Antimanic Efficacy of a Novel Kv3 Potassium Channel Modulator

Abstract

Kv3.1 and Kv3.2 voltage-gated potassium channels are expressed on parvalbumin-positive GABAergic interneurons in corticolimbic brain regions and contribute to high-frequency neural firing. The channels are also expressed on GABAergic neurons of the basal ganglia, substantia nigra, and ventral tegmental area (VTA) where they regulate firing patterns critical for movement control, reward, and motivation. Modulation of Kv3.1 and Kv3.2 channels may therefore have potential in the treatment of disorders in which these systems have been implicated, such as bipolar disorder. Following the recent development of a potassium channel modulator, AUT1-an imidazolidinedione compound that specifically increases currents mediated by Kv3.1 and Kv3.2 channels in recombinant systems-we report that the compound is able to reverse 'manic-like' behavior in two mouse models: amphetamine-induced hyperactivity and ClockΔ19 mutants. AUT1 completely prevented amphetamine-induced hyperactivity in a dose-dependent manner, similar to the atypical antipsychotic, clozapine. Similar efficacy was observed in Kv3.2 knockout mice. In contrast, AUT1 was unable to prevent amphetamine-induced hyperactivity in mice lacking Kv3.1 channels. Notably, Kv3.1-null mice displayed baseline hyperlocomotion, reduced anxiety-like behavior, and antidepressant-like behavior. In ClockΔ19 mice, AUT1 reversed hyperactivity. Furthermore, AUT1 application modulated firing frequency and action potential properties of ClockΔ19 VTA dopamine neurons potentially through network effects. Kv3.1 protein levels in the VTA of ClockΔ19 and WT mice were unaltered by acute AUT1 treatment. Taken together, these results suggest that the modulation of Kv3.1 channels may provide a novel approach to the treatment of bipolar mania.

Prefrontal excitatory/inhibitory balance in stress and emotional disorders: Evidence for over-inhibition

“…The main conclusion currently is that KO females have the lowest anxiety-like behavior and appear resilient to the anxiogenic effects of chronic stress. Low anxiety in Kv3.1 KOs has previously been reported in males (Parekh et al, 2018); these results replicate this observation in females. This study is the first to combine Kv3.1 deficiency with chronic stress.…”

“…The evidence for stress resilience in Kv3.1 KOs supports the hypothesis of overinhibition in stress-induced anxiety. Kv3.1 KO animals have decreased activity of fastspiking interneurons like PV cells and therefore reduced inhibitory signaling (Parekh et al, 2018). We hypothesize, therefore, that this genetic reduction in inhibitory neurotransmission prevents stress-induced over-inhibition and anxiety-like behavior.…”

“…Transgenic mice deficient for the Kv3.1 gene have altered fast-spiking neuron dynamics and show behavioral abnormalities (Ho et al, 1997). Kv3.1-null male mice display hyperlocomotion and decreased anxiety-and depression-like behaviors compared to their wildtype counterparts (Parekh et al, 2018). Interestingly, antidepressants like fluoxetine and paroxetine, which are frequently used to treat anxiety disorders (Feighner, 1999;Davidson, 2004), block the Kv3.1 channel (Sung et al, 2008;Lee et al, 2018).…”

First Evidence of Kv3.1b Potassium Channel Subtype Expression during Neuronal Serotonergic 1C11 Cell Line Development

“…Numerous studies highlighted the growing number of hereditary or acquired diseases with which this channel is associated. Kv3.1 is involved in neurologic epilepsy [ 15 ] and neurodegenerative diseases such as multiple sclerosis [ 16 ] and Alzheimer’s [ 13 ], in cancer tumor hypoxia [ 17 ] and in behavior disorders such as bipolar disorder [ 18 ] and schizophrenia [ 19 ]. Kv3.1 dysfunction was also reported in cases of circadian cycle disturbance, sleep loss [ 20 , 21 ] and depression [ 22 ].…”

The Neurometabolic Basis of Mood Instability: The Parvalbumin Interneuron Link—A Systematic Review and Meta-Analysis

“…This modulation might be therefore a promising therapeutic tool in disorders associated with dysfunctions of inhibitory controls and unstable neuronal excitability, such as affective disorders. Recent pieces of evidence highlighted the potential role of this modulation in MDD and in BPAD, with preclinical studies that demonstrated that reduced K v 3 in PV-INs in the dentate gyrus induced depression phenotypes (Medrihan et al, 2020) and that K v 3.1and K v 3.2-positive modulators are able to reverse and prevent manic behaviors in mouse models (Parekh et al, 2018). For these reasons, K v 3.1-and K v 3.2-positive modulators are now being assessed in clinical trials and appear to be safe for human use (National Library of Medicine (U.S), 2019).…”