BK channel blocker paxilline attenuates thalidomide-caused synaptic and cognitive dysfunctions in mice

Choi, Tae-Yong; Lee, Seung–Hyun; Kim, Soo-Jeong; Jo, Youhwa; Park, Chul–Seung; Choi, Se‐Young

doi:10.1038/s41598-018-36367-3

Cited by 9 publications

(10 citation statements)

References 36 publications

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“…Likewise, cerebellar atropy may represent a consequence of seizures rather than a direct effect of channel dysfunction [48]. BK channel function has been implicated in a range of atypical cognitive phenotypes in animal models that could inform observations from patients [49][50][51][52][53][54][55][56]. Furthermore, BK α expression is upregulated in the late embryonic period and early prenatal period [53,57,58], and this is thought to be linked to functional maturation of affected neuronal populations [59].…”

Section: Current Limitations For Genotype-phenotype Analysismentioning

confidence: 99%

An emerging spectrum of variants and clinical features in KCNMA1-linked channelopathy

et al. 2021

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KCNMA1-linked channelopathy is an emerging neurological disorder characterized by heterogeneous and overlapping combinations of movement disorder, seizure, developmental delay, and intellectual disability. KCNMA1 encodes the BK K + channel, which contributes to both excitatory and inhibitory neuronal and muscle activity. Understanding the basis of the disorder is an important area of active investigation; however, the rare prevalence has hampered the development of large patient cohorts necessary to establish genotype-phenotype correlations. In this review, we summarize 37 KCNMA1 alleles from 69 patients currently defining the channelopathy and assess key diagnostic and clinical hallmarks. At present, 3 variants are classified as gain-offunction with respect to BK channel activity, 14 loss-of-function, 15 variants of uncertain significance, and putative benign/VUS. Symptoms associated with these variants were curated from patient-provided information and prior publications to define the spectrum of clinical phenotypes. In this newly expanded cohort, seizures showed no differential distribution between patients harboring GOF and LOF variants, while movement disorders segregated by mutation type. Paroxysmal non-kinesigenic dyskinesia was predominantly observed among patients with GOF alleles of the BK channel, although not exclusively so, while additional movement disorders were observed in patients with LOF variants. Neurodevelopmental and structural brain abnormalities were prevalent in patients with LOF mutations. In contrast to mutations, disease-associated KCNMA1 single nucleotide polymorphisms were not predominantly related to neurological phenotypes but covered a wider set of peripheral physiological functions. Together, this review provides additional evidence exploring the genetic and biochemical basis for KCNMA1-linked channelopathy and summarizes the clinical repository of patient symptoms across multiple types of KCNMA1 gene variants.

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Section: Current Limitations For Genotype-phenotype Analysismentioning

confidence: 99%

An emerging spectrum of variants and clinical features in KCNMA1-linked channelopathy

et al. 2021

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“…This study supports a link between BKCa activity and a specific type of social behavior. Here we chose the dosage defined in the literature which is known to have physiological and behavioral effects in order to demonstrate “proof of concept” regarding BKCa channels, paxilline, and social behavior (Choi, Lee, Kim, Bae, et al, 2018; Choi, Lee, Kim, Jo, et al, 2018; Knaus et al, 1994; Sanchez & McManus, 1996). Paxilline has been considered as a possible therapeutic agent for epilepsy caused by a BKCa gain of function mutation (Du et al, 2005; Sheehan et al, 2009; Shruti et al, 2008).…”

Section: Discussionmentioning

confidence: 99%

“…Paxilline (Sigma-Aldrich, St. Louis, MO) was dissolved to 10 mM in DMSO and then diluted further to 1:2,000 (also in DMSO) (3 μg/kg). This dosage and pretreatment time were chosen based on previous studies which examined physiological and neurological effects of paxilline on behavior (Choi, Lee, Kim, Bae, et al, 2018; Choi, Lee, Kim, Jo, et al, 2018; Knaus et al, 1994; Sanchez & McManus, 1996; Zhou & Lingle, 2014). Animals were assigned to one of two experimental treatment conditions and administered paxilline (3 μg/kg) or vehicle (0.05% DMSO) by intraperitoneal (i.p.)…”

Section: Methodsmentioning

confidence: 99%

“…Therefore, we hypothesized that pharmacological inhibition of these channels may induce behavioral deficits in wildtype mice. To this aim, we used the highly specific BKCa channel blocker paxilline in combination with behavioral tests for anxiety-like, locomotion, and social behaviors to investigate if acute pharmacological inhibition of these channels would produce phenotypes relevant to neurodevelopmental disorders (Choi, Lee, Kim, Bae, et al, 2018; Choi, Lee, Kim, Jo, et al, 2018; Imlach et al, 2008; Sanchez & McManus, 1996; Sheehan et al, 2009; Strøbaek et al, 1996; Wang et al, 2016; Zhou & Lingle, 2014). Due to the relationship to both non-syndromic and syndromic ASD (e.g., FXS) we used two different social behavioral assays to investigate for unique social deficits related to acute paxilline treatment.…”

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confidence: 99%

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Pharmacological inhibition of BKCa channels induces a specific social deficit in adult C57BL6/J mice.

Fyke¹,

Alarcón²,

Velinov³

et al. 2021

Behavioral Neuroscience

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Genetic variants in large conductance voltage and calcium sensitive potassium (BKCa) channels have associations with neurodevelopmental disorders such as autism spectrum disorder, fragile X syndrome, and intellectual disability. In the case of fragile X syndrome, early preclinical studies suggest that BKCa channels may be a promising treatment target for neurodevelopmental disorders. While BKCa channel dysfunction has been investigated within the context of fragile X syndrome, it is unknown whether interference with BKCa channel function is inductive for deficits in behavioral domains relevant to neurodevelopmental disorders. This represents a critical gap in our knowledge regarding the relationship between BKCa dysfunction and neurodevelopmental disorders. To explore this concept, we used the BKCa channel antagonist paxilline to evaluate the role of BKCa channel function in phenotypes of neurodevelopmental disorders. Here we used adult male C57BL/6J mice and a series of behavioral paradigms which assessed anxiety-like behavior, locomotor activity, social behavior, and repetitive self-grooming. We found that acute inhibition with paxilline induced a specific social deficit, but not anxiety-like behavior, or hyperactivity. These findings demonstrate proof-of-concept regarding a relationship between BKCa channel impairment and social behavior. Although this is a limited characterization of the BKCa channel in autistic-like behaviors, it provides evidence for this link. Future studies which examine the effective dose range of paxilline and exhaustive assays of behavior relevant to neurodevelopmental disorders will be needed to delineate the parametric space of the paxilline effect, particularly during critical periods of development, and its potential for therapeutic use.

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“…Thus, the thalidomide-binding and E3 ligase activities of vertebrate CRBN are conserved, but different substrates are recruited for ubiquitination, resulting in species-specific teratogenic effects (27). Thalidomide-sensitive CRBN signaling, such as regulation of AMP-activated protein kinase activity (29) and of calciumactivated potassium channels (30), has also been reported in mice and rats, respectively.…”

mentioning

confidence: 99%

Hypnotic effect of thalidomide is independent of teratogenic ubiquitin/proteasome pathway

Hirose

Kitazono

Sezaki

et al. 2020

Proc. Natl. Acad. Sci. U.S.A.

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Thalidomide exerts its teratogenic and immunomodulatory effects by binding to cereblon (CRBN) and thereby inhibiting/modifying the CRBN-mediated ubiquitination pathway consisting of the Cullin4-DDB1-ROC1 E3 ligase complex. The mechanism of thalidomide’s classical hypnotic effect remains largely unexplored, however. Here we examined whether CRBN is involved in the hypnotic effect of thalidomide by generating mice harboring a thalidomide-resistant mutant allele of Crbn (Crbn YW/AA knock-in mice). Thalidomide increased non-REM sleep time in Crbn YW/AA knock-in homozygotes and heterozygotes to a similar degree as seen in wild-type littermates. Thalidomide similarly depressed excitatory synaptic transmission in the cortical slices obtained from wild-type and Crbn YW/AA homozygous knock-in mice without affecting GABAergic inhibition. Thalidomide induced Fos expression in vasopressin-containing neurons of the supraoptic nucleus and reduced Fos expression in the tuberomammillary nuclei. Thus, thalidomide’s hypnotic effect seems to share some downstream mechanisms with general anesthetics and GABAA-activating sedatives but does not involve the teratogenic CRBN-mediated ubiquitin/proteasome pathway.

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BK channel blocker paxilline attenuates thalidomide-caused synaptic and cognitive dysfunctions in mice

Cited by 9 publications

References 36 publications

An emerging spectrum of variants and clinical features in KCNMA1-linked channelopathy

An emerging spectrum of variants and clinical features in KCNMA1-linked channelopathy

Pharmacological inhibition of BKCa channels induces a specific social deficit in adult C57BL6/J mice.

Hypnotic effect of thalidomide is independent of teratogenic ubiquitin/proteasome pathway

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