016/j.pnpbp.2023.110829

Cited by 5 publications

(1 citation statement)

References 54 publications

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“…[ 48 , 49 ] Furthermore, Kv3 has been reported to regulate fear discrimination by regulating interneuron firing in the underpinning corticolimbic circuitry. [ 50 ] Ablation of Kv3.1 and Kv3.3 channels has been shown to disrupt thalamocortical oscillations both in vitro and in vivo. [ 51 ] Despite evidence indicating the influence of Kv3 on thalamocortical circuit function and suggesting that the Kv3 channel is a promising drug target, the current array of specific targeted molecules for therapeutic intervention remains relatively scarce.…”

Section: Discussionmentioning

confidence: 99%

Restoring the Function of Thalamocortical Circuit Through Correcting Thalamic Kv3.2 Channelopathy Normalizes Fear Extinction Impairments in a PTSD Mouse Model

Xiao,

Xi,

Wang

et al. 2023

Advanced Science

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Impaired extinction of fear memory is one of the most common symptoms in post‐traumatic stress disorder (PTSD), with limited therapeutic strategies due to the poor understanding of its underlying neural substrates. In this study, functional screening is performed and identified hyperactivity in the mediodorsal thalamic nucleus (MD) during fear extinction. Furthermore, the encoding patterns of the hyperactivated MD is investigated during persistent fear responses using multiple machine learning algorithms. The anterior cingulate cortex (ACC) is also identified as a functional downstream region of the MD that mediates the extinction of fear memory. The thalamocortical circuit is comprehensively analyzed and found that the MD‐ACC parvalbumin interneurons circuit is preferentially enhanced in PTSD mice, disrupting the local excitatory and inhibitory balance. It is found that decreased phosphorylation of the Kv3.2 channel contributed to the hyperactivated MD, primarily to the malfunctioning thalamocortical circuit. Using a lipid nanoparticle‐based RNA therapy strategy, channelopathy is corrected via a methoxylated siRNA targeting the protein phosphatase 6 catalytic subunit and restored fear memory extinction in PTSD mice. These findings highlight the function of the thalamocortical circuit in PTSD‐related impaired extinction of fear memory and provide therapeutic insights into Kv3.2‐targeted RNA therapy for PTSD.

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Section: Discussionmentioning

confidence: 99%

Restoring the Function of Thalamocortical Circuit Through Correcting Thalamic Kv3.2 Channelopathy Normalizes Fear Extinction Impairments in a PTSD Mouse Model

Xiao,

Xi,

Wang

et al. 2023

Advanced Science

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Kv3.1 Voltage-gated Potassium Channels Modulate Anxiety-like Behaviors in Female Mice

Page,

Coutellier

2024

Neuroscience

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Pharmacological modulation of Kv3 voltage-gated potassium channels regulates fear discrimination and expression in a response-dependent manner

Cited by 5 publications

References 54 publications

Restoring the Function of Thalamocortical Circuit Through Correcting Thalamic Kv3.2 Channelopathy Normalizes Fear Extinction Impairments in a PTSD Mouse Model

Restoring the Function of Thalamocortical Circuit Through Correcting Thalamic Kv3.2 Channelopathy Normalizes Fear Extinction Impairments in a PTSD Mouse Model

Kv3.1 Voltage-gated Potassium Channels Modulate Anxiety-like Behaviors in Female Mice

Targeted therapy improves cellular dysfunction, ataxia, and seizure susceptibility in a model of a progressive myoclonus epilepsy

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