Potassium channels and autism spectrum disorder: An overview

Cheng, Peipei; Qiu, Zilong; Du, Yasong

doi:10.1002/jdn.10123

Cited by 24 publications

(12 citation statements)

References 77 publications

(117 reference statements)

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“…Changes in BK channel function and/or KCNMA1 expression are associated with a growing number of neurodevelopmental disorders including epilepsy, dyskinesia, autism, Angelman’s syndrome, Fragile X syndrome, and brain and skeletal malformations ( Cheng et al, 2021 ; Deng and Klyachko, 2016 ; Du et al, 2020 ; Kessi et al, 2020 ; Kshatri et al, 2020 ; Laumonnier et al, 2006 ; Liang et al, 2019 ; Miller et al, 2021 ; N’Gouemo, 2014 ; Sun et al, 2019a ; Sun et al, 2019b ). Neuropathology in these disorders is associated with changes in BK channel activity in both directions.…”

Section: Discussionmentioning

confidence: 99%

BK channel properties correlate with neurobehavioral severity in three KCNMA1-linked channelopathy mouse models

Park

Roache

Iffland

et al. 2022

eLife

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KCNMA1 forms the pore of BK K+ channels, which regulate neuronal and muscle excitability. Recently, genetic screening identified heterozygous KCNMA1 variants in a subset of patients with debilitating paroxysmal non-kinesigenic dyskinesia, presenting with or without epilepsy (PNKD3). However, the relevance of KCNMA1 mutations and the basis for clinical heterogeneity in PNKD3 has not been established. Here, we evaluate the relative severity of three KCNMA1 patient variants in BK channels, neurons, and mice. In heterologous cells, BKN999S and BKD434G channels displayed gain-of-function (GOF) properties, whereas BKH444Q channels showed loss-of-function (LOF) properties. The relative degree of channel activity was BKN999S > BKD434G>WT > BKH444Q. BK currents and action potential firing were increased, and seizure thresholds decreased, in Kcnma1N999S/WT and Kcnma1D434G/WT transgenic mice but not Kcnma1H444Q/WT mice. In a novel behavioral test for paroxysmal dyskinesia, the more severely affected Kcnma1N999S/WT mice became immobile after stress. This was abrogated by acute dextroamphetamine treatment, consistent with PNKD3-affected individuals. Homozygous Kcnma1D434G/D434G mice showed similar immobility, but in contrast, homozygous Kcnma1H444Q/H444Q mice displayed hyperkinetic behavior. These data establish the relative pathogenic potential of patient alleles as N999S>D434G>H444Q and validate Kcnma1N999S/WT mice as a model for PNKD3 with increased seizure propensity.

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Section: Discussionmentioning

confidence: 99%

BK channel properties correlate with neurobehavioral severity in three KCNMA1-linked channelopathy mouse models

Park

Roache

Iffland

et al. 2022

eLife

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“…3e and SM 4). Although none of these genes overlapped with existing PD-risk gene sets, most of them were candidate genes related to autism 37 , dyskinesia 38 , schizophrenia 39 . We speculated that these genes might be involved in the development of PD.…”

Section: Resultsmentioning

confidence: 99%

Defining specific cell states of MPTP-induced Parkinson’s disease by single-nucleus RNA sequencing

Guo

Huang

et al. 2022

Preprint

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Parkinson's disease (PD), a neurodegenerative disease with the impairment of movement execution that is related to age, genetic and environmental factors. 1-methyl-4-phenyl-1,2,3,6-tetrahydropyri-dine (MPTP) is a neurotoxin widely used to induce PD models, but the effect of MPTP on cell-gene of PD has not been fully elucidated. By single-nucleus RNA sequencing, we uncovered the PD-specific cells and revealed remarkable changes in their cellular states, including astrocytosis, endothelial cells absence, as well as a cluster of PD-exclusive medium spiny neuron cells. Furthermore, trajectory analysis of astrocyte and endothelial cells populations predicted candidate target gene sets that might be associated with PD. Notably, the detailed regulatory roles of astrocyte-specific transcription factors Dbx2 and Sox13 in PD were first revealed in our work. Finally, we characterized the cell-cell communications of PD-specific cells and found that the overall communication strength was enhanced in PD compared with matched control, especially the signaling pathways of NRXN and NEGR. Our work provides comprehensive overview on the changes of cellular states of the MPTP-induced mouse brain.

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“…Meanwhile, a growing body of evidence from whole-genome and whole-exome sequencing has suggested a linkage of several ASD susceptibility genes for potassium channels in subjects with ASD. Genetic dysfunction of potassium channels may be involved in the altered neuronal excitability and abnormal brain function in the pathogenesis of ASD [ 72 , 73 ]. In addition, the roles of ribosomal and mitochondria-related activities were also highlighted.…”

Section: Discussionmentioning

confidence: 99%

Amelioration of Maternal Immune Activation-Induced Autism Relevant Behaviors by Gut Commensal Parabacteroides goldsteinii

Lin

Chen

et al. 2022

IJMS

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Autism spectrum disorder (ASD) is characterized by cognitive inflexibility and social deficits. Probiotics have been demonstrated to play a promising role in managing the severity of ASD. However, there are no effective probiotics for clinical use. Identifying new probiotic strains for ameliorating ASD is therefore essential. Using the maternal immune activation (MIA)-based offspring ASD-like mouse model, a probiotic-based intervention strategy was examined in female mice. The gut commensal microbe Parabacteroides goldsteinii MTS01, which was previously demonstrated to exert multiple beneficial effects on chronic inflammation-related-diseases, was evaluated. Prenatal lipopolysaccharide (LPS) exposure induced leaky gut-related inflammatory phenotypes in the colon, increased LPS activity in sera, and induced autistic-like behaviors in offspring mice. By contrast, P. goldsteinii MTS01 treatment significantly reduced intestinal and systemic inflammation and ameliorated disease development. Transcriptomic analyses of MIA offspring indicated that in the intestine, P. goldsteinii MTS01 enhanced neuropeptide-related signaling and suppressed aberrant cell proliferation and inflammatory responses. In the hippocampus, P. goldsteinii MTS01 increased ribosomal/mitochondrial and antioxidant activities and decreased glutamate receptor signaling. Together, significant ameliorative effects of P. goldsteinii MTS01 on ASD relevant behaviors in MIA offspring were identified. Therefore, P. goldsteinii MTS01 could be developed as a next-generation probiotic for ameliorating ASD.

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Potassium channels and autism spectrum disorder: An overview

Cited by 24 publications

References 77 publications

BK channel properties correlate with neurobehavioral severity in three KCNMA1-linked channelopathy mouse models

BK channel properties correlate with neurobehavioral severity in three KCNMA1-linked channelopathy mouse models

Defining specific cell states of MPTP-induced Parkinson’s disease by single-nucleus RNA sequencing

Amelioration of Maternal Immune Activation-Induced Autism Relevant Behaviors by Gut Commensal Parabacteroides goldsteinii

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