Regulation of auditory fear discrimination by the novel Kv3 voltage-gated potassium channel modulator AUT00206

Stubbendorff, C.; Hale, E.; Day, H. L. L.; Smith, J.; Alvaro, G. S.; Large, C. H.; Stevenson, C. W.

doi:10.1101/2021.06.15.448180

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bioRxiv · 10.1101/2021.06.15.448180

Regulation of auditory fear discrimination by the novel Kv3 voltage-gated potassium channel modulator AUT00206

Stubbendorff, C.·Hale, E.·Day, H. L. L.·Smith, J.·Alvaro, G. S.·Large, C. H.·Stevenson, C. W.

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Abstract

Psychiatric diseases like anxiety-related disorders and schizophrenia are characterized by impaired cognition and emotional regulation linked to corticolimbic disinhibition. Restoring the balance between excitation and inhibition in corticolimbic circuits may therefore ameliorate certain features of these disorders, such as inappropriately attributing affective salience to innocuous cues. Corticolimbic activity is tightly controlled by parvalbumin-expressing GABAergic interneurons, which also regulate fear discrimination. The voltage-gated potassium channels Kv3.1 and Kv3.2 are highly expressed in these neurons, therefore Kv3.1/3.2 modulation may have potential for treating disorders associated with cognitive and emotional dysregulation. We determined the effects of the novel Kv3.1/3.2 positive modulator AUT00206 on fear discrimination. Female rats underwent limited or extended auditory fear discrimination training that we previously showed leads to discrimination or generalization, respectively, based on passive fear responding (i.e. freezing). We also assessed darting as an active fear response. We found that limited training resulted in discrimination based on freezing, which was unaffected by AUT00206. In contrast, we found that extended training resulted in generalization based on freezing and the emergence of discrimination based on darting. Importantly, AUT00206 had dissociable effects on fear discrimination and expression with extended training. While AUT00206 mitigated generalization without affecting expression based on freezing, it reduced expression without affecting discrimination based on darting. Our results indicate that Kv3.1/3.2 modulation regulates the attribution of affective significance to threat- and safety-related cues in a response-specific manner. This suggests that targeting Kv3.1 and Kv3.2 channels may provide a promising avenue for treating cognitive and emotional dysregulation in psychiatric disease.

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Stubbendorff, C., Hale, E., Day, H. L. L., Smith, J., Alvaro, G. S., Large, C. H., Stevenson, C. W.. 2021-06-15. Regulation of auditory fear discrimination by the novel Kv3 voltage-gated potassium channel modulator AUT00206. https://doi.org/10.1101/2021.06.15.448180

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