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1.
J Headache Pain ; 24(1): 96, 2023 Jul 26.
Artículo en Inglés | MEDLINE | ID: mdl-37495957

RESUMEN

BACKGROUND: Cortical spreading depolarization (CSD), the neurophysiological correlate of the migraine aura, can activate trigeminal pain pathways, but the neurobiological mechanisms and behavioural consequences remain unclear. Here we investigated effects of optogenetically-induced CSDs on headache-related behaviour and neuroinflammatory responses in transgenic mice carrying a familial hemiplegic migraine type 1 (FHM1) mutation. METHODS: CSD events (3 in total) were evoked in a minimally invasive manner by optogenetic stimulation through the intact skull in freely behaving wildtype (WT) and FHM1 mutant mice. Related behaviours were analysed using mouse grimace scale (MGS) scoring, head grooming, and nest building behaviour. Neuroinflammatory changes were investigated by assessing HMGB1 release with immunohistochemistry and by pre-treating mice with a selective Pannexin-1 channel inhibitor. RESULTS: In both WT and FHM1 mutant mice, CSDs induced headache-related behaviour, as evidenced by increased MGS scores and the occurrence of oculotemporal strokes, at 30 min. Mice of both genotypes also showed decreased nest building behaviour after CSD. Whereas in WT mice MGS scores had normalized at 24 h after CSD, in FHM1 mutant mice scores were normalized only at 48 h. Of note, oculotemporal stroke behaviour already normalized 5 h after CSD, whereas nest building behaviour remained impaired at 72 h; no genotype differences were observed for either readout. Nuclear HMGB1 release in the cortex of FHM1 mutant mice, at 30 min after CSD, was increased bilaterally in both WT and FHM1 mutant mice, albeit that contralateral release was more pronounced in the mutant mice. Only in FHM1 mutant mice, contralateral release remained higher at 24 h after CSD, but at 48 h had returned to abnormal, elevated, baseline values, when compared to WT mice. Blocking Panx1 channels by TAT-Panx308 inhibited CSD-induced headache related behaviour and HMGB1 release. CONCLUSIONS: CSDs, induced in a minimally invasive manner by optogenetics, investigated in freely behaving mice, cause various migraine relevant behavioural and neuroinflammatory phenotypes that are more pronounced and longer-lasting in FHM1 mutant compared to WT mice. Prevention of CSD-related neuroinflammatory changes may have therapeutic potential in the treatment of migraine.


Asunto(s)
Depresión de Propagación Cortical , Proteína HMGB1 , Trastornos Migrañosos , Migraña con Aura , Ratones , Animales , Migraña con Aura/genética , Migraña con Aura/metabolismo , Proteína HMGB1/genética , Proteína HMGB1/farmacología , Optogenética , Depresión de Propagación Cortical/fisiología , Modelos Animales de Enfermedad , Trastornos Migrañosos/genética , Ratones Transgénicos , Cefalea , Inflamación , Proteínas del Tejido Nervioso/genética , Conexinas/genética , Conexinas/farmacología
2.
J Neurosci ; 41(3): 524-537, 2021 01 20.
Artículo en Inglés | MEDLINE | ID: mdl-33234612

RESUMEN

Dravet syndrome (DS) is an epileptic encephalopathy that still lacks biomarkers for epileptogenesis and its treatment. Dysfunction of NaV1.1 sodium channels, which are chiefly expressed in inhibitory interneurons, explains the epileptic phenotype. Understanding the network effects of these cellular deficits may help predict epileptogenesis. Here, we studied θ-γ coupling as a potential marker for altered inhibitory functioning and epileptogenesis in a DS mouse model. We found that cortical θ-γ coupling was reduced in both male and female juvenile DS mice and persisted only if spontaneous seizures occurred. θ-γ Coupling was partly restored by cannabidiol (CBD). Locally disrupting NaV1.1 expression in the hippocampus or cortex yielded early attenuation of θ-γ coupling, which in the hippocampus associated with fast ripples, and which was replicated in a computational model when voltage-gated sodium currents were impaired in basket cells (BCs). Our results indicate attenuated θ-γ coupling as a promising early indicator of inhibitory dysfunction and seizure risk in DS.


Asunto(s)
Epilepsias Mioclónicas/fisiopatología , Epilepsia/fisiopatología , Ritmo Gamma , Convulsiones/fisiopatología , Ritmo Teta , Animales , Anticonvulsivantes/uso terapéutico , Biomarcadores , Cannabidiol/uso terapéutico , Corteza Cerebral/metabolismo , Corteza Cerebral/fisiopatología , Simulación por Computador , Electroencefalografía , Epilepsias Mioclónicas/tratamiento farmacológico , Epilepsia/tratamiento farmacológico , Femenino , Hipocampo/metabolismo , Hipocampo/fisiopatología , Interneuronas/metabolismo , Masculino , Ratones , Ratones Noqueados , Canal de Sodio Activado por Voltaje NAV1.1/genética , Canales de Potasio con Entrada de Voltaje/metabolismo , Convulsiones/tratamiento farmacológico
3.
Neurobiol Dis ; 156: 105424, 2021 08.
Artículo en Inglés | MEDLINE | ID: mdl-34118418

RESUMEN

Neuroinflammatory changes involving neuronal HMGB1 release and astrocytic NF-κB nuclear translocation occur following cortical spreading depolarization (CSD) in wildtype (WT) mice but it is unknown to what extent this occurs in the migraine brain. We therefore investigated in familial hemiplegic migraine type 1 (FHM1) knock-in mice, which express an intrinsic hyperexcitability phenotype, the extent of neuroinflammation without and after CSD. CSD was evoked in one hemisphere by pinprick (single CSD) or topical KCl application (multiple CSDs). Neuroinflammatory (HMGB1, NF-κB) and neuronal activation (pERK) markers were investigated by immunohistochemistry in the brains of WT and FHM1 mutant mice without and after CSD. Effects of NMDA receptor antagonism on basal and CSD-induced neuroinflammatory changes were examined by, respectively, systemically administered MK801 and ifenprodil or topical MK801 application. In FHM1 mutant mice, CSD caused enhanced neuronal HMGB1 release and astrocytic NF-κB nuclear translocation in the cortex and subcortical areas that were equally high in both hemispheres. In WT mice such effects were only pronounced in the hemisphere in which CSD was induced. Neuroinflammatory responses were associated with pERK expression indicating neuronal activation. Upon CSD, contralateral cortical and striatal HMGB1 release was reduced by topical application of MK801 in the hemisphere contralateral to the one in which CSD was induced. This study reveals that neuroinflammatory activation after CSD is widespread and extends to the contralateral hemisphere, particularly in brains of FHM1 mutant mice. Effective blockade of CSD-induced neuroinflammatory responses in the contralateral hemisphere in FHM1 mice by local NMDA receptor antagonism suggests that neuronal hyperexcitability-related neuroinflammation is relevant in migraine pathophysiology, but possibly also other neurological disorders in which spreading depolarization is involved.


Asunto(s)
Encéfalo/metabolismo , Ataxia Cerebelosa/metabolismo , Depresión de Propagación Cortical/fisiología , Proteína HMGB1/metabolismo , Trastornos Migrañosos/metabolismo , FN-kappa B/metabolismo , Tejido Parenquimatoso/metabolismo , Animales , Astrocitos/metabolismo , Encéfalo/fisiopatología , Ataxia Cerebelosa/genética , Ataxia Cerebelosa/fisiopatología , Femenino , Proteína HMGB1/genética , Humanos , Ratones , Ratones Transgénicos , Trastornos Migrañosos/genética , Trastornos Migrañosos/fisiopatología , FN-kappa B/genética , Tejido Parenquimatoso/fisiopatología
4.
Epilepsia ; 61(4): e30-e36, 2020 04.
Artículo en Inglés | MEDLINE | ID: mdl-32190912

RESUMEN

Early onset seizures are a hallmark of Dravet syndrome. Previous studies in rodent models have shown that the epileptic phenotype is caused by loss-of-function of voltage-gated NaV 1.1 sodium channels, which are chiefly expressed in γ-aminobutyric acid (GABA)ergic neurons. Recently, a possibly critical role has been attributed to the hippocampus in the seizure phenotype, as local hippocampal ablation of NaV 1.1 channels decreased the threshold for hyperthermia-induced seizures. However, the effect of ablation of NaV 1.1 channels restricted to cortical sites has not been tested. Here we studied local field potential (LFP) and behavior in mice following local hippocampal and cortical ablation of Scn1a, a gene encoding the α1 subunit of NaV 1.1 channels, and we compared seizure characteristics with those of heterozygous global knockout Scn1-/+ mice. We found a high incidence of spontaneous seizures following either local hippocampal or cortical ablation, notably during a transient time window, similar to Scn1a-/+ mice. Nonconvulsive seizure activity in the injected area was common and preceded generalized seizures. Moreover, mice were susceptible to hyperthermia-induced seizures. In conclusion, local ablation of NaV 1.1 channels in the hippocampus and cortex results in focal seizure activity that can generalize. These data indicate that spontaneous epileptic activity may initiate in multiple brain regions in Dravet syndrome.


Asunto(s)
Corteza Cerebral/fisiopatología , Hipocampo/fisiopatología , Canal de Sodio Activado por Voltaje NAV1.1/genética , Convulsiones/genética , Convulsiones/fisiopatología , Animales , Epilepsias Mioclónicas/genética , Epilepsias Mioclónicas/fisiopatología , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados
5.
Ann Clin Transl Neurol ; 7(1): 132-138, 2020 01.
Artículo en Inglés | MEDLINE | ID: mdl-31880072

RESUMEN

Here we show, for the first time, spontaneous cortical spreading depolarization (CSD) events - the electrophysiological correlate of the migraine aura - in animals by using the first generated familial hemiplegic migraine type 3 (FHM3) transgenic mouse model. The mutant mice express L263V-mutated α1 subunits in voltage-gated NaV 1.1 sodium channels (Scn1aL263V ). CSDs consistently propagated from visual to motor cortex, recapitulating what has been shown in patients with migraine with aura. This model may be valuable for the preclinical study of migraine with aura and other diseases in which spreading depolarization is a prominent feature.


Asunto(s)
Depresión de Propagación Cortical/fisiología , Trastornos Migrañosos/fisiopatología , Corteza Motora/fisiopatología , Corteza Visual/fisiopatología , Animales , Modelos Animales de Enfermedad , Electroencefalografía , Ratones , Ratones Endogámicos C57BL , Ratones Transgénicos , Canal de Sodio Activado por Voltaje NAV1.1/genética
6.
Curr Neuropharmacol ; 17(10): 961-973, 2019.
Artículo en Inglés | MEDLINE | ID: mdl-31092180

RESUMEN

Migraine, an extremely disabling neurological disorder, has a strong genetic component. Since monogenic migraines (resulting from mutations or changes in a single gene) may help researchers discover migraine pathophysiology, transgenic mice models harboring gene mutations identified in Familial Hemiplegic Migraine (FHM) patients have been generated. Studies in these FHM mutant mice models have shed light on the mechanisms of migraine and may aid in the identification of novel targets for treatment. More specifically, the studies shed light on how gene mutations, hormones, and other factors impact the pathophysiology of migraine. The models may also be of relevance to researchers outside the field of migraine as some of their aspects are relevant to pain in general. Additionally, because of the comorbidities associated with migraine, they share similarities with the mutant mouse models of epilepsy, stroke, and perhaps depression. Here, we review the experimental data obtained from these mutant mice and focus on how they can be used to investigate the pathophysiology of migraine, including synaptic plasticity, neuroinflammation, metabolite alterations, and molecular and behavioral mechanisms of pain.


Asunto(s)
Modelos Animales de Enfermedad , Migraña con Aura/genética , Migraña con Aura/fisiopatología , Mutación , Animales , Epilepsia , Humanos , Ratones , Ratones Transgénicos , Dolor , Accidente Cerebrovascular
7.
Sci Rep ; 8(1): 14770, 2018 10 03.
Artículo en Inglés | MEDLINE | ID: mdl-30282977

RESUMEN

The initial phase of neuronal death is not well characterized. Here, we show that expansion of the nuclear membrane without losing its integrity along with peripheralization of chromatin are immediate signs of neuronal injury. Importantly, these changes can be identified with commonly used nuclear stains and used as markers of poor perfusion-fixation. Although frozen sections are widely used, no markers are available to ensure that the observed changes were not confounded by perfusion-induced hypoxia/ischemia. Moreover, HMGB1 was immediately released and p53 translocated to mitochondria in hypoxic/ischemic neurons, whereas nuclear pore complex inhibitors prevented the nuclear changes, identifying novel neuroprotection targets.


Asunto(s)
Encéfalo/ultraestructura , Hipoxia-Isquemia Encefálica/genética , Neuronas/ultraestructura , Membrana Nuclear/ultraestructura , Animales , Animales Recién Nacidos , Encéfalo/diagnóstico por imagen , Encéfalo/patología , Muerte Celular/genética , Núcleo Celular/genética , Núcleo Celular/patología , Corteza Cerebral/diagnóstico por imagen , Corteza Cerebral/ultraestructura , Cromatina/genética , Cuerpo Calloso/diagnóstico por imagen , Cuerpo Calloso/ultraestructura , Modelos Animales de Enfermedad , Glucosa/genética , Proteína HMGB1/genética , Humanos , Hipoxia-Isquemia Encefálica/patología , Ratones , Microscopía Electrónica de Rastreo , Mitocondrias/genética , Mitocondrias/patología , Mitocondrias/ultraestructura , Neuronas/patología , Membrana Nuclear/patología , Fijación del Tejido/normas
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