Interneuron FGF13 regulates seizure susceptibility via a sodium channel-independent mechanism

eLife, Год журнала: 2025, Номер 13

Опубликована: Янв. 8, 2025

Developmental and epileptic encephalopathies (DEEs), a class of devastating neurological disorders characterized by recurrent seizures exacerbated disruptions to excitatory/inhibitory balance in the brain, are commonly caused mutations ion channels. Disruption of, or variants in, FGF13 were implicated as causal for set DEEs, but underlying mechanisms clouded because is expressed both excitatory inhibitory neurons, undergoes extensive alternative splicing producing multiple isoforms with distinct functions, overall roles neurons incompletely cataloged. To overcome these challenges, we generated novel cell-type-specific conditional knockout mice. Interneuron-targeted deletion Fgf13 led perinatal mortality associated impaired hippocampal inhibitory/excitatory while neuron-targeted no detectable survival deficits. While best studied voltage-gated sodium channel (Na v ) regulator, observed effect ablation interneurons on Na s rather marked reduction K + currents. Re-expressing different splice could partially rescue deficits interneuron excitability restore current amplitude. These results enhance our understanding molecular that drive pathogenesis Fgf13- related expand functions neuron subsets.

Язык: Английский

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Association of Seizure Control with Mortality, Cognition, and Function in People With Dementia

Annals of Neurology, Год журнала: 2024, Номер unknown

Опубликована: Окт. 30, 2024

Objectives The effects of seizure control on outcomes in persons with dementia (PWD) remain unclear. Our study aimed to investigate the impact mortality, function, cognition, and mood among PWD. Methods This longitudinal, multicenter is based 39 Alzheimer's disease centers (ADCs) United States from September 2005 December 2021. PWD were grouped by status into recurrent (seizures past year), remote (prior seizures but none no (controls). primary outcome was all‐cause mortality groups. We used Weibull survival analysis assess risks after adjusting for age, sex, education, race, ethnicity, hypertension, diabetes, hyperlipidemia, degree cognitive impairment, dominant (AD) mutation, brain trauma, stroke, Parkinson's disease, alcohol abuse, depression. Cognition (Clinical Dementia Rating), function (physical dependence nursing home residence), day‐to‐day activities (Functional Assessment Scores), (Geriatric Depression Scale) compared groups duration age. Results Among 26,501 participants, 374 (1.4%) had 510 (1.9%) seizures. In multivariable analysis, associated a higher risk than (adjusted hazard ratio [aHR], 95% confidence interval [95% CI]; aHR = 1.79, CI 1.51 2.12; 1.17, 0.98 1.38). Median time‐to‐death recurrent, remote, 2.4, 4.0, 4.7 years, respectively. People worse physical those controls. Interpretation poorly controlled have functional, These findings underscore need timely identification management ongoing ANN NEUROL 2024

Язык: Английский

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Imperatives and co-benefits of research into climate change and neurological disease

Nature Reviews Neurology, Год журнала: 2025, Номер unknown

Опубликована: Янв. 20, 2025

Язык: Английский

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Sudden Unexpected Death in Epilepsy: Central Respiratory Chemoreception

International Journal of Molecular Sciences, Год журнала: 2025, Номер 26(4), С. 1598 - 1598

Опубликована: Фев. 13, 2025

Sudden unexpected death in epilepsy (SUDEP) is a critical concern for individuals suffering from epilepsy, with respiratory dysfunction playing significant role its pathology. Fatal seizures are often characterized by central apnea and hypercapnia (elevated CO2 levels), indicating failure ventilatory control. Research has shown that both human patients animal models exhibit reduced hypercapnic response the interictal (non-seizure) period, suggesting an impaired ability to regulate breathing high levels. This review examines of chemoreceptors-specifically retrotrapezoid nucleus, raphe nuclei, nucleus tractus solitarius, locus coeruleus, hypothalamus this These structures sensing maintaining homeostasis. Emerging evidence also implicates neuropeptidergic pathways within these chemoreceptive regions SUDEP. Neuropeptides like galanin, pituitary adenylate cyclase-activating peptide (PACAP), orexin, somatostatin, bombesin-like peptides may modulate chemosensitivity function, potentially exacerbating during seizures. Understanding mechanisms linking chemoreception, control, signaling essential developing targeted interventions reduce risk SUDEP patients.

Язык: Английский

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Effect of adenosinergic manipulations on amygdala‐kindled seizures in mice: Implications for sudden unexpected death in epilepsy

Epilepsia, Год журнала: 2024, Номер 65(9), С. 2812 - 2826

Опубликована: Июль 9, 2024

Abstract Objective Sudden unexpected death in epilepsy (SUDEP) results more years of potential life lost than any neurological condition with the exception stroke. It is generally agreed that SUDEP happens due to some form respiratory, cardiac, and electrocerebral dysfunction following a seizure; however, mechanistic cause these perturbations unclear. One possible explanation lies adenosinergic signaling. Extracellular levels inhibitory neuromodulator adenosine rapidly rise during seizures, countermeasure necessary for seizure termination. Previous evidence has suggested excessive inhibition could increase risk by silencing brain areas life, such as respiratory nuclei brainstem. The goal this investigation was further clarify role seizure‐induced dysfunction. Methods To determine postictal physiological dysregulation, we pharmacologically manipulated signaling prior amygdala‐kindled seizures mice while recording electroencephalogram (EEG), electromyogram, breathing using whole body plethysmography. drugs used study included selective nonselective receptor antagonists inhibitors metabolism. Results We found high doses caused result death; counterintuitively, animals conditions did not experience had little or no generalized EEG suppression. Inhibitors metabolism effect on but worsen outcomes. Significance observed may be severity, vasoconstriction, phosphodiesterase at doses. These findings have implications consumption caffeine patients prevention SUDEP.

Язык: Английский

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Are we there yet? A critical evaluation of sudden and unexpected death in epilepsy models

Epilepsia, Год журнала: 2023, Номер 65(1), С. 9 - 25

Опубликована: Ноя. 2, 2023

Although animal models have helped to elaborate meaningful hypotheses about the pathophysiology of sudden and unexpected death in epilepsy (SUDEP), specific prevention strategies are still lacking, potentially reflecting limitations these intrinsic difficulties investigating SUDEP. The interpretation preclinical data their translation diagnostic therapeutic developments patients thus require a high level confidence relevance model human situation. Preclinical SUDEP heterogeneous include rodent nonrodent species. A critical aspect is whether animals isolated seizures exclusively induced by trigger, such as where elicited electrical stimulation, pharmacological intervention, or DBA mouse strains, they suffer from with spontaneous seizures, without SUDEP, either nongenetic etiology genetically based developmental epileptic encephalopathies. All advantages potential disadvantages, but it important be aware interpret appropriately translational perspective. majority genetic basis, whereas cases basis represent only small proportion total number. In almost all models, cardiorespiratory arrest occurs during course seizure, contrary that observed at time death, raising issue we studying periseizure death. However, some impossible avoid can part dependent on features which may difficult model. Several tools available address certain gaps pathophysiology, used further validate current models.

Язык: Английский

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Altered ventilatory responses to hypercapnia-hypoxia challenges in a preclinical SUDEP model involve orexin neurons

Neurobiology of Disease, Год журнала: 2024, Номер 199, С. 106592 - 106592

Опубликована: Июль 4, 2024

Failure to recover from repeated hypercapnia and hypoxemia (HH) challenges caused by severe GCS postictal apneas may contribute sudden unexpected death in epilepsy (SUDEP). Our previous studies found orexinergic dysfunction contributes respiratory abnormalities a preclinical model of SUDEP, Kcna1−/− mice. Here, we developed two gas consisting HH exposures used whole body plethysmography determine whether mice have detrimental ventilatory responses. exhibited an elevated response mild hypercapnia-hypoxia challenge compared WT. Moreover, 71% failed survive challenge, whereas all WT recovered. We next determined orexin was involved these differences. Pretreating with dual receptor antagonist rescued the during subjects survived challenge. In ex vivo extracellular recordings lateral hypothalamus coronal brain slices, reducing pH either inhibits or stimulates putative neurons similar other chemosensitive neurons; however, significantly greater percentage Kcna1−/−mice were stimulated magnitude stimulation increased resulting augmentation calculated chemosensitivity index relative Collectively, our data suggest that activity be pathologic mouse those at high risk for SUDEP more sensitive challenges, induced seizures means; depth length exposure could dictate probability survival.

Язык: Английский

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MK-212 precipitates seizure-induced death in amygdala-kindled mice via a non-5-HT2C receptor-mediated mechanism

Epilepsy & Behavior, Год журнала: 2025, Номер 167, С. 110385 - 110385

Опубликована: Март 25, 2025

Язык: Английский

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Lower respiratory rate during sleep in children with angelman syndrome compared to age-matched controls

Orphanet Journal of Rare Diseases, Год журнала: 2025, Номер 20(1)

Опубликована: Апрель 8, 2025

Abstract Background Angelman syndrome (AS) is a rare genetic neurodevelopmental disorder caused by the absence of functional UBE3A gene, leading to developmental, behavioral, and medical challenges. Sleep disturbances, including sleep-disordered breathing, are common in AS. This study, for first time, investigates nocturnal respiration individuals with AS healthy controls at home long term setting. Methods A non-invasive ballistocardiography-based (BCG) sleep monitoring device (“sleep mat”) placed under participants’ mattresses, was used remotely monitor children aged 1 12 years (6.0 ± 3.2 years, n = 40) age-matched typically developing (TDC) (6.2 3.5 20) approximately months. The mat recorded physiological signals during times bed. We applied fast-Fourier transformation (FFT) exclude segments without clear respiratory signal, thereby minimizing impact large body movements, wakefulness, or seizure activity. Moreover, polysomnography (PSG) collected up three nights each participant their home. Clinical characteristics, genotype, Bayley Scales Infant Toddler Development ® (Bayley-III) were also analyzed. Results average median BCG-derived rate over entire study duration significantly lower compared TDCs (Cohen’s d 1.31). PSG-derived data corroborated breathing 0.77) revealed strong correlation between BCG PSG derived ( r 0.85) thus convergent validity against “gold standard” measures. Next, we defined two groups based on rates: normal group rates above minimum TDC, low below TDC group’s minimum. higher prevalence abnormalities observed deletion carriers (55.2%) versus non-deletion (9.1%). Pulse oximetry indicated oxygen saturation levels 1.60). Bayley-III scores group, suggesting link dysfunction outcomes Medication use, particularly antiepileptic drugs, found suppress rates, highlighting complex interplay concomitant medication Conclusion Our provides long-term observational evidence persistent bradypnea-like phenotype AS, which may have significant implications clinical management. successful use as ambulatory tool demonstrates its potential digital health technology detecting pediatric disorders. These findings should be further assessed biomarker utility relation management cognitive development.

Язык: Английский

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Lethal Interactions of neuronal networks in epilepsy mediated by both synaptic and volume transmission indicate approaches to prevention

Progress in Neurobiology, Год журнала: 2025, Номер 249, С. 102770 - 102770

Опубликована: Апрель 19, 2025

Язык: Английский

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