MicroRNA inhibition upregulates hippocampal A-type potassium current and reduces seizure frequency in a mouse model of epilepsy

Tiwari, Durgesh; Brager, Darrin H.; Rymer, Jeffrey K.; Bunk, Alexander T.; White, Angela R.; Elsayed, Nada A.; Krzeski, Joseph C.; Snider, Andrew; Carter, Lindsay M. Schroeder; Danzer, Steve C.; Groß, Christina

doi:10.1016/j.nbd.2019.104508

Cited by 36 publications

(63 citation statements)

References 56 publications

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“…The I A is closely involved in many brain diseases (Tiwari et al, ). Neuronal hyperexcitability occurs early in the pathogenesis of Alzheimer's disease due to Kv4.2 channel subunit depletion and a decrease in the I A density (Hall et al, ).…”

Section: Discussionmentioning

confidence: 99%

“…Neuronal hyperexcitability occurs early in the pathogenesis of Alzheimer's disease due to Kv4.2 channel subunit depletion and a decrease in the I A density (Hall et al, ). Recent studies have found that the up‐regulation of I A suppresses neuronal hyperexcitability and reduces seizure frequency in a mouse model of epilepsy (Hu et al, ; Tiwari et al, ). The role of I A in excitotoxicity is not clear.…”

Section: Discussionmentioning

confidence: 99%

“…Auxiliary KChIPs (KChIP1‐4) contain an alternatively spliced N‐terminal domain and a conserved C‐terminal core domain with four EF‐hand‐like calcium binding motifs, which binds to the Kv4 N‐terminus to stabilize channel complexes (Jerng & Pfaffinger, , ; Norris, Foeger, & Nerbonne, ; Wang et al, ). It has been reported that I A is altered in multiple neuronal disorders, such as epilepsy and Alzheimer's disease, and the recovery of the I A may be protective in such disorders (Hall et al, ; Tiwari et al, ). However, the roles of KChIPs in the pathology of neuronal disorders, especially in excitotoxicity, are still unclear.…”

Section: Introductionmentioning

confidence: 99%

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Down‐regulation of miR‐3068‐3p enhances kcnip4‐regulated A‐type potassium current to protect against glutamate‐induced excitotoxicity

Wang

Zhou

et al. 2019

Journal of Neurochemistry

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The main cause of excitotoxic neuronal death in ischemic stroke is the massive release of glutamate. Recently, microRNAs (miRNAs) have been found to play an essential role in stroke pathology, although the molecular mechanisms remain to be investigated. Here, to identify potential candidate miRNAs involved in excitotoxicity, we treated rat primary cortical neurons with glutamate and found that miR‐3068‐3p, a novel miRNA, was up‐regulated. We hypothesized that restoring miR‐3068‐3p expression might influence the neuronal injury outcomes. The inhibition of miR‐3068‐3p, using tough decoy lentiviruses, significantly attenuated the effects of glutamate on neuronal viability and intracellular calcium overload. To unravel the mechanisms, we employed bioinformatics analysis and RNA sequencing to identify downstream target genes. Additional luciferase assays and western blots validated kcnip4, a Kv4‐mediated A‐type potassium current (IA) regulator, as a direct target of miR‐3068‐3p. The inhibition of miR‐3068‐3p increased kcnip4 expression and vice versa. In addition, the knockdown of kcnip4 by shRNA abolished the protective effect of miR‐3068‐3p, and over‐expressing kcnip4 alone was sufficient to play a neuroprotective role in excitotoxicity. Moreover the inhibition of miR‐3068‐3p enhanced the IA density, and the pharmacological inhibition of IA abrogated the protective role of miR‐3068‐3p inhibition and kcnip4 over‐expression. Therefore, we conclude that inhibition of miR‐3068‐3p protects against excitotoxicity via its target gene, kcnip4, and kcnip4‐regulated IA. Our data suggest that the miR‐3068‐3p/kcnip4 axis may serve as a novel target for the treatment of ischemic stroke.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Down‐regulation of miR‐3068‐3p enhances kcnip4‐regulated A‐type potassium current to protect against glutamate‐induced excitotoxicity

Wang

Zhou

et al. 2019

Journal of Neurochemistry

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“…Nowadays, it is also debated that miRNAs can have a nuclear function by modulating gene expression directly at the transcriptional level (reviewed by Catalanotto et al, 2016). Numerous miRNAs have been identified in relation to epilepsy pathogenesis (reviewed by Reschke and Henshall, 2015;Henshall et al, 2016;Shao and Chen, 2017;Tiwari et al, 2018), and also several ion channels appear to be under control of miRNAs, including K v 1.1, K v 4.2, Kcnk10 and Grin2a (Sosanya et al, 2013;Alsharafi et al, 2016;Gross et al, 2016;Haenisch et al, 2016;Tiwari et al, 2019; Table 1).…”

Section: Regulation Of Acquired Ion Channelopathies By Micrornasmentioning

confidence: 99%

Transcriptional Regulation of Channelopathies in Genetic and Acquired Epilepsies

Loo

Becker

2020

Front. Cell. Neurosci.

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Epilepsy is a common neurological disorder characterized by recurrent uncontrolled seizures and has an idiopathic "genetic" etiology or a symptomatic "acquired" component. Genetic studies have revealed that many epilepsy susceptibility genes encode ion channels, including voltage-gated sodium, potassium and calcium channels. The high prevalence of ion channels in epilepsy pathogenesis led to the causative concept of "ion channelopathies," which can be elicited by specific mutations in the coding or promoter regions of genes in genetic epilepsies. Intriguingly, expression changes of the same ion channel genes by augmentation of specific transcription factors (TFs) early after an insult can underlie acquired epilepsies. In this study, we review how the transcriptional regulation of ion channels in both genetic and acquired epilepsies can be controlled, and compare these epilepsy "ion channelopathies" with other neurodevelopmental disorders.

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“…As a consequence, the primary A-type channel expressed in CA1 pyramidal neuron dendrites, Kv4.2, plays an active role in shaping propagation of synaptic input, hippocampal synaptic plasticity, and learning (5,8,(12)(13)(14)(15)(16)(17)(18). Dysregulation of IA has been reported in both animal models and human cases of Alzheimer's disease, epilepsy, and pain sensitization (19)(20)(21)(22)(23)(24)(25)(26). A better understanding of the mechanisms underlying neuronal IA would facilitate the identification of therapeutic targets.…”

Section: Introductionmentioning

confidence: 99%

R-type voltage-gated Ca²⁺channels mediate A-type K⁺current regulation of synaptic input in hippocampal dendrites

Murphy

Gutzmann

Lin

et al. 2020

Preprint

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15The transient voltage-gated K + current (IA) mediated by Kv4.2 in CA1 hippocampal pyramidal 16 neurons regulates dendritic excitability, synaptic plasticity, and learning. Here we report that Ca 2+ 17 entry mediated by the voltage-gated Ca 2+ channel subunit Cav2.3 regulates Kv4.2 function in CA1 18 pyramidal neurons through Ca 2+ binding auxiliary subunits known as K + channel interacting 19 proteins (KChIPs). We characterized an interaction between Cav2.3 and Kv4.2 using 20 immunofluorescence colocalization, coimmunoprecipitation, electron microscopy, FRAP, and 21 FRET. We found that Ca 2+ -entry via Cav2.3 increases Kv4.2-mediated whole-cell current due in 22 part to an increase in Kv4.2 surface expression. In hippocampal neurons, pharmacological block 23 of Cav2.3 reduced whole-cell IA. We also found reduced IA in Cav2.3 knockout mouse neurons 24 with a loss of the dendritic IA gradient. Furthermore, the Cav2.3-Kv4.2 complex was found to 25 regulate the size of synaptic currents and spine Ca 2+ transients. These results reveal an 26 intermolecular Cav2.3-Kv4.2 complex impacting synaptic integration in CA1 hippocampal 27 neurons. 28 29 30 31 32 33 34 93 and Kv4.2 that regulates Kv4.2 function by a novel mechanism. 94 95 96 97 98 99 100 101 4 RESULTS 102 103 Cav2.3 and Kv4.2 form an ion channel complex in hippocampal neurons 104The characteristic kinetics of neuronal IA requires expression of KChIP and DPP 105 accessory subunits that had been identified and described nearly two decades ago (27, 28). In 106 an effort to identify novel Kv4.2 protein interactions and modifying enzymes in hippocampal 107 neurons we used tandem affinity purification (TAP) and protein identification with mass 108 spectrometry (MS) (58). As expected, Kv4.2 pulled down Kv4.1, Kv4.2, Kv4.3, and previously 109 described auxiliary subunits (DPPs and KChIPs) confirming the specificity of the assay (Figure 1110 -Figure supplement 1A). In addition to known binding partners, we also identified peptides 111 representing a significant proportion of the Cav2.3 amino acid sequence (Figure 1 -Figure 112 supplement 1B,C). Cav2.3 was the only voltage-gated Ca 2+ channel identified in this screen.113 To confirm the presence of a hippocampal Cav2.3 and Kv4.2 molecular complex we 114 carried out several immunological measurements using hippocampal tissue. Broad neuropil 115 colocalization of endogenous Cav2.3 and Kv4.2 immunofluorescent signal was consistent with 116 enrichment in the dendrite layers of the hippocampus as has been previously reported for each 117 channel separately (Figure 1A) (51, 59). Both Cav2.3 and Kv4.2 are also known to be expressed 118 in dendrites and spines. To evaluate Cav2.3-Kv4.2 colocalization, we transfected cultured 119 hippocampal neurons with Cav2.3-GFP (i), Kv4.2-myc (ii), and mCherry (iii) plasmids (Figure 1B). 120In addition to immunofluorescent colocalization in dendrites, both channels were enriched in 121 spines when compared to the free cytosolic mCherry fluorescent protein (Figure 1C,D). 122Immunofluorescent...

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MicroRNA inhibition upregulates hippocampal A-type potassium current and reduces seizure frequency in a mouse model of epilepsy

Cited by 36 publications

References 56 publications

Down‐regulation of miR‐3068‐3p enhances kcnip4‐regulated A‐type potassium current to protect against glutamate‐induced excitotoxicity

Down‐regulation of miR‐3068‐3p enhances kcnip4‐regulated A‐type potassium current to protect against glutamate‐induced excitotoxicity

Transcriptional Regulation of Channelopathies in Genetic and Acquired Epilepsies

R-type voltage-gated Ca²⁺channels mediate A-type K⁺current regulation of synaptic input in hippocampal dendrites

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MicroRNA inhibition upregulates hippocampal A-type potassium current and reduces seizure frequency in a mouse model of epilepsy

Cited by 36 publications

References 56 publications

Down‐regulation of miR‐3068‐3p enhances kcnip4‐regulated A‐type potassium current to protect against glutamate‐induced excitotoxicity

Down‐regulation of miR‐3068‐3p enhances kcnip4‐regulated A‐type potassium current to protect against glutamate‐induced excitotoxicity

Transcriptional Regulation of Channelopathies in Genetic and Acquired Epilepsies

R-type voltage-gated Ca2+channels mediate A-type K+current regulation of synaptic input in hippocampal dendrites

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R-type voltage-gated Ca²⁺channels mediate A-type K⁺current regulation of synaptic input in hippocampal dendrites