RESUMEN
Heterozygous variants in SLC6A1, encoding the GAT-1 GABA transporter, are associated with seizures, developmental delay, and autism. The majority of affected individuals carry missense variants, many of which are recurrent germline de novo mutations, raising the possibility of gain-of-function or dominant-negative effects. To understand the functional consequences, we performed an in vitro GABA uptake assay for 213 unique variants, including 24 control variants. De novo variants consistently resulted in a decrease in GABA uptake, in keeping with haploinsufficiency underlying all neurodevelopmental phenotypes. Where present, ClinVar pathogenicity reports correlated well with GABA uptake data; the functional data can inform future reports for the remaining 72% of unscored variants. Surface localization was assessed for 86 variants; two-thirds of loss-of-function missense variants prevented GAT-1 from being present on the membrane while GAT-1 was on the surface but with reduced activity for the remaining third. Surprisingly, recurrent de novo missense variants showed moderate loss-of-function effects that reduced GABA uptake with no evidence for dominant-negative or gain-of-function effects. Using linear regression across multiple missense severity scores to extrapolate the functional data to all potential SLC6A1 missense variants, we observe an abundance of GAT-1 residues that are sensitive to substitution. The extent of this missense vulnerability accounts for the clinically observed missense enrichment; overlap with hypermutable CpG sites accounts for the recurrent missense variants. Strategies to increase the expression of the wild-type SLC6A1 allele are likely to be beneficial across neurodevelopmental disorders, though the developmental stage and extent of required rescue remain unknown.
Asunto(s)
Proteínas Transportadoras de GABA en la Membrana Plasmática , Haploinsuficiencia , Mutación Missense , Humanos , Proteínas Transportadoras de GABA en la Membrana Plasmática/genética , Haploinsuficiencia/genética , Ácido gamma-Aminobutírico/metabolismo , Trastornos del Neurodesarrollo/genética , Discapacidades del Desarrollo/genética , Trastorno Autístico/genética , Células HEK293RESUMEN
Over four decades of research support the link between Alzheimer's disease (AD) and somatostatin (somatotropin-releasing inhibitory factor, SRIF). SRIF and SRIF-expressing neurons play an essential role in brain function, modulating hippocampal activity and memory formation. Loss of SRIF and SRIF-expressing neurons in the brain rests at the center of a series of interdependent pathological events driven by amyloid-beta peptide (Aß), culminating in cognitive decline and dementia. The connection between the SRIF and AD further extends to the neuropsychiatric symptoms, seizure activity, and inflammation. Whereas, preclinical AD investigations show SRIF or SRIF-receptor agonist administration capable of enhancing cognition. SRIF receptor subtype-4 activation in particular presents unique attributes, with the potential to mitigate learning and memory decline, reduce comorbid symptoms, and enhance enzymatic degradation of Aß in the brain. Here we review the links between SRIF and AD, along with the therapeutic implications. Significance Statement Somatostatin and somatostatin-expressing neurons in the brain are extensively involved in cognition. Loss of somatostatin and somatostatin-expressing neurons in Alzheimer's disease rests at the center of a series of interdependent pathological events contributing to cognitive decline and dementia. Targeting somatostatin mediated processes has significant therapeutic potential for the treatment of Alzheimer's disease.
RESUMEN
Various subjective and objective methods have been proposed to identify which interictal epileptiform discharge (IED)-related EEG-fMRI results are more likely to delineate seizure generating tissue in patients with drug-resistant focal epilepsy for the purposes of surgical planning. In this intracranial EEG-fMRI study, we evaluated the utility of these methods to localize clinically relevant regions pre-operatively and compared the extent of resection of these areas to post-operative outcome. Seventy patients admitted for intracranial video-EEG monitoring were recruited for a simultaneous intracranial EEG-fMRI study. For all analyses of blood oxygen level-dependent responses associated with IEDs, an experienced epileptologist identified the most Clinically Relevant brain activation cluster using available clinical information. The Maximum cluster (the cluster with the highest z-score) was also identified for all analyses and assigned to one of three confidence levels (low, medium, or high) based on the difference of the peak z-scores between the Maximum and Second Maximum cluster (the cluster with the second highest peak z-value). The distance was measured and compared between the peak voxel of the aforementioned clusters and the electrode contacts where the interictal discharge and seizure onset were recorded. In patients who subsequently underwent epilepsy surgery, the spatial concordance between the aforementioned clusters and the area of resection was determined and compared to post-operative outcome. We evaluated 106 different IEDs in 70 patients. Both subjective (identification of the Clinically Relevant cluster) and objective (Maximum cluster much more significant than the second maximum cluster) methods of culling non-localizing EEG-fMRI activation maps increased the spatial concordance between these clusters and the corresponding IED or seizure onset zone contacts. However, only the objective methods of identifying medium and high confidence maps resulted in a significant association between resection of the peak voxel of the Maximum cluster and post-operative outcome. Resection of this area was associated with good post-operative outcomes but was not sufficient for seizure freedom. On the other hand, we found that failure to resect the medium and high confidence Maximum clusters was associated with a poor post-surgical outcome (negative predictive value = 1.0, sensitivity = 1.0). Objective methods to identify higher confidence EEG-fMRI results are needed to localize areas necessary for good post-operative outcomes. However, resection of the peak voxel within higher confidence Maximum clusters is not sufficient for good outcomes. Conversely, failure to resect the peak voxel in these clusters is associated with a poor post-surgical outcome.
RESUMEN
One striking clinical hallmark in patients with autoantibodies to leucine-rich glioma inactivated 1 (LGI1) is the very frequent focal seizure semiologies, including faciobrachial dystonic seizures (FBDS), in addition to the amnesia. Polyclonal serum IgGs have successfully modelled the cognitive changes in vivo but not seizures. Hence, it remains unclear whether LGI1-autoantibodies are sufficient to cause seizures. We tested this with the molecularly precise monoclonal antibodies directed against LGI1 [LGI1-monoclonal antibodies (mAbs)], derived from patient circulating B cells. These were directed towards both major domains of LGI1, leucine-rich repeat and epitempin repeat, and infused intracerebroventricularly over 7 days into juvenile male Wistar rats using osmotic pumps. Continuous wireless EEG was recorded from a depth electrode placed in hippocampal CA3 plus behavioural tests for memory and hyperexcitability were performed. Following infusion completion (Day 9), post-mortem brain slices were studied for antibody binding and effects on Kv1.1. The LGI1-mAbs bound most strongly in the hippocampal CA3 region and induced a significant reduction in Kv1.1 cluster number in this subfield. By comparison to control-Ab injected rats video-EEG analysis over 9 days revealed convulsive and non-convulsive seizure activity in rats infused with LGI1-mAbs, with a significant number of ictal events. Memory was not impaired in the novel object recognition test. Peripherally-derived human LGI1-mAbs infused into rodent CSF provide strong evidence of direct in vivo epileptogenesis with molecular correlations. These findings fulfill criteria for LGI1-antibodies in seizure causation.
Asunto(s)
Anticuerpos Monoclonales , Autoanticuerpos , Péptidos y Proteínas de Señalización Intracelular , Ratas Wistar , Animales , Masculino , Ratas , Péptidos y Proteínas de Señalización Intracelular/inmunología , Humanos , Convulsiones/inmunología , Electroencefalografía , Proteínas/inmunología , Epilepsia/inmunologíaRESUMEN
Focal seizures are a type of epileptic event that has plagued the medical community for a long time, and the existing drug treatment is mainly based on the modulation of ${GABA}_a$-receptors to affect GABAergic signaling to achieve the therapeutic purpose. The majority of research currently focuses on the impact of ${GABA}_a$-receptors on neuronal firing, failing to analyze the molecular and ionic mechanisms involved. Specifically, the research on deeper-level mechanisms on how ${GABA}_a$-receptors affect neuronal firing by altering ion activity has not been addressed. This research aimed to study the effects of different ${GABA}_a$-receptor structures on ion activity in focal seizures model by adjusting parameters of the ${GABA}_a$-receptors: the rise time constant (${tau}_1$) and decay time constant (${tau}_2$). The research indicates that as the values of ${tau}_1$ and ${tau}_2$ of the ${GABA}_a$-receptor change, the ion concentration will vary based on the change of the ${GABA}_a$-receptor potential. To a certain extent, the duration of epileptic activity will also be affected to a certain extent. In conclusion, the alteration of ${GABA}_a$-receptor structure will affect the inhibitory effect of interneurons on pyramidal neurons, and different parameters of the ${GABA}_a$-receptor will directly impact the therapeutic effect.
Asunto(s)
Epilepsia , Alta del Paciente , Humanos , Neuronas/fisiología , Convulsiones , Receptores de GABA-A/fisiología , Ácido gamma-Aminobutírico/farmacologíaRESUMEN
BACKGROUND: Stroke is associated with a risk of epilepsy, but associations with age, sex, stroke type and severity, time trends, and mortality are uncertain. We studied the risk of epilepsy after stroke while accounting for sex, age, stroke types and severity, calendar time, and death. METHODS: This was a prospective nationwide register-based, matched cohort study of patients admitted with a validated first stroke in Denmark from April 1, 2004, to December 16, 2018, excluding those with prior epilepsy. Patients with stroke were matched 10:1 on age, sex, and calendar time with reference people without prior epilepsy or stroke. We estimated the cumulative incidence of an epilepsy diagnosis in the Danish National Patient Registry (International Classification of Diseases Tenth Revision: G40) with death as a competing risk using competing risk regression and estimated adjusted hazard ratios by Cox regression models. RESULTS: We identified 101â 034 patients with stroke (46.5% female; mean age, 70.4 years) who survived 14 days after stroke along with 1â 010â 333 matched reference people. Two years after the stroke, the cumulative incidence of epilepsy was 3.0% (95% CI, 2.9-3.2) after ischemic stroke and 8.6% (95% CI, 8.0-9.2) after intracerebral hemorrhage versus 0.7% (95% CI, 0.7-0.7) in the matched references. Compared with the reference population, the 2-year hazard ratio of epilepsy was 21.7 (95% CI, 20.3-23.2) after ischemic stroke and 61.3 (95% CI, 51.1-73.4) after intracerebral hemorrhage. The risk of epilepsy increased with stroke severity; the 2-year cumulative incidence of epilepsy was 10.5% (95% CI, 9.5-11.4) for very severe ischemic stroke and 13.1% (95% CI, 11.1-15.1) after very severe intracerebral hemorrhage. CONCLUSIONS: In this population-based study of patients with validated stroke, the absolute and relative risk estimates of poststroke epilepsy were lower compared with previous studies. Reasons for the lower risk estimates include accounting for the high mortality associated with stroke, which had a significant impact on risk especially for severe stroke.
Asunto(s)
Epilepsia , Accidente Cerebrovascular Isquémico , Accidente Cerebrovascular , Humanos , Femenino , Anciano , Masculino , Estudios de Cohortes , Estudios Prospectivos , Factores de Riesgo , Accidente Cerebrovascular/complicaciones , Hemorragia Cerebral/complicaciones , Epilepsia/epidemiología , Accidente Cerebrovascular Isquémico/complicaciones , Dinamarca/epidemiologíaRESUMEN
Centromedian nucleus (CM) is one of several intralaminar nuclei of the thalamus and is thought to be involved in consciousness, arousal, and attention. CM has been suggested to play a key role in the control of attention, by regulating the flow of information to different brain regions such as the ascending reticular system, basal ganglia, and cortex. While the neurophysiology of attention in visual and auditory systems has been studied in animal models, combined single unit and LFP recordings in human have not, to our knowledge, been reported. Here, we recorded neuronal activity in the CM nucleus in 11 patients prior to insertion of deep brain stimulation electrodes for the treatment of epilepsy while subjects performed an auditory attention task. Patients were requested to attend and count the infrequent (p = 0.2) odd or "deviant" tones, ignore the frequent standard tones and report the total number of deviant tones at trial completion. Spikes were discriminated, and LFPs were band pass filtered (5-45 Hz). Average peristimulus time histograms and spectra were constructed by aligning on tone onsets and statistically compared. The firing rate of CM neurons showed selective, multi-phasic responses to deviant tones in 81% of the tested neurons. Local field potential analysis showed selective beta and low gamma (13-45 Hz) modulations in response to deviant tones, also in a multi-phasic pattern. The current study demonstrates that CM neurons are under top-down control and participate in the selective processing during auditory attention and working memory. These results, taken together, implicate the CM in selective auditory attention and working memory and support a role of beta and low gamma oscillatory activity in cognitive processes. It also has potential implications for DBS therapy for epilepsy and non-motor symptoms of PD, such as apathy and other disorders of attention.
Asunto(s)
Atención , Percepción Auditiva , Núcleos Talámicos Intralaminares , Memoria a Corto Plazo , Neuronas , Humanos , Atención/fisiología , Masculino , Femenino , Memoria a Corto Plazo/fisiología , Adulto , Percepción Auditiva/fisiología , Núcleos Talámicos Intralaminares/fisiología , Persona de Mediana Edad , Neuronas/fisiología , Adulto Joven , Estimulación Acústica , Estimulación Encefálica Profunda/métodosRESUMEN
Medium-chain fatty acids (MCFAs), particularly decanoic acid (C10) and octanoic acid (C8), have garnered attention in recent years for their potential antiepileptic properties. A previous study from our laboratory demonstrated that C10 targets the PPARγ nuclear receptor, increasing the activity of the antioxidant enzyme catalase and thereby possibly modulating peroxisomal content. Here, we examined markers of peroxisomal content and activity in response to C10 and C8 exposure in neuronal-like SH-SY5Y cells. SH-SY5Y were treated with 250 mM C10 or C8 for a period of 6 days. Following this, biochemical markers of peroxisomal content and function were assessed, including acyl-coA oxidase activity, peroxisomal gene expression and peroxisomal VLCFA ß-oxidation. Our findings revealed that C10 treatment augments acyl-CoA oxidase 1 (ACOx1) activity by 129% in comparison to control cells. An exploration into genes related to peroxisomal biosynthesis showed 23% increased expression of PEX11α upon C10 exposure, implying peroxisomal proliferation. Furthermore, it was observed that C10 exposure not only elevated ACOx1 activity but also enhanced peroxisomal ß-oxidation of docosanoic acid (C22). Our findings bolster the premise that C10 functions as a peroxisome proliferator, influencing peroxisomal content and function. Further investigations are required to fully understand the mechanistic details as to how this may be beneficial in epilepsy and the potential implications with regards to peroxisomal disease.
RESUMEN
A dysfunctional gut microbiota-brain axis is emerging as a potential pathogenic mechanism in epilepsy, particularly in pediatric forms of epilepsy. To add new insights into gut-related changes in acquired epilepsy that develops early in life, we used a multi-omics approach in a rat model with a 56% incidence of epilepsy. The presence of spontaneous seizures was assessed in adult rats (n = 46) 5 months after status epilepticus induced by intra-amygdala kainate at postnatal day 13, by 2 weeks (24/7) ECoG monitoring. Twenty-six rats developed epilepsy (Epi) while the remaining 20 rats (No-Epi) did not show spontaneous seizures. At the end of ECoG monitoring, all rats and their sham controls (n = 20) were sacrificed for quantitative histopathological and immunohistochemical analyses of the gut structure, glia and macrophages, as well as RTqPCR analysis of inflammation/oxidative stress markers. By comparing Epi, No-Epi rats, and sham controls, we found structural, cellular, and molecular alterations reflecting a dysfunctional gut, which were specifically associated with epilepsy. In particular, the villus height-to-crypt depth ratio and number of Goblet cells were reduced in the duodenum of Epi rats vs both No-Epi rats and sham controls (p < 0.01). Villus height and crypt depth in the duodenum and jejunum (p < 0.01) were increased in No-Epi vs both Epi and sham controls. We also detected enhanced Iba1-positive macrophages, together with increased IL1b and NFE2L2 transcripts and TNF protein, in the small intestine of Epi vs both No-Epi and sham control rats (p < 0.01), denoting the presence of inflammation and oxidative stress. Astroglial GFAP-immunostaining was similar in all experimental groups. Metagenomic analysis in the feces collected 5 months after status epilepticus showed that the ratio of two dominant phyla (Bacteroidota-to-Firmicutes) was similarly increased in Epi and No-Epi rats vs sham control rats. Notably, the relative abundance of families, genera, and species associated with SCFA production differed in Epi vs No-Epi rats, describing a bacterial imprint associated with epilepsy. Furthermore, Epi rats showed a blood metabolic signature characterized by changes in lipid metabolism compared to both No-Epi and sham control rats. Our study provides new evidence of long-term gut alterations, along with microbiota-related metabolic changes, occurring specifically in rats that develop epilepsy after brain injury early in life.
Asunto(s)
Epilepsia , Microbioma Gastrointestinal , Estado Epiléptico , Humanos , Niño , Ratas , Animales , Convulsiones , InflamaciónRESUMEN
Children who experienced moderate perinatal asphyxia (MPA) are at risk of developing long lasting subtle cognitive and behavioral deficits, including learning disabilities and emotional problems. The prefrontal cortex (PFC) regulates cognitive flexibility and emotional behavior. Neurons that release serotonin (5-HT) project to the PFC, and compounds modulating 5-HT activity influence emotion and cognition. Whether 5-HT dysregulations contribute to MPA-induced cognitive problems is unknown. We established a MPA mouse model, which displays recognition and spatial memory impairments and dysfunctional cognitive flexibility. We found that 5-HT expression levels, quantified by immunohistochemistry, and 5-HT release, quantified by in vivo microdialysis in awake mice, are reduced in PFC of adult MPA mice. MPA mice also show impaired body temperature regulation following injection of the 5-HT1A receptor agonist 8-OH-DPAT, suggesting the presence of deficits in 5-HT auto-receptor function on raphe neurons. Finally, chronic treatment of adult MPA mice with fluoxetine, an inhibitor of 5-HT reuptake transporter, or the 5-HT1A receptor agonist tandospirone rescues cognitive flexibility and memory impairments. All together, these data demonstrate that the development of 5-HT system function is vulnerable to moderate perinatal asphyxia. 5-HT hypofunction might in turn contribute to long-term cognitive impairment in adulthood, indicating a potential target for pharmacological therapies.
Asunto(s)
Inhibidores Selectivos de la Recaptación de Serotonina , Serotonina , Humanos , Niño , Ratones , Animales , Serotonina/metabolismo , Receptor de Serotonina 5-HT1A , Asfixia , Fluoxetina/farmacología , Agonistas de Receptores de Serotonina/farmacología , Receptores de Serotonina , Cognición , 8-Hidroxi-2-(di-n-propilamino)tetralin/farmacología , HipoxiaRESUMEN
STriatal-Enriched protein tyrosine Phosphatase (STEP) is a brain-specific tyrosine phosphatase that is associated with numerous neurological and neuropsychiatric disorders. STEP dephosphorylates and inactivates various kinases and phosphatases critical for neuronal function and health including Fyn, Pyk2, ERK1/2, p38, and PTPα. Importantly, STEP dephosphorylates NMDA and AMPA receptors, two major glutamate receptors that mediate fast excitatory synaptic transmission. This STEP-mediated dephosphorylation leads to their internalization and inhibits both Hebbian synaptic potentiation and homeostatic synaptic scaling. Hence, STEP has been widely accepted to weaken excitatory synaptic strength. However, emerging evidence implicates a novel role of STEP in neuronal hyperexcitability and seizure disorders. Genetic deletion and pharmacological blockade of STEP reduces seizure susceptibility in acute seizure mouse models and audiogenic seizures in a mouse model of Fragile X syndrome. Pharmacologic inhibition of STEP also decreases hippocampal activity and neuronal intrinsic excitability. Here, we will highlight the divergent roles of STEP in excitatory synaptic transmission and neuronal intrinsic excitability, present the potential underlying mechanisms, and discuss their impact on STEP-associated neurologic and neuropsychiatric disorders.
RESUMEN
Failure to recover from repeated hypercapnia and hypoxemia (HH) challenges caused by severe GCS and postictal apneas may contribute to sudden unexpected death in epilepsy (SUDEP). Our previous studies found orexinergic dysfunction contributes to respiratory abnormalities in a preclinical model of SUDEP, Kcna1-/- mice. Here, we developed two gas challenges consisting of repeated HH exposures and used whole body plethysmography to determine whether Kcna1-/- mice have detrimental ventilatory responses. Kcna1-/- mice exhibited an elevated ventilatory response to a mild repeated hypercapnia-hypoxia (HH) challenge compared to WT. Moreover, 71% of Kcna1-/- mice failed to survive a severe repeated HH challenge, whereas all WT mice recovered. We next determined whether orexin was involved in these differences. Pretreating Kcna1-/- mice with a dual orexin receptor antagonist rescued the ventilatory response during the mild challenge and all subjects survived the severe challenge. In ex vivo extracellular recordings in the lateral hypothalamus of coronal brain slices, we found reducing pH either inhibits or stimulates putative orexin neurons similar to other chemosensitive neurons; however, a significantly greater percentage of putative orexin neurons from Kcna1-/-mice were stimulated and the magnitude of stimulation was increased resulting in augmentation of the calculated chemosensitivity index relative to WT. Collectively, our data suggest that increased chemosensitive activity of orexin neurons may be pathologic in the Kcna1-/- mouse model of SUDEP, and contribute to elevated ventilatory responses. Our preclinical data suggest that those at high risk for SUDEP may be more sensitive to HH challenges, whether induced by seizures or other means; and the depth and length of the HH exposure could dictate the probability of survival.
Asunto(s)
Modelos Animales de Enfermedad , Hipercapnia , Hipoxia , Ratones Noqueados , Neuronas , Orexinas , Muerte Súbita e Inesperada en la Epilepsia , Animales , Hipercapnia/fisiopatología , Hipercapnia/metabolismo , Hipoxia/metabolismo , Hipoxia/fisiopatología , Orexinas/metabolismo , Ratones , Neuronas/metabolismo , Canal de Potasio Kv.1.1/genética , Canal de Potasio Kv.1.1/metabolismo , Masculino , Ratones Endogámicos C57BLRESUMEN
BACKGROUND: Epilepsy is a paroxysmal abnormal hypersynchronous electrical discharge characterized by recurrent seizures. It affects more than 50 million people worldwide. Stress is the leading cause of neurodegeneration and can produce seizures that may lead to or aggravate epilepsy. Inflammation plays a vital role in epilepsy by modulating oxidative stress, and levels of neuroinflammatory cytokines including NF-κB, TNF-α, and IL-1ß. METHODS: Stress-induced changes in behavior were evaluated in mice by employing behavioral assessment tests such as an elevated plus maze, light-dark box, open field test, tail suspension test, Y-maze, novel object recognition test, and Morris water maze in pentylenetetrazole (PTZ) kindled mice. Behavioral changes in all these paradigms including seizure score, latency, and frequency showed an increase in symptoms in PTZ (35 mg/kg) induced seizures in stressed mice (RS-PTZ) as compared to PTZ, Stress, and normal animals. RESULTS: The Enzyme-linked immunosorbent assay (ELISA) results confirmed increased in serum cortisol levels. Histological examinations showed neurodegenerative changes in the hippocampus and cortex regions. The spectrophotometric evaluation showed an increase in oxidative stress by decreasing antioxidant production i.e. reduced glutathione, glutathione -s- transferase, and catalase (CAT), and increasing oxidant levels such as maloaldehyde and nitric oxide. Immunohistochemistry results showed increased expression of NF-κB, TNF-α, and IL-1ß in the cortex and hippocampus of mice brains. CONCLUSIONS: Results from the study conclude that stress increases the likelihood of eliciting an epileptic attack by increasing the level of reactive oxygen species and neuroinflammation.
Asunto(s)
Enfermedades Neuroinflamatorias , Estrés Oxidativo , Pentilenotetrazol , Convulsiones , Animales , Ratones , Convulsiones/metabolismo , Convulsiones/inducido químicamente , Convulsiones/patología , Masculino , Enfermedades Neuroinflamatorias/metabolismo , Enfermedades Neuroinflamatorias/etiología , Enfermedades Neuroinflamatorias/patología , Estrés Psicológico/complicaciones , Estrés Psicológico/metabolismo , Hipocampo/metabolismo , Hipocampo/patología , Enfermedad Crónica , Conducta AnimalRESUMEN
Whether striatal fast-spiking interneurons are involved in cortical synchronization remains elusive. We performed acute microinjections of a selective FSI-AMPA receptor antagonist into the sensorimotor striatum of non-human primates to verify whether selective FSI inhibition within the sensorimotor striatum could potentially modify cortical excitability, thereby triggering focal seizures. Experiments were performed on three fascicularis monkeys. During each experimental session, low volumes of IEM-1460 (4-8 µL) were injected slowly at 1 µL/min. Spontaneous behavioral changes were classified according to the Racine scale modified for primates. These induced motor behaviors were correlated with electroencephalographic (EEG and EMG) measures. Power spectrum and time-frequency analysis were performed and compared between each period of interest. Pharmacological selective inhibition of striatal fast-spiking INs induced focal motor seizures. Back averaging confirmed that myoclonic activity was closely linked to cortical spikes-and-waves epileptic activity, with a significant increase in cortical EEG power in all studied frequency bands (p < .0001). Thus, striatal FSIs likely play a role in controlling cortical excitability through the cortico-striato-thalamo-cortical pathway. They may contribute to the pathophysiology of focal motor epilepsies by modulating the threshold at which focal motor seizures are triggered.
Asunto(s)
Cuerpo Estriado , Convulsiones , Animales , Convulsiones/inducido químicamente , Inhibición Psicológica , Interneuronas , PrimatesRESUMEN
The central nervous system has long been thought to lack a clearance system similar to the peripheral lymphatic system. Therefore, the clearance of metabolic waste in the central nervous system has been a subject of great interest in neuroscience. Recently, the cerebral lymphatic drainage system, including the parenchymal clearance system and the meningeal lymphatic network, has attracted considerable attention. It has been extensively studied in various neurological disorders. Solute accumulation and neuroinflammation after epilepsy impair the blood-brain barrier, affecting the exchange and clearance between cerebrospinal fluid and interstitial fluid. Restoring their normal function may improve the prognosis of epilepsy. However, few studies have focused on providing a comprehensive overview of the brain clearance system and its significance in epilepsy. Therefore, this review addressed the structural composition, functions, and methods used to assess the cerebral lymphatic system, as well as the neglected association with epilepsy, and provided a theoretical basis for therapeutic approaches in epilepsy.
Asunto(s)
Epilepsia , Humanos , Sistema Linfático , Sistema Nervioso Central , Encéfalo , Barrera HematoencefálicaRESUMEN
Genetic epilepsy with febrile seizures plus (GEFS+) is a genetic epilepsy syndrome characterized by a marked hereditary tendency inherited as an autosomal dominant trait. Patients with GEFS+ may develop typical febrile seizures (FS), while generalized tonic-clonic seizures (GTCSs) with fever commonly occur between 3 months and 6 years of age, which is generally followed by febrile seizure plus (FS+), with or without absence seizures, focal seizures, or GTCSs. GEFS+ exhibits significant genetic heterogeneity, with polymerase chain reaction, exon sequencing, and single nucleotide polymorphism analyses all showing that the occurrence of GEFS+ is mainly related to mutations in the gamma-aminobutyric acid type A receptor gamma 2 subunit (GABRG2) gene. The most common mutations in GABRG2 are separated in large autosomal dominant families, but their pathogenesis remains unclear. The predominant types of GABRG2 mutations include missense (c.983A â T, c.245G â A, p.Met199Val), nonsense (R136*, Q390*, W429*), frameshift (c.1329delC, p.Val462fs*33, p.Pro59fs*12), point (P83S), and splice site (IVS6+2T â G) mutations. All of these mutations types can reduce the function of ion channels on the cell membrane; however, the degree and mechanism underlying these dysfunctions are different and could be linked to the main mechanism of epilepsy. The γ2 subunit plays a special role in receptor trafficking and is closely related to its structural specificity. This review focused on investigating the relationship between GEFS+ and GABRG2 mutation types in recent years, discussing novel aspects deemed to be great significance for clinically accurate diagnosis, anti-epileptic treatment strategies, and new drug development.
Asunto(s)
Mutación , Receptores de GABA-A , Convulsiones Febriles , Humanos , Receptores de GABA-A/genética , Convulsiones Febriles/genética , Mutación/genética , Epilepsia/genética , AnimalesRESUMEN
BACKGROUND: We compared dissociative seizure specific cognitive behavior therapy (DS-CBT) plus standardized medical care (SMC) to SMC alone in a randomized controlled trial. DS-CBT resulted in better outcomes on several secondary trial outcome measures at the 12-month follow-up point. The purpose of this paper is to evaluate putative treatment mechanisms. METHODS: We carried out a secondary mediation analysis of the CODES trial. 368 participants were recruited from the National Health Service in secondary / tertiary care in England, Scotland, and Wales. Sixteen mediation hypotheses corresponding to combinations of important trial outcomes and putative mediators were assessed. Twelve-month trial outcomes considered were final-month seizure frequency, Work and Social Adjustment Scale (WSAS), and the SF-12v2, a quality-of-life measure providing physical (PCS) and mental component summary (MCS) scores. Mediators chosen for analysis at six months (broadly corresponding to completion of DS-CBT) included: (a) beliefs about emotions, (b) a measure of avoidance behavior, (c) anxiety and (d) depression. RESULTS: All putative mediator variables except beliefs about emotions were found to be improved by DS-CBT. We found evidence for DS-CBT effect mediation for the outcome variables dissociative seizures (DS), WSAS and SF-12v2 MCS scores by improvements in target variables avoidance behavior, anxiety, and depression. The only variable to mediate the DS-CBT effect on the SF-12v2 PCS score was avoidance behavior. CONCLUSIONS: Our findings largely confirmed the logic model underlying the development of CBT for patients with DS. Interventions could be additionally developed to specifically address beliefs about emotions to assess whether it improves outcomes.
Asunto(s)
Terapia Cognitivo-Conductual , Análisis de Mediación , Convulsiones , Humanos , Terapia Cognitivo-Conductual/métodos , Masculino , Femenino , Adulto , Convulsiones/terapia , Persona de Mediana Edad , Trastornos Disociativos/terapia , Calidad de Vida , Resultado del Tratamiento , Ansiedad/terapia , Evaluación de Resultado en la Atención de Salud , Depresión/terapia , EscociaRESUMEN
Blockade of Angiotensin type 1 receptor (AT1R) has potential therapeutic utility in the treatment of numerous detrimental consequences of epileptogenesis, including oxidative stress, neuroinflammation, blood-brain barrier (BBB) dysfunction. We have recently shown that many of these pathological processes played a critical role in seizure onset and propagation in the Scn8a-N1768D mouse model. Here we investigate the efficacy and potential mechanism(s) of action of candesartan (CND), an FDA-approved angiotensin receptor blocker (ARB) indicated for hypertension, in improving outcomes in this model of pediatric epilepsy. We compared length of lifespan, seizure frequency, and BBB permeability in juvenile (D/D) and adult (D/+) mice treated with CND at times after seizure onset. We performed RNAseq on hippocampal tissue to quantify differences in genome-wide patterns of transcript abundance and inferred beneficial and detrimental effects of canonical pathways identified by enrichment methods in untreated and treated mice. Our results demonstrate that treatment with CND gives rise to increased survival, longer periods of seizure freedom, and diminished BBB permeability, as well as partially reversed or "normalized" disease-induced genome-wide gene expression profiles associated with inhibition of NF-κB, TNFα, IL-6, and TGF-ß signaling in juvenile and adult mice. Pathway analyses reveal that efficacy of CND is due to its known dual mechanism of action as both an AT1R antagonist and a PPARγ agonist. The robust efficacy of CND across ages, sexes and mouse strains is a positive indication for its translation to humans and its suitability of use for clinical trials in children with SCN8A epilepsy.
RESUMEN
Microglia are key players in maintaining brain homeostasis and exhibit phenotypic alterations in response to epileptic stimuli. However, it is still relatively unknown if these alterations are pro- or anti-epileptic. To unravel this dilemma, we employed chemogenetic manipulation of microglia using the artificial Gi-Dreadd receptor within a kainic acid (KA) induced murine seizure model. Our results indicate that acute Gi-Dreadd activation with Clozapine-N-Oxide can reduce seizure severity. Additionally, we observed increased interaction between microglia and neuronal soma, which correlated with reduced neuronal hyperactivity. Interestingly, prolonged activation of microglial Gi-Dreadds by repeated doses of CNO over 3 days, arrested microglia in a less active, homeostatic-like state, which associated with increased neuronal loss after KA induced seizures. RNAseq analysis revealed that prolonged activation of Gi-Dreadd interferes with interferon ß signaling and microglia proliferation. Thus, our findings highlight the importance of microglial Gi signaling not only during status epilepticus (SE) but also within later seizure induced pathology.
Asunto(s)
Microglía , Estado Epiléptico , Ratones , Animales , Microglía/patología , Convulsiones/inducido químicamente , Estado Epiléptico/inducido químicamente , Anticonvulsivantes , Encéfalo/patología , Ácido Kaínico/farmacologíaRESUMEN
The gut microbiota is altered in epilepsy and is emerging as a potential target for new therapies. We studied the effects of rifaximin, a gastrointestinal tract-specific antibiotic, on seizures and neuropathology and on alterations in the gut and its microbiota in a mouse model of temporal lobe epilepsy (TLE). Epilepsy was induced by intra-amygdala kainate injection causing status epilepticus (SE) in C57Bl6 adult male mice. Sham mice were injected with vehicle. Two cohorts of SE mice were fed a rifaximin-supplemented diet for 21 days, starting either at 24 h post-SE (early disease stage) or at day 51 post-SE (chronic disease stage). Corresponding groups of SE mice (one each disease stage) were fed a standard (control) diet. Cortical ECoG recording was done at each disease stage (24/7) for 21 days in all SE mice to measure the number and duration of spontaneous seizures during either rifaximin treatment or control diet. Then, epileptic mice ± rifaximin and respective sham mice were sacrificed and brain, gut and feces collected. Biospecimens were used for: (i) quantitative histological analysis of the gut structural and cellular components; (ii) markers of gut inflammation and intestinal barrier integrity by RTqPCR; (iii) 16S rRNA metagenomics analysis in feces. Hippocampal neuronal cell loss was assessed in epileptic mice killed in the early disease phase. Rifaximin administered for 21 days post-SE (early disease stage) reduced seizure duration (p < 0.01) and prevented hilar mossy cells loss in the hippocampus compared to epileptic mice fed a control diet. Epileptic mice fed a control diet showed a reduction of both villus height and villus height/crypt depth ratio (p < 0.01) and a decreased number of goblet cells (p < 0.01) in the duodenum, as well as increased macrophage (Iba1)-immunostaining in the jejunum (p < 0.05), compared to respective sham mice. Rifaximin's effect on seizures was associated with a reversal of gut structural and cellular changes, except for goblet cells which remained reduced. Seizure duration in epileptic mice was negatively correlated with the number of mossy cells (p < 0.01) and with villus height/crypt depth ratio (p < 0.05). Rifaximin-treated epileptic mice also showed increased tight junctions (occludin and ZO-1, p < 0.01) and decreased TNF mRNA expression (p < 0.01) in the duodenum compared to epileptic mice fed a control diet. Rifaximin administered for 21 days in chronic epileptic mice (chronic disease stage) did not change the number or duration of seizures compared to epileptic mice fed a control diet. Chronic epileptic mice fed a control diet showed an increased crypt depth (p < 0.05) and reduced villus height/crypt depth ratio (p < 0.01) compared to respective sham mice. Rifaximin treatment did not affect these intestinal changes. At both disease stages, rifaximin modified α- and ß-diversity in epileptic and sham mice compared to respective mice fed a control diet. The microbiota composition in epileptic mice, as well as the effects of rifaximin at the phylum, family and genus levels, depended on the stage of the disease. During the early disease phase, the abundance of specific taxa was positively correlated with seizure duration in epileptic mice. In conclusion, gut-related alterations reflecting a dysfunctional state, occur during epilepsy development in a TLE mouse model. A short-term treatment with rifaximin during the early phase of the disease, reduced seizure duration and neuropathology, and reversed some intestinal changes, strengthening the therapeutic effects of gut-based therapies in epilepsy.