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1.
Int J Mol Sci ; 25(16)2024 Aug 09.
Artículo en Inglés | MEDLINE | ID: mdl-39201380

RESUMEN

Based on the pathophysiological changes observed in schizophrenia, the gamma-aminobutyric acid (GABA) hypothesis may facilitate the development of targeted treatments for this disease. This hypothesis, mainly derived from postmortem brain results, postulates dysfunctions in a subset of GABAergic neurons, particularly parvalbumin-containing interneurons. In the cerebral cortex, the fast spike firing of parvalbumin-positive GABAergic interneurons is regulated by the Kv3.1 and Kv3.2 channels, which belong to a potassium channel subfamily. Decreased Kv3.1 levels have been observed in the prefrontal cortex of patients with schizophrenia, prompting the investigation of Kv3 channel modulators for the treatment of schizophrenia. However, biomarkers that capture the dysfunction of parvalbumin neurons are required for these modulators to be effective in the pharmacotherapy of schizophrenia. Electroencephalography and magnetoencephalography studies have demonstrated impairments in evoked gamma oscillations in patients with schizophrenia, which may reflect the dysfunction of cortical parvalbumin neurons. This review summarizes these topics and provides an overview of how the development of therapeutics that incorporate biomarkers could innovate the treatment of schizophrenia and potentially change the targets of pharmacotherapy.


Asunto(s)
Parvalbúminas , Esquizofrenia , Canales de Potasio Shaw , Esquizofrenia/metabolismo , Esquizofrenia/tratamiento farmacológico , Esquizofrenia/fisiopatología , Humanos , Parvalbúminas/metabolismo , Canales de Potasio Shaw/metabolismo , Animales , Neuronas GABAérgicas/metabolismo , Neuronas GABAérgicas/efectos de los fármacos , Interneuronas/metabolismo
2.
Aging Cell ; 23(8): e14185, 2024 Aug.
Artículo en Inglés | MEDLINE | ID: mdl-38725150

RESUMEN

The voltage-gated Kv3.1/KCNC1 channel is abundantly expressed in fast-spiking principal neurons and GABAergic inhibitory interneurons throughout the ascending auditory pathway and in various brain regions. Inactivating mutations in the KCNC1 gene lead to forms of epilepsy and a decline in the expression of the Kv3.1 channel is involved in age-related hearing loss. As oxidative stress plays a fundamental role in the pathogenesis of epilepsy and age-related hearing loss, we hypothesized that an oxidative insult might affect the function of this channel. To verify this hypothesis, the activity and expression of endogenous and ectopic Kv3.1 were measured in models of oxidative stress-related aging represented by cell lines exposed to 100 mM d-galactose. In these models, intracellular reactive oxygen species, thiobarbituric acid reactive substances, sulfhydryl groups of cellular proteins, and the activity of catalase and superoxide dismutase were dysregulated, while the current density of Kv3.1 was significantly reduced. Importantly, the antioxidant melatonin reverted all these effects. The reduction of function of Kv3.1 was not determined by direct oxidation of amino acid side chains of the protein channel or reduction of transcript or total protein levels but was linked to reduced trafficking to the cell surface associated with Src phosphorylation as well as metabolic and endoplasmic reticulum stress. The data presented here specify Kv3.1 as a novel target of oxidative stress and suggest that Kv3.1 dysfunction might contribute to age-related hearing loss and increased prevalence of epilepsy during aging. The pharmacological use of the antioxidant melatonin can be protective in this setting.


Asunto(s)
Senescencia Celular , Melatonina , Estrés Oxidativo , Estrés Oxidativo/efectos de los fármacos , Humanos , Melatonina/farmacología , Melatonina/metabolismo , Senescencia Celular/efectos de los fármacos , Canales de Potasio Shaw/metabolismo , Canales de Potasio Shaw/genética , Animales , Especies Reactivas de Oxígeno/metabolismo , Antioxidantes/farmacología , Antioxidantes/metabolismo , Ratones
3.
BMC Neurol ; 24(1): 169, 2024 May 23.
Artículo en Inglés | MEDLINE | ID: mdl-38783211

RESUMEN

BACKGROUND: Progressive Myoclonic Epilepsy (PME) is a group of rare diseases that are difficult to differentiate from one another based on phenotypical characteristics. CASE REPORT: We report a case of PME type 7 due to a pathogenic variant in KCNC1 with myoclonus improvement after epileptic seizures. DISCUSSION: Myoclonus improvement after seizures may be a clue to the diagnosis of Progressive Myoclonic Epilepsy type 7.


Asunto(s)
Epilepsias Mioclónicas Progresivas , Convulsiones , Humanos , Epilepsias Mioclónicas Progresivas/complicaciones , Epilepsias Mioclónicas Progresivas/diagnóstico , Convulsiones/diagnóstico , Convulsiones/complicaciones , Convulsiones/etiología , Convulsiones/tratamiento farmacológico , Mioclonía/diagnóstico , Mioclonía/etiología , Mioclonía/complicaciones , Mioclonía/tratamiento farmacológico , Masculino , Canales de Potasio Shaw/genética , Femenino , Electroencefalografía/métodos
4.
Nat Commun ; 15(1): 2533, 2024 Mar 21.
Artículo en Inglés | MEDLINE | ID: mdl-38514618

RESUMEN

Small-molecule modulators of diverse voltage-gated K+ (Kv) channels may help treat a wide range of neurological disorders. However, developing effective modulators requires understanding of their mechanism of action. We apply an orthogonal approach to elucidate the mechanism of action of an imidazolidinedione derivative (AUT5), a highly selective positive allosteric modulator of Kv3.1 and Kv3.2 channels. AUT5 modulation involves positive cooperativity and preferential stabilization of the open state. The cryo-EM structure of the Kv3.1/AUT5 complex at a resolution of 2.5 Å reveals four equivalent AUT5 binding sites at the extracellular inter-subunit interface between the voltage-sensing and pore domains of the channel's tetrameric assembly. Furthermore, we show that the unique extracellular turret regions of Kv3.1 and Kv3.2 essentially govern the selective positive modulation by AUT5. High-resolution apo and bound structures of Kv3.1 demonstrate how AUT5 binding promotes turret rearrangements and interactions with the voltage-sensing domain to favor the open conformation.


Asunto(s)
Canales de Potasio Shaw , Sitios de Unión , Canales de Potasio Shaw/metabolismo
5.
Proc Natl Acad Sci U S A ; 121(3): e2307776121, 2024 Jan 16.
Artículo en Inglés | MEDLINE | ID: mdl-38194456

RESUMEN

De novo heterozygous variants in KCNC2 encoding the voltage-gated potassium (K+) channel subunit Kv3.2 are a recently described cause of developmental and epileptic encephalopathy (DEE). A de novo variant in KCNC2 c.374G > A (p.Cys125Tyr) was identified via exome sequencing in a patient with DEE. Relative to wild-type Kv3.2, Kv3.2-p.Cys125Tyr induces K+ currents exhibiting a large hyperpolarizing shift in the voltage dependence of activation, accelerated activation, and delayed deactivation consistent with a relative stabilization of the open conformation, along with increased current density. Leveraging the cryogenic electron microscopy (cryo-EM) structure of Kv3.1, molecular dynamic simulations suggest that a strong π-π stacking interaction between the variant Tyr125 and Tyr156 in the α-6 helix of the T1 domain promotes a relative stabilization of the open conformation of the channel, which underlies the observed gain of function. A multicompartment computational model of a Kv3-expressing parvalbumin-positive cerebral cortex fast-spiking γ-aminobutyric acidergic (GABAergic) interneuron (PV-IN) demonstrates how the Kv3.2-Cys125Tyr variant impairs neuronal excitability and dysregulates inhibition in cerebral cortex circuits to explain the resulting epilepsy.


Asunto(s)
Epilepsia , Canales de Potasio Shaw , Humanos , Canales de Potasio Shaw/genética , Interneuronas , Corteza Cerebral , Epilepsia/genética , Mutación
6.
Int J Mol Sci ; 25(2)2024 Jan 17.
Artículo en Inglés | MEDLINE | ID: mdl-38256219

RESUMEN

Developmental and epileptic encephalopathies (DEE) are severe neurodevelopmental disorders characterized by recurrent, usually early-onset, epileptic seizures accompanied by developmental impairment often related to both underlying genetic etiology and abnormal epileptiform activity. Today, next-generation sequencing technologies (NGS) allow us to sequence large portions of DNA quickly and with low costs. The aim of this study is to evaluate the use of whole-exome sequencing (WES) as a first-line molecular genetic test in a sample of subjects with DEEs characterized by early-onset drug-resistant epilepsies, associated with global developmental delay and/or intellectual disability (ID). We performed 82 WESs, identifying 35 pathogenic variants with a detection rate of 43%. The identified variants were highlighted on 29 different genes including, 3 new candidate genes (KCNC2, STXBP6, DHRS9) for DEEs never identified before. In total, 23 out of 35 (66%) de novo variants were identified. The most frequently identified type of inheritance was autosomal dominant de novo (60%) followed by autosomal recessive in homozygosity (17%) and heterozygosity (11%), autosomal dominant inherited from parental mosaicism (6%) and X-linked dominant de novo (6%). The most frequent mutations identified were missense (75%) followed by frameshift deletions (16%), frameshift duplications (5%), and splicing mutations (3%). Considering the results obtained in the present study we support the use of WES as a form of first-line molecular genetic testing in DEEs.


Asunto(s)
Epilepsia Generalizada , Trastornos del Neurodesarrollo , Humanos , Secuenciación del Exoma , Mosaicismo , Biología Molecular , Canales de Potasio Shaw
7.
Neuroscience ; 538: 68-79, 2024 Feb 06.
Artículo en Inglés | MEDLINE | ID: mdl-38157976

RESUMEN

Inhibitory parvalbumin (PV) interneurons regulate the activity of neural circuits within brain regions involved in emotional processing, including the prefrontal cortex (PFC). Recently, rodent studies have implicated a stress-induced increase in prefrontal PV neuron activity in the development of anxiety behaviors, particularly in females. However, the mechanisms through which stress increases activity of prefrontal PV neurons remain unknown. The fast-spiking properties of PV neurons in part come from their expression of voltage-gated potassium (K+) ion channels, particularly Kv3.1 channels. We therefore suggest that stress-induced changes in Kv3.1 channels contribute to the appearance of an anxious phenotype following chronic stress in female mice. Here, we first showed that unpredictable chronic mild stress (UCMS) increased expression of Kv3.1 channels on prefrontal PV neurons in female mice, a potential mechanism underlying the previously observed hyperactivity of these neurons after stress. We then showed that female mice deficient in Kv3.1 channels displayed resilience to UCMS-induced anxiety-like behaviors. Altogether, our findings implicate Kv3.1 channels in the development of anxiety-like behaviors following UCMS, particularly in females, providing a novel mechanism to understand sex-specific vulnerabilities to stress-induced psychopathologies.


Asunto(s)
Canales de Potasio con Entrada de Voltaje , Masculino , Ratones , Femenino , Animales , Canales de Potasio con Entrada de Voltaje/metabolismo , Neuronas/metabolismo , Interneuronas/metabolismo , Encéfalo/metabolismo , Ansiedad/metabolismo , Canales de Potasio Shaw/metabolismo
8.
Mol Psychiatry ; 28(9): 3994-4010, 2023 Sep.
Artículo en Inglés | MEDLINE | ID: mdl-37833406

RESUMEN

The pathogenesis of schizophrenia is believed to involve combined dysfunctions of many proteins including microtubule-associated protein 6 (MAP6) and Kv3.1 voltage-gated K+ (Kv) channel, but their relationship and functions in behavioral regulation are often not known. Here we report that MAP6 stabilizes Kv3.1 channels in parvalbumin-positive (PV+ ) fast-spiking GABAergic interneurons, regulating behavior. MAP6-/- and Kv3.1-/- mice display similar hyperactivity and avoidance reduction. Their proteins colocalize in PV+ interneurons and MAP6 deletion markedly reduces Kv3.1 protein level. We further show that two microtubule-binding modules of MAP6 bind the Kv3.1 tetramerization domain with high affinity, maintaining the channel level in both neuronal soma and axons. MAP6 knockdown by AAV-shRNA in the amygdala or the hippocampus reduces avoidance or causes hyperactivity and recognition memory deficit, respectively, through elevating projection neuron activity. Finally, knocking down Kv3.1 or disrupting the MAP6-Kv3.1 binding in these brain regions causes avoidance reduction and hyperactivity, consistent with the effects of MAP6 knockdown. Thus, disrupting this conserved cytoskeleton-membrane interaction in fast-spiking neurons causes different degrees of functional vulnerability in various neural circuits.


Asunto(s)
Neuronas , Canales de Potasio con Entrada de Voltaje , Ratones , Animales , Neuronas/metabolismo , Canales de Potasio con Entrada de Voltaje/farmacología , Citoesqueleto/metabolismo , Microtúbulos/metabolismo , Emociones , Canales de Potasio Shaw/metabolismo
9.
J Transl Med ; 21(1): 628, 2023 09 15.
Artículo en Inglés | MEDLINE | ID: mdl-37715200

RESUMEN

BACKGROUND: Owing to the heterogeneity of Alzheimer's disease (AD), its pathogenic mechanisms are yet to be fully elucidated. Evidence suggests an important role of metabolism in the pathophysiology of AD. Herein, we identified the metabolism-related AD subtypes and feature genes. METHODS: The AD datasets were obtained from the Gene Expression Omnibus database and the metabolism-relevant genes were downloaded from a previously published compilation. Consensus clustering was performed to identify the AD subclasses. The clinical characteristics, correlations with metabolic signatures, and immune infiltration of the AD subclasses were evaluated. Feature genes were screened using weighted correlation network analysis (WGCNA) and processed via Gene Ontology and Kyoto Encyclopedia of Genes and Genomes pathway analyses. Furthermore, three machine-learning algorithms were used to narrow down the selection of the feature genes. Finally, we identified the diagnostic value and expression of the feature genes using the AD dataset and quantitative reverse-transcription polymerase chain reaction (qRT-PCR) analysis. RESULTS: Three AD subclasses were identified, namely Metabolism Correlated (MC) A (MCA), MCB, and MCC subclasses. MCA contained signatures associated with high AD progression and may represent a high-risk subclass compared with the other two subclasses. MCA exhibited a high expression of genes related to glycolysis, fructose, and galactose metabolism, whereas genes associated with the citrate cycle and pyruvate metabolism were downregulated and associated with high immune infiltration. Conversely, MCB was associated with citrate cycle genes and exhibited elevated expression of immune checkpoint genes. Using WGCNA, 101 metabolic genes were identified to exhibit the strongest association with poor AD progression. Finally, the application of machine-learning algorithms enabled us to successfully identify eight feature genes, which were employed to develop a nomogram model that could bring distinct clinical benefits for patients with AD. As indicated by the AD datasets and qRT-PCR analysis, these genes were intimately associated with AD progression. CONCLUSION: Metabolic dysfunction is associated with AD. Hypothetical molecular subclasses of AD based on metabolic genes may provide new insights for developing individualized therapy for AD. The feature genes highly correlated with AD progression included GFAP, CYB5R3, DARS, KIAA0513, EZR, KCNC1, COLEC12, and TST.


Asunto(s)
Enfermedad de Alzheimer , Humanos , Enfermedad de Alzheimer/genética , Algoritmos , Citratos , Ácido Cítrico , Análisis por Conglomerados , Canales de Potasio Shaw , Proteínas del Tejido Nervioso
10.
Elife ; 122023 05 09.
Artículo en Inglés | MEDLINE | ID: mdl-37158590

RESUMEN

Complex motor skills in vertebrates require specialized upper motor neurons with precise action potential (AP) firing. To examine how diverse populations of upper motor neurons subserve distinct functions and the specific repertoire of ion channels involved, we conducted a thorough study of the excitability of upper motor neurons controlling somatic motor function in the zebra finch. We found that robustus arcopallialis projection neurons (RAPNs), key command neurons for song production, exhibit ultranarrow spikes and higher firing rates compared to neurons controlling non-vocal somatic motor functions (dorsal intermediate arcopallium [AId] neurons). Pharmacological and molecular data indicate that this striking difference is associated with the higher expression in RAPNs of high threshold, fast-activating voltage-gated Kv3 channels, that likely contain Kv3.1 (KCNC1) subunits. The spike waveform and Kv3.1 expression in RAPNs mirror properties of Betz cells, specialized upper motor neurons involved in fine digit control in humans and other primates but absent in rodents. Our study thus provides evidence that songbirds and primates have convergently evolved the use of Kv3.1 to ensure precise, rapid AP firing in upper motor neurons controlling fast and complex motor skills.


Asunto(s)
Corteza Motora , Canales de Potasio con Entrada de Voltaje , Pájaros Cantores , Animales , Potenciales de Acción/fisiología , Interneuronas , Neuronas Motoras , Canales de Potasio Shaw
11.
Int J Dev Neurosci ; 83(4): 357-367, 2023 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-37203270

RESUMEN

The KCNC2 gene encodes Kv3.2, which is a member of the voltage-gated potassium channel subfamily. It is crucial for the generation of fast-spiking properties in cortical GABAergic interneurons. Recently, KCNC2 variations were found to be associated with epileptic encephalopathy in unrelated individuals. Here, we report a Chinese patient with developmental and epileptic encephalopathy (DEE) and motor development delay. Whole-exome sequencing (WES) revealed a novel heterozygous variant in the KCNC2 gene NM_139137.4:c.1163T>C (p.Phe388Ser), and subsequent Sanger sequencing showed that it was a de novo mutation. We identified the KCNC2 likely pathogenic variant in a DEE patient by reanalysis of WES data in a Chinese family. Our study enriched the variation spectrum of the KCNC2 gene and promoted the application of WES technology and data reanalysis in the diagnosis of epilepsy.


Asunto(s)
Epilepsia , Trastornos de la Destreza Motora , Humanos , Epilepsia/genética , Epilepsia/complicaciones , Pueblo Asiatico , Trastornos de la Destreza Motora/complicaciones , Secuenciación del Exoma , Canales de Potasio Shaw/genética
12.
Chem Biol Drug Des ; 102(1): 88-100, 2023 07.
Artículo en Inglés | MEDLINE | ID: mdl-36977503

RESUMEN

The objective of this study was to analyze potential targets of metformin against ovarian cancer (OC) through network pharmacology. Pharmacodynamic targets of metformin were predicted using the Bioinformatics Analysis Tool for the molecular mechanism of traditional Chinese medicine (BATMAN), Drugbank, PharmMapper, SwissTargetPrediction, and TargetNet databases. R was utilized to analyze the gene expression of OC tissues, normal/adjacent noncancerous tissues, and screen differentially expressed genes (DEGs) in the Gene Expression Omnibus (GEO) and the Cancer Genome Atlas (TCGA) + Genotype-Tissue Expression (GTEx) datasets. STRING 11.0 was utilized to explore the protein-protein interaction (PPI) of metformin target genes differentially expressed in OC. Cytoscape 3.8.0 was used to construct the network and screen the core targets. Additionally, gene ontology (GO) annotation and enrichment and the Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis were performed for the common targets of metformin and OC through the DAVID 6.8 database. A total of 95 potential common targets of metformin and OC were identified from the intersection of 255 potential pharmacodynamic targets of metformin and 10,463 genes associated with OC. Furthermore, 10 core targets were screened from the PPI network [e.g., interleukin (IL) 1B, KCNC1, ESR1, HTR2C, MAOB, GRIN2A, F2, GRIA2, APOE, PTPRC]. In addition, it was shown in GO enrichment analysis that the common targets were mainly associated with biological processes (i.e., response to stimuli or chemical, cellular processes, and transmembrane transport), cellular components (i.e., plasma membrane, cell junction, and cell projection), and molecular functions (i.e., binding, channel activities, transmembrane transporter activity, and signaling receptor activities). Furthermore, it was indicated by KEGG pathway analysis that the common targets were enriched in metabolic pathways. The critical molecular targets and molecular pathways of metformin against OC were preliminarily determined by bioinformatics-based network pharmacology analysis, providing a basis, and reference for further experimental studies.


Asunto(s)
Medicamentos Herbarios Chinos , Neoplasias Ováricas , Femenino , Humanos , Farmacología en Red , Neoplasias Ováricas/tratamiento farmacológico , Neoplasias Ováricas/genética , Transporte Biológico , Membrana Celular , Biología Computacional , Simulación del Acoplamiento Molecular , Canales de Potasio Shaw
13.
Ann Clin Transl Neurol ; 10(1): 111-117, 2023 01.
Artículo en Inglés | MEDLINE | ID: mdl-36419348

RESUMEN

OBJECTIVE: To further clarify genotype:phenotype correlations associated with variants in KCNC1 encoding the voltage-gated potassium (K+) channel subunit Kv3.1 and which are an emerging cause of a spectrum of neurological disease including intellectual disability, isolated myoclonus, progressive myoclonus epilepsy, and developmental and epileptic encephalopathy. METHODS: We describe the clinical and genetic characteristics of a series of three patients with de novo heterozygous missense variants in KCNC1 associated with nonspecific developmental delay/intellectual disability and central hypotonia without epilepsy or ataxia. All three variants lead to amino acids alterations with mild predicted differences in physicochemical properties yet are localized to the S6 pore region of the Kv3.1 protein between the selectivity filter and PXP motif important for K+ channel gating. We performed whole-cell voltage clamp electrophysiological recording of wild-type versus variants in a heterologous mammalian expression system. RESULTS: We demonstrate a prominent leftward (hyperpolarized) shift in the voltage dependence of activation and slowed deactivation of all variants in the clinically defined series. INTERPRETATION: Electrophysiological recordings are consistent with a gain of K+ channel function that is predicted to exert a loss of function on the excitability of Kv3-expressing high frequency- firing neurons based on the unique electrophysiological properties of Kv3 channels. These results define a clinical-genetic syndrome within the spectrum of KCNC1-related neurological disorders.


Asunto(s)
Epilepsia , Discapacidad Intelectual , Epilepsias Mioclónicas Progresivas , Canales de Potasio Shaw , Animales , Ataxia/genética , Epilepsia/genética , Discapacidad Intelectual/genética , Mamíferos , Mutación Missense , Epilepsias Mioclónicas Progresivas/genética , Canales de Potasio Shaw/genética , Síndrome
14.
Food Chem Toxicol ; 171: 113540, 2023 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-36460224

RESUMEN

Raspberry ketone (RK; [4-(4-hydroxyphenyl)-2-butanone]) is a synthetic flavoring agent and dietary supplement for weight control. This study investigated the metabolic signature of oral doses of RK that prevent weight gain or promote loss of righting reflex (LORR) in C57Bl/6J mice. Daily RK 200 mg/kg prevented high-fat diet (HFD; 45% Kcal fat) fed weight gain (∼8% reduction) over 35 days. RNA-seq of inguinal white adipose tissue (WAT) performed in males revealed 12 differentially expressed genes. Apelin (Apln) and potassium voltage-gated channel subfamily C member (Kcnc3) expression were elevated with HFD and normalized with RK dosing, which was confirmed by qPCR. Acute RK 640 mg/kg produced a LORR with a <5 min onset with a >30 min duration. Acute RK 200 mg/kg increased gene expression of Apln, Kcnc3, and nuclear factor erythroid 2-related factor 2 (Nrf2), but reduced acetyl-COA carboxylase (Acc1) and NAD(P)H quinone dehydrogenase 1 (Nqo1) in inguinal WAT. Acute RK 640 mg/kg elevated interleukin 6 (Il 6) and heme oxygenase 1 (Hmox1) expression, but reduced Nrf2 in inguinal and epididymal WAT. Our findings suggest that RK has a dose-dependent metabolic signature in WAT associated with either weight control or LORR.


Asunto(s)
Factor 2 Relacionado con NF-E2 , Aumento de Peso , Ratones , Masculino , Animales , Factor 2 Relacionado con NF-E2/metabolismo , Reflejo de Enderezamiento , Tejido Adiposo Blanco/metabolismo , Dieta Alta en Grasa , Ratones Endogámicos C57BL , Canales de Potasio Shaw/metabolismo
15.
Acta Neurol Scand ; 146(6): 699-707, 2022 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-36225112

RESUMEN

With the development and application of next-generation sequencing technology, the aetiological diagnosis of genetic epilepsy is rapidly becoming easier and less expensive. Additionally, there is a growing body of research into precision therapy based on genetic diagnosis. The numerous genes in the potassium ion channel family constitute the largest family of ion channels: this family is divided into different subtypes. Potassium ion channels play a crucial role in the electrical activity of neurons and are directly involved in the mechanism of epileptic seizures. In China, scientific research on genetic diagnosis and studies of precision therapy for genetic epilepsy are progressing rapidly. Many cases of epilepsy caused by mutation of potassium channel genes have been identified, and several potassium channel gene targets and drug candidates have been discovered. The purpose of this review is to briefly summarize the progress of research on the precise diagnosis and treatment of potassium ion channel-related genetic epilepsy, especially the research conducted in China. Here in, we review several large cohort studies on the genetic diagnosis of epilepsy in China in recent years, summarized the proportion of potassium channel genes. We focus on the progress of precison therapy on some hot epilepsy related potassium channel genes: KCNA1, KCNA2, KCNB1, KCNC1, KCND2, KCNQ2, KCNQ3, KCNMA1, and KCNT1.


Asunto(s)
Epilepsia , Canales de Potasio , Humanos , Canales de Potasio/genética , Canal de Potasio KCNQ3/genética , Canal de Potasio KCNQ2/genética , Epilepsia/diagnóstico , Epilepsia/genética , Mutación/genética , Canales de Potasio Shaw/genética , Canales de potasio activados por Sodio/genética , Proteínas del Tejido Nervioso/genética
16.
Seizure ; 101: 218-224, 2022 Oct.
Artículo en Inglés | MEDLINE | ID: mdl-36087422

RESUMEN

Purpose The voltage-gated potassium channel Kv3.2, encoded by KCNC2, facilitates fast-spiking GABAergic interneurons to fire action potentials at high frequencies. It is pivotal to maintaining excitation/inhibition balance in mammalian brains. This study identified two novel de novo KCNC2 variants, p.Pro470Ser (P470S) and p.Phe382Leu (F382L), in patients with early onset developmental and epileptic encephalopathy (DEE). Methods To examine the molecular basis of DEE, we studied the functional characteristics of variant channels using patch-clamp techniques and computational modeling. Results Whole-cell patch clamp recordings from infected HEK293 cells revealed that channel activation and deactivation kinetics strongly decreased in both Kv3.2 P470S and F382L variant channels. This decrease also occurred in Kv3.2 p.Val471Leu (V471L) channels, known to be associated with DEE. In addition, Kv3.2 F382L and V471L variants exhibited a significant increase in channel conductance and a ∼20 mV negative shift in the threshold for voltage-dependent activation. Simulations of model GABAergic interneurons revealed that all variants decreased neuronal firing frequency. Thus, the variants' net loss-of-function effects disinhibited neural networks. Conclusion Our findings provide compelling evidence supporting the role of KCNC2 as a disease-causing gene in human neurodevelopmental delay and epilepsy.


Asunto(s)
Encefalopatías , Canales de Potasio con Entrada de Voltaje , Potenciales de Acción/genética , Animales , Células HEK293 , Humanos , Mamíferos , Técnicas de Placa-Clamp , Canales de Potasio con Entrada de Voltaje/farmacología , Canales de Potasio Shaw/genética
17.
Psychopharmacology (Berl) ; 239(10): 3313-3323, 2022 Oct.
Artículo en Inglés | MEDLINE | ID: mdl-36094619

RESUMEN

The pathophysiology of schizophrenia involves abnormal reward processing, thought to be due to disrupted striatal and dopaminergic function. Consistent with this hypothesis, functional magnetic resonance imaging (fMRI) studies using the monetary incentive delay (MID) task report hypoactivation in the striatum during reward anticipation in schizophrenia. Dopamine neuron activity is modulated by striatal GABAergic interneurons. GABAergic interneuron firing rates, in turn, are related to conductances in voltage-gated potassium 3.1 (Kv3.1) and 3.2 (Kv3.2) channels, suggesting that targeting Kv3.1/3.2 could augment striatal function during reward processing. Here, we studied the effect of a novel potassium Kv3.1/3.2 channel modulator, AUT00206, on striatal activation in patients with schizophrenia, using the MID task. Each participant completed the MID during fMRI scanning on two occasions: once at baseline, and again following either 4 weeks of AUT00206 or placebo treatment. We found a significant inverse relationship at baseline between symptom severity and reward anticipation-related neural activation in the right associative striatum (r = -0.461, p = 0.035). Following treatment with AUT00206, there was a significant increase in reward anticipation-related activation in the left associative striatum (t(13) = 4.23, peak-level p(FWE) < 0.05)), but no significant effect in the ventral striatum. This provides preliminary evidence that the Kv3.1/3.2 potassium channel modulator, AUT00206, may address reward-related striatal abnormalities in schizophrenia.


Asunto(s)
Esquizofrenia , Estriado Ventral , Humanos , Imagen por Resonancia Magnética , Recompensa , Esquizofrenia/diagnóstico por imagen , Esquizofrenia/tratamiento farmacológico , Canales de Potasio Shaw , Estriado Ventral/fisiología
18.
J Psychopharmacol ; 36(9): 1061-1069, 2022 Sep.
Artículo en Inglés | MEDLINE | ID: mdl-36164687

RESUMEN

BACKGROUND: Current treatments for schizophrenia act directly on dopamine (DA) receptors but are ineffective for many patients, highlighting the need to develop new treatment approaches. Striatal DA dysfunction, indexed using [18F]-FDOPA imaging, is linked to the pathoetiology of schizophrenia. We evaluated the effect of a novel drug, AUT00206, a Kv3.1/3.2 potassium channel modulator, on dopaminergic function in schizophrenia and its relationship with symptom change. Additionally, we investigated the test-retest reliability of [18F]-FDOPA PET in schizophrenia to determine its potential as a biomarker for drug discovery. METHODS: Twenty patients with schizophrenia received symptom measures and [18F]-FDOPA PET scans, before and after being randomised to AUT00206 or placebo groups for up to 28 days treatment. RESULTS: AUT00206 had no significant effect on DA synthesis capacity. However, there was a correlation between reduction in striatal dopamine synthesis capacity (indexed as Kicer) and reduction in symptoms, in the AUT00206 group (r = 0.58, p = 0.03). This was not observed in the placebo group (r = -0.15, p = 0.75), although the placebo group may have been underpowered to detect an effect. The intraclass correlation coefficients of [18F]-FDOPA indices in the placebo group ranged from 0.83 to 0.93 across striatal regions. CONCLUSIONS: The relationship between reduction in DA synthesis capacity and improvement in symptoms in the AUT00206 group provides evidence for a pharmacodynamic effect of the Kv3 channel modulator. The lack of a significant overall reduction in DA synthesis capacity in the AUT00206 group could be due to variability and the low number of subjects in this study. These findings support further investigation of Kv3 channel modulators for schizophrenia treatment. [18F]-FDOPA PET imaging showed very good test-retest reliability in patients with schizophrenia.


Asunto(s)
Dopamina , Esquizofrenia , Biomarcadores , Cuerpo Estriado/diagnóstico por imagen , Dihidroxifenilalanina/farmacología , Dihidroxifenilalanina/uso terapéutico , Dopamina/farmacología , Humanos , Tomografía de Emisión de Positrones/métodos , Canales de Potasio/farmacología , Canales de Potasio/uso terapéutico , Reproducibilidad de los Resultados , Esquizofrenia/diagnóstico por imagen , Esquizofrenia/tratamiento farmacológico , Canales de Potasio Shaw
19.
Neuropsychopharmacology ; 47(12): 2071-2080, 2022 11.
Artículo en Inglés | MEDLINE | ID: mdl-35995972

RESUMEN

During adolescence, frequent and heavy cannabis use can lead to serious adverse health effects and cannabis use disorder (CUD). Rodent models of adolescent exposure to the main psychoactive component of cannabis, delta-9-tetrahydrocannabinol (THC), mimic the behavioral alterations observed in adolescent users. However, the underlying molecular mechanisms remain largely unknown. Here, we treated female and male C57BL6/N mice with high doses of THC during early adolescence and assessed their memory and social behaviors in late adolescence. We then profiled the transcriptome of five brain regions involved in cognitive and addiction-related processes. We applied gene coexpression network analysis and identified gene coexpression modules, termed cognitive modules, that simultaneously correlated with THC treatment and memory traits reduced by THC. The cognitive modules were related to endocannabinoid signaling in the female dorsal medial striatum, inflammation in the female ventral tegmental area, and synaptic transmission in the male nucleus accumbens. Moreover, cross-brain region module-module interaction networks uncovered intra- and inter-region molecular circuitries influenced by THC. Lastly, we identified key driver genes of gene networks associated with THC in mice and genetic susceptibility to CUD in humans. This analysis revealed a common regulatory mechanism linked to CUD vulnerability in the nucleus accumbens of females and males, which shared four key drivers (Hapln4, Kcnc1, Elavl2, Zcchc12). These genes regulate transcriptional subnetworks implicated in addiction processes, synaptic transmission, brain development, and lipid metabolism. Our study provides novel insights into disease mechanisms regulated by adolescent exposure to THC in a sex- and brain region-specific manner.


Asunto(s)
Cannabis , Expresión Génica , Alucinógenos , Factores Sexuales , Adolescente , Animales , Encéfalo , Agonistas de Receptores de Cannabinoides/farmacología , Cannabis/efectos adversos , Dronabinol/metabolismo , Endocannabinoides/metabolismo , Femenino , Redes Reguladoras de Genes , Alucinógenos/farmacología , Humanos , Masculino , Ratones , Ratones Endogámicos C57BL , Canales de Potasio Shaw/metabolismo
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