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1.
Proc Natl Acad Sci U S A ; 117(12): 6836-6843, 2020 03 24.
Artigo em Inglês | MEDLINE | ID: mdl-32144139

RESUMO

Visuomotor impairments characterize numerous neurological disorders and neurogenetic syndromes, such as autism spectrum disorder (ASD) and Dravet, Fragile X, Prader-Willi, Turner, and Williams syndromes. Despite recent advances in systems neuroscience, the biological basis underlying visuomotor functional impairments associated with these clinical conditions is poorly understood. In this study, we used neuroimaging connectomic approaches to map the visuomotor integration (VMI) system in the human brain and investigated the topology approximation of the VMI network to the Allen Human Brain Atlas, a whole-brain transcriptome-wide atlas of cortical genetic expression. We found the genetic expression of four genes-TBR1, SCN1A, MAGEL2, and CACNB4-to be prominently associated with visuomotor integrators in the human cortex. TBR1 gene transcripts, an ASD gene whose expression is related to neural development of the cortex and the hippocampus, showed a central spatial allocation within the VMI system. Our findings delineate gene expression traits underlying the VMI system in the human cortex, where specific genes, such as TBR1, are likely to play a central role in its neuronal organization, as well as on specific phenotypes of neurogenetic syndromes.


Assuntos
Canais de Cálcio/genética , Córtex Motor/fisiopatologia , Canal de Sódio Disparado por Voltagem NAV1.1/genética , Transtornos do Neurodesenvolvimento/patologia , Proteínas/genética , Proteínas com Domínio T/genética , Córtex Visual/fisiopatologia , Adulto , Idoso , Transtorno do Espectro Autista/genética , Transtorno do Espectro Autista/patologia , Mapeamento Encefálico , Estudos de Coortes , Epilepsias Mioclônicas/genética , Epilepsias Mioclônicas/patologia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Transtornos do Neurodesenvolvimento/genética , Síndrome de Prader-Willi/genética , Síndrome de Prader-Willi/patologia , Desempenho Psicomotor , Percepção Visual
2.
Neuron ; 106(3): 421-437.e11, 2020 05 06.
Artigo em Inglês | MEDLINE | ID: mdl-32126198

RESUMO

Autism is characterized by repetitive behaviors, impaired social interactions, and communication deficits. It is a prevalent neurodevelopmental disorder, and available treatments offer little benefit. Here, we show that genetically reducing the protein tau prevents behavioral signs of autism in two mouse models simulating distinct causes of this condition. Similar to a proportion of people with autism, both models have epilepsy, abnormally enlarged brains, and overactivation of the phosphatidylinositol 3-kinase (PI3K)/Akt (protein kinase B)/ mammalian target of rapamycin (mTOR) signaling pathway. All of these abnormalities were prevented or markedly diminished by partial or complete genetic removal of tau. We identify disinhibition of phosphatase and tensin homolog deleted on chromosome 10 (PTEN), a negative PI3K regulator that tau controls, as a plausible mechanism and demonstrate that tau interacts with PTEN via tau's proline-rich domain. Our findings suggest an enabling role of tau in the pathogenesis of autism and identify tau reduction as a potential therapeutic strategy for some of the disorders that cause this condition.


Assuntos
Transtorno Autístico/genética , Megalencefalia/genética , Proteínas tau/genética , Animais , Transtorno Autístico/metabolismo , Sítios de Ligação , Encéfalo/metabolismo , Encéfalo/patologia , Células Cultivadas , Células HEK293 , Humanos , Megalencefalia/metabolismo , Proteínas de Membrana/genética , Camundongos , Camundongos Endogâmicos C57BL , Canal de Sódio Disparado por Voltagem NAV1.1/genética , Proteínas do Tecido Nervoso/genética , Proteínas do Tecido Nervoso/metabolismo , PTEN Fosfo-Hidrolase/química , PTEN Fosfo-Hidrolase/metabolismo , Fosfatidilinositol 3-Quinases/metabolismo , Domínios Proteicos Ricos em Prolina , Ligação Proteica , Ratos , Ratos Sprague-Dawley , Proteínas tau/metabolismo
3.
J Neurosci ; 40(13): 2764-2775, 2020 03 25.
Artigo em Inglês | MEDLINE | ID: mdl-32102923

RESUMO

Recurrent seizures, which define epilepsy, are transient abnormalities in the electrical activity of the brain. The mechanistic basis of seizure initiation, and the contribution of defined neuronal subtypes to seizure pathophysiology, remains poorly understood. We performed in vivo two-photon calcium imaging in neocortex during temperature-induced seizures in male and female Dravet syndrome (Scn1a+/-) mice, a neurodevelopmental disorder with prominent temperature-sensitive epilepsy. Mean activity of both putative principal cells and parvalbumin-positive interneurons (PV-INs) was higher in Scn1a+/- relative to wild-type controls during quiet wakefulness at baseline and at elevated core body temperature. However, wild-type PV-INs showed a progressive synchronization in response to temperature elevation that was absent in PV-INs from Scn1a+/- mice. Hence, PV-IN activity remains intact interictally in Scn1a+/- mice, yet exhibits decreased synchrony immediately before seizure onset. We suggest that impaired PV-IN synchronization may contribute to the transition to the ictal state during temperature-induced seizures in Dravet syndrome.SIGNIFICANCE STATEMENT Epilepsy is a common neurological disorder defined by recurrent, unprovoked seizures. However, basic mechanisms of seizure initiation and propagation remain poorly understood. We performed in vivo two-photon calcium imaging in an experimental model of Dravet syndrome (Scn1a+/- mice)-a severe neurodevelopmental disorder defined by temperature-sensitive, treatment-resistant epilepsy-and record activity of putative excitatory neurons and parvalbumin-positive GABAergic neocortical interneurons (PV-INs) during naturalistic seizures induced by increased core body temperature. PV-IN activity was higher in Scn1a+/- relative to wild-type controls during quiet wakefulness. However, wild-type PV-INs showed progressive synchronization in response to temperature elevation that was absent in PV-INs from Scn1a+/- mice before seizure onset. Hence, impaired PV-IN synchronization may contribute to transition to seizure in Dravet syndrome.


Assuntos
Epilepsias Mioclônicas/fisiopatologia , Interneurônios/fisiologia , Convulsões/fisiopatologia , Potenciais de Ação/fisiologia , Animais , Modelos Animais de Doenças , Epilepsias Mioclônicas/genética , Feminino , Masculino , Camundongos , Camundongos Knockout , Canal de Sódio Disparado por Voltagem NAV1.1/genética , Convulsões/genética
4.
Ann Neurol ; 87(2): 281-288, 2020 02.
Artigo em Inglês | MEDLINE | ID: mdl-31755124

RESUMO

OBJECTIVE: Febrile seizures may follow vaccination. Common variants in the sodium channel gene, SCN1A, are associated with febrile seizures, and rare pathogenic variants in SCN1A cause the severe developmental and epileptic encephalopathy Dravet syndrome. Following vaccination, febrile seizures may raise the specter of poor outcome and inappropriately implicate vaccination as the cause. We aimed to determine the prevalence of SCN1A variants in children having their first febrile seizure either proximal to vaccination or unrelated to vaccination compared to controls. METHODS: We performed SCN1A sequencing, blind to clinical category, in a prospective cohort of children presenting with their first febrile seizure as vaccine proximate (n = 69) or as non-vaccine proximate (n = 75), and children with no history of seizures (n = 90) recruited in Australian pediatric hospitals. RESULTS: We detected 2 pathogenic variants in vaccine-proximate cases (p.R568X and p.W932R), both of whom developed Dravet syndrome, and 1 in a non-vaccine-proximate case (p.V947L) who had febrile seizures plus from 9 months. All had generalized tonic-clonic seizures lasting >15 minutes. We also found enrichment of a reported risk allele, rs6432860-T, in children with febrile seizures compared to controls (odds ratio = 1.91, 95% confidence interval = 1.31-2.81). INTERPRETATION: Pathogenic SCN1A variants may be identified in infants with vaccine-proximate febrile seizures. As early diagnosis of Dravet syndrome is essential for optimal management and outcome, SCN1A sequencing in infants with prolonged febrile seizures, proximate to vaccination, should become routine. ANN NEUROL 2020;87:281-288.


Assuntos
Predisposição Genética para Doença/genética , Canal de Sódio Disparado por Voltagem NAV1.1/genética , Convulsões Febris/genética , Vacinas/efeitos adversos , Estudos de Casos e Controles , Pré-Escolar , Feminino , Humanos , Lactente , Masculino , Mutação , Estudos Prospectivos
5.
PLoS One ; 14(11): e0224856, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31697745

RESUMO

Epilepsy is a significant contributor to worldwide disability. In epilepsy, disability can be broadly divided into two components: ictal (pertaining to the burden of unpredictable seizures and associated medical complications including death) and interictal (pertaining to more pervasive debilitating changes in cognitive and emotional behavior). In this study, we objectively and noninvasively appraise aspects of ictal and interictal behavior in mice using instrumented home-cage chambers designed to assay kinematic and appetitive behavioral measures. Through daily intraperitoneal injections of the chemoconvulsant pentylenetetrazole (PTZ) applied to C57BL/6J mice, we coordinately measure how "behavioral severity" (complex dynamic changes in movement and sheltering behavior) and convulsive severity (latency and occurrence of convulsive seizures) evolve or kindle with repeated injections. By closely studying long epochs between PTZ injections, we identify an interictal syndrome of nocturnal hypoactivity and increased sheltering behavior which remits with the cessation of seizure induction. We observe elements of this interictal behavioral syndrome in seizure-prone DBA/2J mice and in mice with a pathogenic Scn1a mutation (modeling Dravet syndrome). Through analyzing their responses to PTZ, we illustrate how convulsive severity and "behavioral" severity are distinct and independent aspects of the overall severity of a PTZ-induced seizure. Our results illustrate the utility of an ethologically centered automated approach to quantitatively appraise murine expressions of disability in mouse models of seizures and epilepsy. In doing so, this study highlights the very unique psychopharmacological profile of PTZ.


Assuntos
Comportamento Animal , Monitorização Fisiológica , Convulsões/patologia , Animais , Anticonvulsivantes/uso terapêutico , Modelos Animais de Doenças , Epilepsias Mioclônicas/patologia , Camundongos , Canal de Sódio Disparado por Voltagem NAV1.1/metabolismo , Pentilenotetrazol/administração & dosagem
6.
Tunis Med ; 97(4): 525-532, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-31729702

RESUMO

BACKGROUND: FS are the most benign occasional seizures in childhood. Little is known about the long term follow up.  Aim: To describe a long term follow-up of FS in Tunisian families. METHODS: Field study was conducted for 30 patients with FS. We analyzed clinical phenotype of FS and associated afebrile seizures with genetic study. RESULTS: We collected 107 individuals with febrile and / or afebrile seizures. Afebrile seizures were found in 28.3% of patients. The "FS" phenotype was found in 18 families (60%), "GEFS +" in 7 (23.33%), and idiopathic generalized epilepsy in 5 (16.66%). Sequencing analyses of SCN1A, SCN1B and GABRG2 genes revealed a novel SCN1B gene mutation in one family with FS and a known SCN1A mutation in GEFS+ family. CONCLUSION: If FS are apparently isolated and infrequent, they occur most often in a family setting. The genetic studies remain difficult mainly because of the lack of phenotype-genotype correlation.


Assuntos
Linhagem , Convulsões Febris/epidemiologia , Convulsões Febris/genética , Adolescente , Adulto , Idoso , Substituição de Aminoácidos , Criança , Pré-Escolar , Consanguinidade , Epilepsia Generalizada/epidemiologia , Epilepsia Generalizada/genética , Feminino , Seguimentos , Haplótipos , Heterozigoto , Humanos , Masculino , Pessoa de Meia-Idade , Mutação , Canal de Sódio Disparado por Voltagem NAV1.1/genética , Fenótipo , Polimorfismo de Nucleotídeo Único , Estudos Prospectivos , Receptores de GABA-A/genética , Tunísia/epidemiologia , Subunidade beta-1 do Canal de Sódio Disparado por Voltagem/genética , Adulto Jovem
7.
J Headache Pain ; 20(1): 107, 2019 Nov 15.
Artigo em Inglês | MEDLINE | ID: mdl-31730442

RESUMO

BACKGROUND: Familial hemiplegic migraine (FHM) is a group of genetic migraine, associated with hemiparesis and aura. Three causative different genes have been identified, all of which are involved in membrane ion transport. Among these, SCN1A encodes the voltage-gated Na+ channel Nav1.1, and FHM caused by mutations of SCN1A is named FHM3. For 7 of the 12 known FHM3-causing SCNA1 mutations functional consequences have been investigated, and even if gain of function effect seems to be a predominant phenotype, for several mutations conflicting results have been obtained and the available data do not reveal a univocal FHM3 pathomechanism. METHODS: To obtain a more complete picture, here, we characterized by patch clamp approach the remaining 5 mutations (Q1489H, I1498M, F1499 L, M1500 V, F1661 L) in heterologous expression systems. RESULTS: With the exception of I1498M, all mutants exhibited the same current density as WT and exhibited a shift of the steady state inactivation to more positive voltages, an accelerated recovery from inactivation, and an increase of the persistent current, revealing that most FHM3 mutations induce a gain of function. We also determined the effect of GS967, a late Na+ current blocker, on the above mentioned mutants as well as on previously characterized ones (L1649Q, L1670 W, F1774S). GS967 inhibited persistent currents of all SCNA1 FMH3-related mutants and dramatically slowed the recovery from fast inactivation of WT and mutants, consistent with the hypothesis that GS967 specifically binds to and thereby stabilizes the fast inactivated state. Simulation of neuronal firing showed that enhanced persistent currents cause an increase of ionic fluxes during action potential repolarization and consequent accumulation of K+ and/or exhaustion of neuronal energy resources. In silico application of GS967 largely reduced net ionic currents in neurons without impairing excitability. CONCLUSION: In conclusion, late Na+ current blockers appear a promising specific pharmacological treatment of FHM3.


Assuntos
Transtornos de Enxaqueca/fisiopatologia , Enxaqueca com Aura/fisiopatologia , Canal de Sódio Disparado por Voltagem NAV1.1/fisiologia , Piridinas/farmacologia , Triazóis/farmacologia , Potenciais de Ação , Epilepsia , Células HEK293 , Humanos , Transtornos de Enxaqueca/genética , Mutação , Canal de Sódio Disparado por Voltagem NAV1.1/química , Neurônios/metabolismo , Sódio
8.
Epilepsia ; 60(11): 2224-2234, 2019 11.
Artigo em Inglês | MEDLINE | ID: mdl-31625159

RESUMO

OBJECTIVE: Cannabidiol (CBD) has been approved by the US Food and Drug Administration (FDA) to treat intractable childhood epilepsies, such as Dravet syndrome and Lennox-Gastaut syndrome. However, the intrinsic anticonvulsant activity of CBD has been questioned due to a pharmacokinetic interaction between CBD and a first-line medication, clobazam. This recognized interaction has led to speculation that the anticonvulsant efficacy of CBD may simply reflect CBD augmenting clobazam exposure. The present study aimed to address the nature of the interaction between CBD and clobazam. METHODS: We examined whether CBD inhibits human CYP3A4 and CYP2C19 mediated metabolism of clobazam and N-desmethylclobazam (N-CLB), respectively, and performed studies assessing the effects of CBD on brain and plasma pharmacokinetics of clobazam in mice. We then used the Scn1a+/- mouse model of Dravet syndrome to examine how CBD and clobazam interact. We compared anticonvulsant effects of CBD-clobazam combination therapy to monotherapy against thermally-induced seizures, spontaneous seizures and mortality in Scn1a+/- mice. In addition, we used Xenopus oocytes expressing γ-aminobutyric acid (GABA)A receptors to investigate the activity of GABAA receptors when treated with CBD and clobazam together. RESULTS: CBD potently inhibited CYP3A4 mediated metabolism of clobazam and CYP2C19 mediated metabolism of N-CLB. Combination CBD-clobazam treatment resulted in greater anticonvulsant efficacy in Scn1a+/- mice, but only when an anticonvulsant dose of CBD was used. It is important to note that a sub-anticonvulsant dose of CBD did not promote greater anticonvulsant effects despite increasing plasma clobazam concentrations. In addition, we delineated a novel pharmacodynamic mechanism where CBD and clobazam together enhanced inhibitory GABAA receptor activation. SIGNIFICANCE: Our study highlights the involvement of both pharmacodynamic and pharmacokinetic interactions between CBD and clobazam that may contribute to its efficacy in Dravet syndrome.


Assuntos
Anticonvulsivantes/farmacocinética , Canabidiol/farmacocinética , Clobazam/farmacocinética , Epilepsias Mioclônicas/metabolismo , Animais , Anticonvulsivantes/administração & dosagem , Canabidiol/administração & dosagem , Clobazam/administração & dosagem , Relação Dose-Resposta a Droga , Avaliação Pré-Clínica de Medicamentos/métodos , Interações Medicamentosas/fisiologia , Quimioterapia Combinada , Epilepsias Mioclônicas/tratamento farmacológico , Epilepsias Mioclônicas/genética , Humanos , Camundongos , Camundongos Transgênicos , Canal de Sódio Disparado por Voltagem NAV1.1/genética
10.
J Enzyme Inhib Med Chem ; 34(1): 1465-1473, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31411081

RESUMO

In this investigation, we studied a family of compounds with an oxathiazolidine-4-one-2,2-dioxide skeleton and their amide synthetic precursors as new anticonvulsant drugs. The cyclic structures were synthesized using a three-step protocol that include solvent-free reactions and microwave-assisted heating. The compounds were tested in vivo through maximal electroshock seizure test in mice. All the structures showed activity at the lower doses tested (30 mg/Kg) and no signs of neurotoxicity were detected. Compound encoded as 1g displayed strong anticonvulsant effects in comparison with known anticonvulsants (ED50 = 29 mg/Kg). First approximations about the mechanisms of action of the cyclic structures were proposed by docking simulations and in vitro assays against sodium channels (patch clamp methods).


Assuntos
Anticonvulsivantes/química , Anticonvulsivantes/farmacologia , Desenho de Fármacos , Imidas/química , Imidas/farmacologia , Tiazóis/química , Animais , Anticonvulsivantes/administração & dosagem , Anticonvulsivantes/síntese química , Espectroscopia de Ressonância Magnética Nuclear de Carbono-13 , Relação Dose-Resposta a Droga , Células HEK293 , Humanos , Imidas/síntese química , Masculino , Camundongos , Canal de Sódio Disparado por Voltagem NAV1.1/efeitos dos fármacos , Óxidos/química , Técnicas de Patch-Clamp , Espectroscopia de Prótons por Ressonância Magnética
11.
Stem Cell Res ; 39: 101523, 2019 08.
Artigo em Inglês | MEDLINE | ID: mdl-31400703

RESUMO

Dravet syndrome (DS) is a childhood epilepsy syndrome caused by heterozygous mutations in the SCN1A gene encoding voltage-gated sodium channel Nav1.1. We generated iPSCs from fibroblasts of three DS patients carrying distinct SCN1A mutations (c.5502-5509dupGCTTGAAC, c.2965G>C and c.651C>G). The iPSC lines were genetically stable and each line retained the SCN1A gene mutation of the donor fibroblasts. Characterization of the iPSC lines confirmed expression of pluripotency markers, absence of exogenous vector expression and trilineage differentiation potential. These iPSC lines offer a useful resource to investigate the molecular mechanisms underlying Nav1.1 haploinsufficiency and for drug development to improve treatment of DS patients.


Assuntos
Epilepsias Mioclônicas/genética , Células-Tronco Pluripotentes Induzidas/citologia , Canal de Sódio Disparado por Voltagem NAV1.1/genética , Diferenciação Celular/genética , Diferenciação Celular/fisiologia , Reprogramação Celular/genética , Reprogramação Celular/fisiologia , Humanos , Células-Tronco Pluripotentes Induzidas/metabolismo , Fatores de Transcrição Kruppel-Like/genética , Fatores de Transcrição Kruppel-Like/metabolismo , Mutação/genética , Fator 3 de Transcrição de Octâmero/genética , Fator 3 de Transcrição de Octâmero/metabolismo , Fatores de Transcrição SOXB1/genética , Fatores de Transcrição SOXB1/metabolismo
12.
J Med Case Rep ; 13(1): 266, 2019 Aug 23.
Artigo em Inglês | MEDLINE | ID: mdl-31439038

RESUMO

BACKGROUND: Epilepsy is the most common neurological disorder that causes spontaneous, unprovoked, and recurrent seizures. Epilepsy is clinically and genetically heterogeneous with various modes of inheritance. The complexity of epilepsy presents a challenge and identification of the causal genetic mutation allows diagnosis, genetic counseling, predicting prognosis, and, in some cases, treatment decisions. Clinical exome sequencing is actually becoming a powerful approach for molecular diagnosis of heterogeneous neurological disorders in clinical practice. CASE PRESENTATION: We report our observations of three unrelated Moroccan patients referred to our genetics department for molecular diagnosis of epilepsy: a 4-year-old Moroccan boy, a 3-year-old Moroccan girl, and a 7-year-old Moroccan boy. Due to the heterogeneity and complexity of epilepsy, we performed clinical exome sequencing followed by targeted analysis of 936 epilepsy genes. A total of three mutations were identified in known epilepsy genes (SCN1A, SCN2A). By clinical exome sequencing, we identified two novel mutations: c.4973C>A (p.Thr1658Lys) in SCN1A gene and c.1283A>G (p.Tyr428Cys) in the SCN2A gene, whereas the third mutation c.3295G>T (p.Glu1099*) was already described in patients with Dravet syndrome. CONCLUSION: This study demonstrates that clinical exome sequencing is an effective diagnosis tool to investigate this group of diseases with huge diversity and defends its use in clinical routine.


Assuntos
Epilepsia/genética , Mutação , Canal de Sódio Disparado por Voltagem NAV1.1/genética , Canal de Sódio Disparado por Voltagem NAV1.2/genética , Criança , Pré-Escolar , Feminino , Heterozigoto , Humanos , Masculino , Marrocos , Análise de Sequência de DNA , Sequenciamento Completo do Exoma
13.
Proc Natl Acad Sci U S A ; 116(33): 16571-16576, 2019 08 13.
Artigo em Inglês | MEDLINE | ID: mdl-31346088

RESUMO

Dravet Syndrome is a severe childhood epileptic disorder caused by haploinsufficiency of the SCN1A gene encoding brain voltage-gated sodium channel NaV1.1. Symptoms include treatment-refractory epilepsy, cognitive impairment, autistic-like behavior, and premature death. The specific loci of NaV1.1 function in the brain that underlie these global deficits remain unknown. Here we specifically deleted Scn1a in the hippocampus using the Cre-Lox method in weanling mice. Local gene deletion caused selective reduction of inhibitory neurotransmission measured in dentate granule cells. Mice with local NaV1.1 reduction had thermally evoked seizures and spatial learning deficits, but they did not have abnormalities of locomotor activity or social interaction. Our results show that local gene deletion in the hippocampus can induce two of the most severe dysfunctions of Dravet Syndrome: Epilepsy and cognitive deficit. Considering these results, the hippocampus may be a potential target for future gene therapy for Dravet Syndrome.


Assuntos
Disfunção Cognitiva/complicações , Epilepsias Mioclônicas/complicações , Deleção de Genes , Hipocampo/patologia , Canal de Sódio Disparado por Voltagem NAV1.1/genética , Convulsões/complicações , Temperatura , Animais , Disfunção Cognitiva/patologia , Disfunção Cognitiva/fisiopatologia , Condicionamento Clássico , Giro Denteado/metabolismo , Giro Denteado/fisiopatologia , Dependovirus/metabolismo , Medo , Hipocampo/fisiopatologia , Potenciais Pós-Sinápticos Inibidores , Integrases/metabolismo , Relações Interpessoais , Memória , Camundongos , Camundongos Endogâmicos C57BL , Neurônios/metabolismo , Receptores de GABA/metabolismo , Convulsões/patologia , Convulsões/fisiopatologia , Aprendizagem Espacial
14.
Sleep ; 42(12)2019 12 24.
Artigo em Inglês | MEDLINE | ID: mdl-31346614

RESUMO

STUDY OBJECTIVES: Sleep disturbances are common co-morbidities of epileptic disorders. Dravet syndrome (DS) is an intractable epilepsy accompanied by disturbed sleep. While there is evidence that daily sleep timing is disrupted in DS, the difficulty of chronically recording polysomnographic sleep from patients has left our understanding of the effect of DS on circadian sleep regulation incomplete. We aim to characterize circadian sleep regulation in a mouse model of DS. METHODS: Here we exploit long-term electrocorticographic recordings of sleep in a mouse model of DS in which one copy of the Scn1a gene is deleted. This model both genocopies and phenocopies the disease in humans. We test the hypothesis that the deletion of Scn1a in DS mice is associated with impaired circadian regulation of sleep. RESULTS: We find that DS mice show impairments in circadian sleep regulation, including a fragmented rhythm of non-rapid eye movement (NREM) sleep and an elongated circadian period of sleep. Next, we characterize re-entrainment of sleep stages and siesta following jet lag in the mouse. Strikingly, we find that re-entrainment of sleep following jet lag is normal in DS mice, in contrast to previous demonstrations of slowed re-entrainment of wheel-running activity. Finally, we report that DS mice are more likely to have an absent or altered daily "siesta". CONCLUSIONS: Our findings support the hypothesis that the circadian regulation of sleep is altered in DS and highlight the value of long-term chronic polysomnographic recording in studying the role of the circadian clock on sleep/wake cycles in pre-clinical models of disease.


Assuntos
Ritmo Circadiano/fisiologia , Epilepsias Mioclônicas/fisiopatologia , Síndrome do Jet Lag/fisiopatologia , Fases do Sono/fisiologia , Transtornos do Sono-Vigília/fisiopatologia , Animais , Relógios Circadianos/fisiologia , Eletrocorticografia/métodos , Epilepsias Mioclônicas/genética , Feminino , Síndrome do Jet Lag/genética , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Canal de Sódio Disparado por Voltagem NAV1.1/genética , Transtornos do Sono-Vigília/genética
15.
Elife ; 82019 07 08.
Artigo em Inglês | MEDLINE | ID: mdl-31282864

RESUMO

Dravet Syndrome (DS) is a severe neurodevelopmental disorder caused by pathogenic loss of function variants in the gene SCN1A which encodes the voltage gated sodium (Na+) channel subunit Nav1.1. GABAergic interneurons expressing parvalbumin (PV-INs) and somatostatin (SST-INs) exhibit impaired excitability in DS (Scn1a+/-) mice. However, the function of a third major class of interneurons in DS - those expressing vasoactive intestinal peptide (VIP-IN) -is unknown. We recorded VIP-INs in brain slices from Scn1a+/-mice and wild-type littermate controls and found prominent impairment of irregular spiking (IS), but not continuous adapting (CA) VIP-INs, in Scn1a+/- mice. Application of the Nav1.1-specific toxin Hm1a rescued the observed deficits. The IS vs. CA firing pattern is determined by expression of KCNQ channels; IS VIP-INs switched to tonic firing with both pharmacologic blockade of M-current and muscarinic acetylcholine receptor activation. These results show that VIP-INs express Nav1.1 and are dysfunctional in DS, which may contribute to DS pathogenesis.


Assuntos
Encéfalo/metabolismo , Epilepsias Mioclônicas/metabolismo , Interneurônios/metabolismo , Peptídeo Intestinal Vasoativo/metabolismo , Potenciais de Ação/genética , Potenciais de Ação/fisiologia , Animais , Encéfalo/fisiopatologia , Epilepsias Mioclônicas/genética , Epilepsias Mioclônicas/fisiopatologia , Interneurônios/fisiologia , Camundongos da Linhagem 129 , Camundongos Endogâmicos C57BL , Camundongos Knockout , Camundongos Transgênicos , Canal de Sódio Disparado por Voltagem NAV1.1/genética , Canal de Sódio Disparado por Voltagem NAV1.1/metabolismo , Peptídeo Intestinal Vasoativo/genética
16.
Neurol Res ; 41(10): 930-935, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31256750

RESUMO

Background: IVS5-91G>A (rs3812718) polymorphism of the sodium voltage-gated channel alpha subunit 1 (SCN1A) gene has been associated with inadequate responsiveness to common antiepileptic drugs which act as sodium channel blockers. This study was performed to investigate the effect of IVS5-91G>A (rs3812718) polymorphism on lamotrigine (LTG) efficacy in a cohort of patients with non-lesional focal epilepsy taking LTG as monotherapy. Methods: A total of 100 of patients with non-lesional focal epilepsy on LTG monotherapy was included in this prospective interventional study. After reaching a stable dose of LTG patients were followed-up for 12 consecutive months. LTG responsiveness was defined as a 75% or more reduction in seizure frequency on a stable dose of LTG. Genotyping was performed at the end of the study using standard procedures and data were correlated with clinical data. Results: There were no significant differences in the prevalence of responsiveness to LTG between carriers of different genotypes. Average maintenance LTG doses in the responder group differed by genotype in the order AA>GA>GG, but these differences did not reach statistical significance. Conclusion: Our data suggest lack of association between SCN1A IVS5-91G>A (rs3812718) polymorphism and response to LTG.


Assuntos
Anticonvulsivantes/uso terapêutico , Epilepsia Resistente a Medicamentos/genética , Epilepsias Parciais/tratamento farmacológico , Epilepsias Parciais/genética , Lamotrigina/uso terapêutico , Canal de Sódio Disparado por Voltagem NAV1.1/genética , Adulto , Resistência a Medicamentos/genética , Feminino , Genótipo , Humanos , Masculino , Polimorfismo de Nucleotídeo Único , Estudos Prospectivos , Adulto Jovem
17.
J Headache Pain ; 20(1): 72, 2019 Jun 21.
Artigo em Inglês | MEDLINE | ID: mdl-31226929

RESUMO

BACKGROUND: Migraine is a complex neurovascular disorder with a strong genetic component. There are rare monogenic forms of migraine, as well as more common polygenic forms; research into the genes involved in both types has provided insights into the many contributing genetic factors. This review summarises advances that have been made in the knowledge and understanding of the genes and genetic variations implicated in migraine etiology. FINDINGS: Migraine is characterised into two main types, migraine without aura (MO) and migraine with aura (MA). Hemiplegic migraine is a rare monogenic MA subtype caused by mutations in three main genes - CACNA1A, ATP1A2 and SCN1A - which encode ion channel and transport proteins. Functional studies in cellular and animal models show that, in general, mutations result in impaired glutamatergic neurotransmission and cortical hyperexcitability, which make the brain more susceptible to cortical spreading depression, a phenomenon thought to coincide with aura symptoms. Variants in other genes encoding ion channels and solute carriers, or with roles in regulating neurotransmitters at neuronal synapses, or in vascular function, can also cause monogenic migraine, hemiplegic migraine and related disorders with overlapping symptoms. Next-generation sequencing will accelerate the finding of new potentially causal variants and genes, with high-throughput bioinformatics analysis methods and functional analysis pipelines important in prioritising, confirming and understanding the mechanisms of disease-causing variants. With respect to common migraine forms, large genome-wide association studies (GWAS) have greatly expanded our knowledge of the genes involved, emphasizing the role of both neuronal and vascular pathways. Dissecting the genetic architecture of migraine leads to greater understanding of what underpins relationships between subtypes and comorbid disorders, and may have utility in diagnosis or tailoring treatments. Further work is required to identify causal polymorphisms and the mechanism of their effect, and studies of gene expression and epigenetic factors will help bridge the genetics with migraine pathophysiology. CONCLUSIONS: The complexity of migraine disorders is mirrored by their genetic complexity. A comprehensive knowledge of the genetic factors underpinning migraine will lead to improved understanding of molecular mechanisms and pathogenesis, to enable better diagnosis and treatments for migraine sufferers.


Assuntos
Transtornos de Enxaqueca/genética , Animais , Depressão Alastrante da Atividade Elétrica Cortical/genética , Estudo de Associação Genômica Ampla , Humanos , Enxaqueca com Aura/fisiopatologia , Herança Multifatorial/genética , Mutação , Canal de Sódio Disparado por Voltagem NAV1.1/genética
18.
Seizure ; 71: 20-23, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31176277

RESUMO

PURPOSE: Early myoclonic encephalopathy (EME) is a form of developmental and epileptic encephalopathy with myoclonic seizures and a suppression burst on electroencephalogram, which occurs during the neonatal or early infantile period and is characterized by highly intractable seizures and severe development impairment. Although multiple genetic aetiologies of EME have been identified, no SCN1A mutation has been reported. METHODS: We described a female patient with EME due to an SCN1A mutation. RESULTS: She developed frequent myoclonic and apnoeic seizures during the neonatal period. As her seizures were refractory to many antiepileptic drugs, she underwent a tracheotomy and has since been treated with continuous mechanical ventilation. Eventually, perampanel was added, which resulted in the cessation of the apnoeic seizures. Genetic analysis revealed a heterozygous de novo missense mutation in the SCN1A gene (c.2588 T > C:p.Leu863Ser). CONCLUSION: This is the first patient with EME due to anSCN1A mutation to be successfully treated with perampanel. Recently, perampanel was reported to be effective in treating Dravet syndrome, including cases with an SCN1A mutation. Perampanel may contribute to seizure reduction in patients with intractable epilepsy carrying the SCN1A mutation.


Assuntos
Anticonvulsivantes/farmacologia , Piridonas/farmacologia , Espasmos Infantis/tratamento farmacológico , Espasmos Infantis/genética , Feminino , Humanos , Lactente , Canal de Sódio Disparado por Voltagem NAV1.1
20.
Elife ; 82019 04 26.
Artigo em Inglês | MEDLINE | ID: mdl-31025941

RESUMO

Dravet syndrome (DS) is a form of epilepsy with a high incidence of sudden unexpected death in epilepsy (SUDEP). Respiratory failure is a leading cause of SUDEP, and DS patients' frequently exhibit disordered breathing. Despite this, mechanisms underlying respiratory dysfunction in DS are unknown. We found that mice expressing a DS-associated Scn1a missense mutation (A1783V) conditionally in inhibitory neurons (Slc32a1cre/+::Scn1aA1783V fl/+; defined as Scn1aΔE26) exhibit spontaneous seizures, die prematurely and present a respiratory phenotype including hypoventilation, apnea, and a diminished ventilatory response to CO2. At the cellular level in the retrotrapezoid nucleus (RTN), we found inhibitory neurons expressing the Scn1a A1783V variant are less excitable, whereas glutamatergic chemosensitive RTN neurons, which are a key source of the CO2/H+-dependent drive to breathe, are hyper-excitable in slices from Scn1aΔE26 mice. These results show loss of Scn1a function can disrupt respiratory control at the cellular and whole animal levels.


Assuntos
Epilepsias Mioclônicas/genética , Canal de Sódio Disparado por Voltagem NAV1.1/genética , Respiração/genética , Convulsões/genética , Potenciais de Ação/genética , Animais , Dióxido de Carbono/toxicidade , Modelos Animais de Doenças , Epilepsias Mioclônicas/fisiopatologia , Humanos , Camundongos , Mutação de Sentido Incorreto/genética , Neurônios/metabolismo , Neurônios/patologia , Convulsões/fisiopatologia , Morte Súbita Inesperada na Epilepsia/patologia
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