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Implication of Ion Channels in Neurodevelopmental Disorders
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Implication of Ion Channels in Neurodevelopmental Disorders

A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Biochemistry".

Deadline for manuscript submissions: closed (31 July 2022) | Viewed by 18514

Special Issue Editors

Dr. Maria Cristina D’Adamo

E-Mail Website
Guest Editor
School of Medicine and Surgery, LUM-Giuseppe Degennaro University, 70010 Casamassima (Ba), Italy
Interests: Ion channels physiology; Ion channels pharmacology; Ion channel diseases: channelopathies; Autism; Intellectual disability; Epilepsy; Movement disorders, Ataxia; Neurophysiology; Electrophysiology
Dr. Paola Imbrici

E-Mail Website1 Website2
Guest Editor
Dipartimento di Farmacia, Università degli Studi di Bari, Bari, Italy
Interests: Ion channels physiology; Ion channels pharmacology; Ion channel diseases: channelopathies; Autism; Intellectual disability; Epilepsy; Movement disorders, Ataxia; Neurophysiology; Electrophysiology
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

The distinct electrical features of brain cells and their connectivity are fine-tuned by the proper activation of cationic and anionic currents flowing through ion channels and their specific time- and space-dependent expression in inhibitory or excitatory neurons within neuronal circuits. Key neurotransmitters, including dopamine, serotonin, acetylcholine, GABA, and oxytocin, exert their actions by modulating the activity of ion channels also comprising ligand-gated channels. The complex interaction between neurotransmitters, receptors, and ion channels controls neurodevelopment and behavior. During the past few decades, many studies have demonstrated that abnormal ion channel function results in disabilities associated with brain wiring and functioning. Genetic investigations and the functional characterization of mutated channels using homologous and heterologous expression systems, neurons derived from patient-induced pluripotent stem cells (iPSCs) and gene-targeted animal models confirmed the pathogenic relevance of the genetic defect, providing important insights into the cellular mechanisms by which ion channel dysfunction impair neuronal networks. Worldwide, a significant number of children are affected by neurodevelopmental disorders that include autism, attention-deficit/hyperactivity disorder (ADHD), learning and intellectual disability, cerebral palsy, Down syndrome, hyperekplexia (startle disease), epileptic encephalopathy, and leukoencephalopathy. The key architecture of these diseases that could be targeted for treatment remains an uncharted territory regardless of ion channels and G-protein-coupled receptors being the most common drug targets. Thus, new hopes for children exhibiting neurodevelopmental disorders may result from work that broadens the horizons on the causes and identifies new therapeutic options.

In this Special Issue of IJMS, we will assemble a series of reviews or original research articles to provide the most updated platform of knowledge on neurodevelopmental channelopathies, at clinical, genetic, neurophysiological, and pharmacological levels. This shall pave the way for new advances in the field that could greatly benefit prevention, management, and treatment for these devastating childhood illnesses.

Dr. Maria Cristina D’Adamo
Prof. Paola Imbrici
Guest Editors

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Keywords

  • Neurodevelopmental channelopathies
  • Sodium, potassium, calcium, and chloride channels
  • Ligand-gated channels
  • Autism spectrum disorders
  • Attention-deficit/hyperactivity disorder (ADHD)
  • Epileptic encephalopathy
  • Leukoencephalopathy
  • Cerebral palsy
  • Down syndrome
  • Hyperekplexia (Startle Disease)
  • EAST/SeSAME syndrome
  • Intellectual disability
  • Neurodevelopmental delay
  • Pharmacology of ion channels and receptors

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Published Papers (6 papers)

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Research

12 pages, 2206 KiB  
Article
Locus Coeruleus Neurons’ Firing Pattern Is Regulated by ERG Voltage-Gated K+ Channels
by Sonia Hasan, Francis Delicata, Leonardo Guasti, Claudia Duranti, Fatemah Mousalem Haidar, Annarosa Arcangeli, Paola Imbrici, Mauro Pessia, Mario Valentino and Maria Cristina D’Adamo
Int. J. Mol. Sci. 2022, 23(23), 15334; https://doi.org/10.3390/ijms232315334 - 5 Dec 2022
Cited by 3 | Viewed by 2490
Abstract
Locus coeruleus (LC) neurons, with their extensive innervations throughout the brain, control a broad range of physiological processes. Several ion channels have been characterized in LC neurons that control intrinsic membrane properties and excitability. However, ERG (ether-à-go-go–related gene) K+ channels [...] Read more.
Locus coeruleus (LC) neurons, with their extensive innervations throughout the brain, control a broad range of physiological processes. Several ion channels have been characterized in LC neurons that control intrinsic membrane properties and excitability. However, ERG (ether-à-go-go–related gene) K+ channels that are particularly important in setting neuronal firing rhythms and automaticity have not as yet been discovered in the LC. Moreover, the neurophysiological and pathophysiological roles of ERG channels in the brain remain unclear despite their expression in several structures. By performing immunohistochemical investigations, we found that ERG-1A, ERG-1B, ERG-2 and ERG-3 are highly expressed in the LC neurons of mice. To examine the functional role of ERG channels, current-clamp recordings were performed on mouse LC neurons in brain slices under visual control. ERG channel blockade by WAY-123,398, a class III anti-arrhythmic agent, increased the spontaneous firing activity and discharge irregularity of LC neurons. Here, we have shown the presence of distinct ERG channel subunits in the LC which play an imperative role in modulating neuronal discharge patterns. Thus, we propose that ERG channels are important players behind the changes in, and/or maintenance of, LC firing patterns that are implicated in the generation of different behaviors and in several disorders. Full article
(This article belongs to the Special Issue Implication of Ion Channels in Neurodevelopmental Disorders)
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22 pages, 7264 KiB  
Article
Abnormal Expression of Synaptic and Extrasynaptic GABAA Receptor Subunits in the Dystrophin-Deficient mdx Mouse
by Faouzi Zarrouki, Sébastien Goutal, Ophélie Vacca, Luis Garcia, Nicolas Tournier, Aurélie Goyenvalle and Cyrille Vaillend
Int. J. Mol. Sci. 2022, 23(20), 12617; https://doi.org/10.3390/ijms232012617 - 20 Oct 2022
Cited by 4 | Viewed by 2420
Abstract
Duchenne muscular dystrophy (DMD) is a neurodevelopmental disorder primarily caused by the loss of the full-length Dp427 dystrophin in both muscle and brain. The basis of the central comorbidities in DMD is unclear. Brain dystrophin plays a role in the clustering of central [...] Read more.
Duchenne muscular dystrophy (DMD) is a neurodevelopmental disorder primarily caused by the loss of the full-length Dp427 dystrophin in both muscle and brain. The basis of the central comorbidities in DMD is unclear. Brain dystrophin plays a role in the clustering of central gamma-aminobutyric acid A receptors (GABAARs), and its loss in the mdx mouse alters the clustering of some synaptic subunits in central inhibitory synapses. However, the diversity of GABAergic alterations in this model is still fragmentary. In this study, the analysis of in vivo PET imaging of a benzodiazepine-binding site radioligand revealed that the global density of central GABAARs is unaffected in mdx compared with WT mice. In contrast, semi-quantitative immunoblots and immunofluorescence confocal imaging in tissue sections revealed complex and differential patterns of alterations of the expression levels and/or clustered distribution of a variety of synaptic and extrasynaptic GABAAR subunits in the hippocampus, cerebellum, cortex, and spinal cord. Hence, dystrophin loss not only affects the stabilization of synaptic GABAARs but also influences the subunit composition of GABAARs subtypes at both synaptic and extrasynaptic sites. This study provides new molecular outcome measures and new routes to evaluate the impact of treatments aimed at compensating alterations of the nervous system in DMD. Full article
(This article belongs to the Special Issue Implication of Ion Channels in Neurodevelopmental Disorders)
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13 pages, 2265 KiB  
Article
Clinical and Functional Study of a De Novo Variant in the PVP Motif of Kv1.1 Channel Associated with Epilepsy, Developmental Delay and Ataxia
by Giorgia Dinoi, Michael Morin, Elena Conte, Hagar Mor Shaked, Maria Antonietta Coppola, Maria Cristina D’Adamo, Orly Elpeleg, Antonella Liantonio, Inbar Hartmann, Annamaria De Luca, Rikard Blunck, Angelo Russo and Paola Imbrici
Int. J. Mol. Sci. 2022, 23(15), 8079; https://doi.org/10.3390/ijms23158079 - 22 Jul 2022
Cited by 6 | Viewed by 2470
Abstract
Mutations in the KCNA1 gene, encoding the voltage-gated potassium channel Kv1.1, have been associated with a spectrum of neurological phenotypes, including episodic ataxia type 1 and developmental and epileptic encephalopathy. We have recently identified a de novo variant in KCNA1 in the highly [...] Read more.
Mutations in the KCNA1 gene, encoding the voltage-gated potassium channel Kv1.1, have been associated with a spectrum of neurological phenotypes, including episodic ataxia type 1 and developmental and epileptic encephalopathy. We have recently identified a de novo variant in KCNA1 in the highly conserved Pro-Val-Pro motif within the pore of the Kv1.1 channel in a girl affected by early onset epilepsy, ataxia and developmental delay. Other mutations causing severe epilepsy are located in Kv1.1 pore domain. The patient was initially treated with a combination of antiepileptic drugs with limited benefit. Finally, seizures and ataxia control were achieved with lacosamide and acetazolamide. The aim of this study was to functionally characterize Kv1.1 mutant channel to provide a genotype–phenotype correlation and discuss therapeutic options for KCNA1-related epilepsy. To this aim, we transfected HEK 293 cells with Kv1.1 or P403A cDNAs and recorded potassium currents through whole-cell patch-clamp. P403A channels showed smaller potassium currents, voltage-dependent activation shifted by +30 mV towards positive potentials and slower kinetics of activation compared with Kv1.1 wild-type. Heteromeric Kv1.1+P403A channels, resembling the condition of the heterozygous patient, confirmed a loss-of-function biophysical phenotype. Overall, the functional characterization of P403A channels correlates with the clinical symptoms of the patient and supports the observation that mutations associated with severe epileptic phenotype cluster in a highly conserved stretch of residues in Kv1.1 pore domain. This study also strengthens the beneficial effect of acetazolamide and sodium channel blockers in KCNA1 channelopathies. Full article
(This article belongs to the Special Issue Implication of Ion Channels in Neurodevelopmental Disorders)
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30 pages, 4077 KiB  
Article
Translocation of TMEM175 Lysosomal Potassium Channel to the Plasma Membrane by Dynasore Compounds
by Enikő Pergel, Irén Veres, Gergely Imre Csigi and Gábor Czirják
Int. J. Mol. Sci. 2021, 22(19), 10515; https://doi.org/10.3390/ijms221910515 - 29 Sep 2021
Cited by 9 | Viewed by 4117
Abstract
TMEM175 (transmembrane protein 175) coding sequence variants are associated with increased risk of Parkinson’s disease. TMEM175 is the ubiquitous lysosomal K+ channel regulated by growth factor receptor signaling and direct interaction with protein kinase B (PKB/Akt). In the present study, we show [...] Read more.
TMEM175 (transmembrane protein 175) coding sequence variants are associated with increased risk of Parkinson’s disease. TMEM175 is the ubiquitous lysosomal K+ channel regulated by growth factor receptor signaling and direct interaction with protein kinase B (PKB/Akt). In the present study, we show that the expression of mouse TMEM175 results in very small K+ currents through the plasma membrane in Xenopus laevis oocytes, in good accordance with the previously reported intracellular localization of the channel. However, the application of the dynamin inhibitor compounds, dynasore or dyngo-4a, substantially increased TMEM175 currents measured by the two-electrode voltage clamp method. TMEM175 was more permeable to cesium than potassium ions, voltage-dependently blocked by 4-aminopyridine (4-AP), and slightly inhibited by extracellular acidification. Immunocytochemistry experiments indicated that dyngo-4a increased the amount of epitope-tagged TMEM175 channel on the cell surface. The coexpression of dominant-negative dynamin, and the inhibition of clathrin- or caveolin-dependent endocytosis increased TMEM175 current much less than dynasore. Therefore, dynamin-independent pharmacological effects of dynasore may also contribute to the action on the channel. TMEM175 current rapidly decays after the withdrawal of dynasore, raising the possibility that an efficient internalization mechanism removes the channel from the plasma membrane. Dyngo-4a induced about 20-fold larger TMEM175 currents than the PKB activator SC79, or the coexpression of a constitutively active mutant PKB with the channel. In contrast, the allosteric PKB inhibitor MK2206 diminished the TMEM175 current in the presence of dyngo-4a. These data suggest that, in addition to the lysosomes, PKB-dependent regulation also influences TMEM175 current in the plasma membrane. Full article
(This article belongs to the Special Issue Implication of Ion Channels in Neurodevelopmental Disorders)
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13 pages, 3201 KiB  
Article
In Vivo Neocortical [K]o Modulation by Targeted Stimulation of Astrocytes
by Azin EbrahimAmini, Shanthini Mylvaganam, Paolo Bazzigaluppi, Mohamad Khazaei, Alexander Velumian, Bojana Stefanovic and Peter L. Carlen
Int. J. Mol. Sci. 2021, 22(16), 8658; https://doi.org/10.3390/ijms22168658 - 12 Aug 2021
Cited by 3 | Viewed by 2565
Abstract
A normally functioning nervous system requires normal extracellular potassium ion concentration ([K]o). Throughout the nervous system, several processes, including those of an astrocytic nature, are involved in [K]o regulation. In this study we investigated the effect of astrocytic photostimulation on [K]o. We hypothesized [...] Read more.
A normally functioning nervous system requires normal extracellular potassium ion concentration ([K]o). Throughout the nervous system, several processes, including those of an astrocytic nature, are involved in [K]o regulation. In this study we investigated the effect of astrocytic photostimulation on [K]o. We hypothesized that in vivo photostimulation of eNpHR-expressing astrocytes leads to a decreased [K]o. Using optogenetic and electrophysiological techniques we showed that stimulation of eNpHR-expressing astrocytes resulted in a significantly decreased resting [K]o and evoked K responses. The amplitude of the concomitant spreading depolarization-like events also decreased. Our results imply that astrocytic membrane potential modification could be a potential tool for adjusting the [K]o. Full article
(This article belongs to the Special Issue Implication of Ion Channels in Neurodevelopmental Disorders)
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13 pages, 1605 KiB  
Article
KCNK18 Biallelic Variants Associated with Intellectual Disability and Neurodevelopmental Disorders Alter TRESK Channel Activity
by Lisa Pavinato, Ehsan Nematian-Ardestani, Andrea Zonta, Silvia De Rubeis, Joseph Buxbaum, Cecilia Mancini, Alessandro Bruselles, Marco Tartaglia, Mauro Pessia, Stephen J. Tucker, Maria Cristina D’Adamo and Alfredo Brusco
Int. J. Mol. Sci. 2021, 22(11), 6064; https://doi.org/10.3390/ijms22116064 - 4 Jun 2021
Cited by 7 | Viewed by 2826
Abstract
The TWIK-related spinal cord potassium channel (TRESK) is encoded by KCNK18, and variants in this gene have previously been associated with susceptibility to familial migraine with aura (MIM #613656). A single amino acid substitution in the same protein, p.Trp101Arg, has also been [...] Read more.
The TWIK-related spinal cord potassium channel (TRESK) is encoded by KCNK18, and variants in this gene have previously been associated with susceptibility to familial migraine with aura (MIM #613656). A single amino acid substitution in the same protein, p.Trp101Arg, has also been associated with intellectual disability (ID), opening the possibility that variants in this gene might be involved in different disorders. Here, we report the identification of KCNK18 biallelic missense variants (p.Tyr163Asp and p.Ser252Leu) in a family characterized by three siblings affected by mild-to-moderate ID, autism spectrum disorder (ASD) and other neurodevelopment-related features. Functional characterization of the variants alone or in combination showed impaired channel activity. Interestingly, Ser252 is an important regulatory site of TRESK, suggesting that alteration of this residue could lead to additive downstream effects. The functional relevance of these mutations and the observed co-segregation in all the affected members of the family expand the clinical variability associated with altered TRESK function and provide further insight into the relationship between altered function of this ion channel and human disease. Full article
(This article belongs to the Special Issue Implication of Ion Channels in Neurodevelopmental Disorders)
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