Voltage-gated sodium channels in genetic epilepsy: up and down of excitability.

The past two decades have witnessed a wide range of studies investigating genetic variants of voltage-gated sodium (Na) channels, which are involved in a broad spectrum of diseases, including several types of epilepsy. We have reviewed here phenotypes and pathological mechanisms of genetic epilepsies caused by variants in Na α and β subunits, as well as of some relevant interacting proteins (FGF12/FHF1, PRRT2, and Ankyrin-G). Notably, variants of all these genes can induce either gain- or loss-of-function of Na leading to either neuronal hyperexcitability or hypoexcitability.

Idealized multiple-timescale model of cortical spreading depolarization initiation and pre-epileptic hyperexcitability caused by Na1.1/SCN1A mutations.

Na1.1 (SCN1A) is a voltage-gated sodium channel mainly expressed in GABAergic neurons. Loss of function mutations of Na1.

Neutrophil extracellular traps formed during chemotherapy confer treatment resistance via TGF-β activation.

Metastasis is the major cause of cancer death, and the development of therapy resistance is common. The tumor microenvironment can confer chemotherapy resistance (chemoresistance), but little is known about how specific host cells influence therapy outcome. We show that chemotherapy induces neutrophil recruitment and neutrophil extracellular trap (NET) formation, which reduces therapy response in mouse models of breast cancer lung metastasis.

Gain of function SCN1A disease-causing variants: Expanding the phenotypic spectrum and functional studies guiding the choice of effective antiseizure medication.

Objective: This study was undertaken to refine the spectrum of SCN1A epileptic disorders other than Dravet syndrome (DS) and genetic epilepsy with febrile seizures plus (GEFS+) and optimize antiseizure management by correlating phenotype-genotype relationship and functional consequences of SCN1A variants in a cohort of patients.

Methods: Sixteen probands carrying SCN1A pathogenic variants were ascertained via a national collaborative network. We also performed a literature review including individuals with SCN1A variants causing non-DS and non-GEFS+ phenotypes and compared the features of the two cohorts.

Risk factors associated with immune checkpoint inhibitor-induced acute kidney injury compared with other immune-related adverse events: a case-control study.

Background: Immune checkpoint inhibitors (ICIs) foster anti-cancer immune responses. Their efficacy comes at the cost of immune-related adverse events (IRAEs). The latter affects various organs, including kidneys, mostly as acute tubulointerstitial nephritis, the pathophysiology of which remains unclear.

A companion to the preclinical common data elements for rodent genetic epilepsy models. A report of the TASK3-WG1B: Paediatric and genetic models working group of the ILAE/AES joint translational TASK force.

Rodent models of epilepsy remain the cornerstone of research into the mechanisms underlying genetic epilepsy. Reproducibility of experiments using these rodent models, occurring across a diversity of laboratories and commercial vendors, remains an issue impacting the cost-effectiveness and scientific rigor of the studies performed. Here, we present two case report forms (CRFs) describing common data elements (CDE) for genetic rodent models, developed by the TASK3-WG1B Working Group of the International League Against Epilepsy (ILAE)/American Epilepsy Society (AES) Joint Translational Task Force.

Developmental and epileptic encephalopathies: from genetic heterogeneity to phenotypic continuum.

Developmental and epileptic encephalopathies (DEEs) are a heterogeneous group of disorders characterized by early-onset, often severe epileptic seizures and EEG abnormalities on a background of developmental impairment that tends to worsen as a consequence of epilepsy. DEEs may result from both nongenetic and genetic etiologies. Genetic DEEs have been associated with mutations in many genes involved in different functions including cell migration, proliferation, and organization, neuronal excitability, and synapse transmission and plasticity.

A companion to the preclinical common data elements for rodent models of pediatric acquired epilepsy: A report of the TASK3-WG1B, Pediatric and Genetic Models Working Group of the ILAE/AES Joint Translational Task Force.

Epilepsy syndromes during the early years of life may be attributed to an acquired insult, such as hypoxic-ischemic injury, infection, status epilepticus, or brain trauma. These conditions are frequently modeled in experimental rodents to delineate mechanisms of epileptogenesis and investigate novel therapeutic strategies. However, heterogeneity and subsequent lack of reproducibility of such models across laboratories is an ongoing challenge to maintain scientific rigor and knowledge advancement.

The gain of function SCN1A disorder spectrum: novel epilepsy phenotypes and therapeutic implications.

Brain voltage-gated sodium channel NaV1.1 (SCN1A) loss-of-function variants cause the severe epilepsy Dravet syndrome, as well as milder phenotypes associated with genetic epilepsy with febrile seizures plus. Gain of function SCN1A variants are associated with familial hemiplegic migraine type 3.

IL-17 triggers the onset of cognitive and synaptic deficits in early stages of Alzheimer's disease.

Neuroinflammation in patients with Alzheimer's disease (AD) and related mouse models has been recognized for decades, but the contribution of the recently described meningeal immune population to AD pathogenesis remains to be addressed. Here, using the 3xTg-AD model, we report an accumulation of interleukin-17 (IL-17)-producing cells, mostly γδ T cells, in the brain and the meninges of female, but not male, mice, concomitant with the onset of cognitive decline. Critically, IL-17 neutralization into the ventricles is sufficient to prevent short-term memory and synaptic plasticity deficits at early stages of disease.

Exploring the Mechanisms of Recovery in Anorexia Nervosa through a Translational Approach: From Original Ecological Measurements in Human to Brain Tissue Analyses in Mice.

Anorexia nervosa (AN) is a severe eating disorder where caloric restriction, excessive physical activity and metabolic alterations lead to life-threatening situations. Despite weight restoration after treatment, a significant part of patients experience relapses. In this translational study, we combined clinical and preclinical approaches.

Histone Deacetylase Inhibitors Ameliorate Morphological Defects and Hypoexcitability of iPSC-Neurons from Rubinstein-Taybi Patients.

Rubinstein-Taybi syndrome (RSTS) is a rare neurodevelopmental disorder caused by mutations in or genes encoding CBP/p300 lysine acetyltransferases. We investigated the efficacy of the histone deacetylase inhibitor (HDACi) Trichostatin A (TSA) in ameliorating morphological abnormalities of iPSC-derived young neurons from P149 and P34 -mutated patients and hypoexcitability of mature neurons from P149. Neural progenitors from both patients' iPSC lines were cultured one week with TSA 20 nM and, only P149, for 6 weeks with TSA 0.

ATM Protein Kinase: Old and New Implications in Neuronal Pathways and Brain Circuitry.

Despite that the human autosomal recessive disease ataxia telangiectasia (A-T) is a rare pathology, interest in the function of ataxia-telangiectasia mutated protein (ATM) is extensive. From a clinical point of view, the role of ATM in the central nervous system (CNS) is the most impacting, as motor disability is the predominant symptom affecting A-T patients. Coherently, spino-cerebellar neurodegeneration is the principal hallmark of A-T and other CNS regions such as dentate and olivary nuclei and brain stem are implicated in A-T pathophysiology.

SULT4A1 Modulates Synaptic Development and Function by Promoting the Formation of PSD-95/NMDAR Complex.

Sulfotransferase 4A1 (SULT4A1) is a cytosolic sulfotransferase that is highly conserved across species and extensively expressed in the brain. However, the biological function of SULT4A1 is unclear. SULT4A1 has been implicated in several neuropsychiatric disorders, such as Phelan-McDermid syndrome and schizophrenia.

SCN1A/Na 1.1 channelopathies: Mechanisms in expression systems, animal models, and human iPSC models.

Pathogenic SCN1A/Na 1.1 mutations cause well-defined epilepsies, including genetic epilepsy with febrile seizures plus (GEFS+) and the severe epileptic encephalopathy Dravet syndrome. In addition, they cause a severe form of migraine with aura, familial hemiplegic migraine.

Modeling cortical spreading depression induced by the hyperactivity of interneurons.

Cortical spreading depression (CSD) is a wave of transient intense neuronal firing leading to a long lasting depolarizing block of neuronal activity. It is a proposed pathological mechanism of migraine with aura. Some forms of migraine are associated with a genetic mutation of the Na channel, resulting in its gain of function and implying hyperexcitability of interneurons.

DNA damage and transcriptional regulation in iPSC-derived neurons from Ataxia Telangiectasia patients.

Ataxia Telangiectasia (A-T) is neurodegenerative syndrome caused by inherited mutations inactivating the ATM kinase, a master regulator of the DNA damage response (DDR). What makes neurons vulnerable to ATM loss remains unclear. In this study we assessed on human iPSC-derived neurons whether the abnormal accumulation of DNA-Topoisomerase 1 adducts (Top1ccs) found in A-T impairs transcription elongation, thus favoring neurodegeneration.

A two-hit story: Seizures and genetic mutation interaction sets phenotype severity in SCN1A epilepsies.

SCN1A (Na1.1 sodium channel) mutations cause Dravet syndrome (DS) and GEFS+ (which is in general milder), and are risk factors in other epilepsies. Phenotypic variability limits precision medicine in epilepsy, and it is important to identify factors that set phenotype severity and their mechanisms.

iPSC-derived neurons of CREBBP- and EP300-mutated Rubinstein-Taybi syndrome patients show morphological alterations and hypoexcitability.

Rubinstein-Taybi syndrome (RSTS) is a rare neurodevelopmental disorder characterized by distinctive facial features, growth retardation, broad thumbs and toes and mild to severe intellectual disability, caused by heterozygous mutations in either CREBBP or EP300 genes, encoding the homologous CBP and p300 lysine-acetyltransferases and transcriptional coactivators. No RSTS in vitro induced Pluripotent Stem Cell (iPSC)-neuronal model is available yet to achieve mechanistic insights on cognitive impairment of RSTS patients. We established iPSC-derived neurons (i-neurons) from peripheral blood cells of three CREBBP- and two EP300-mutated patients displaying different levels of intellectual disability, and four unaffected controls.