Interneurons exhibit attenuated ectopic action potential firing in a severe neurodevelopmental disorder.

Dravet syndrome (DS) is a severe neurodevelopmental disorder associated with treatment-resistant epilepsy and features of autism spectrum disorder due to loss of the voltage-gated sodium channel subunit Nav1.1. Recent work suggests that a pathogenic mechanism of DS is impaired action potential propagation along axons of cerebral cortex parvalbumin-positive fast-spiking GABAergic interneurons (PVINs).

Parvalbumin interneuron impairment causes synaptic transmission deficits and seizures in SCN8A developmental and epileptic encephalopathy.

SCN8A developmental and epileptic encephalopathy (DEE) is a severe epilepsy syndrome resulting from mutations in the voltage-gated sodium channel Nav1.6, encoded by the gene SCN8A. Nav1.

Parvalbumin Interneuron Impairment Leads to Synaptic Transmission Deficits and Seizures in Epileptic Encephalopathy.

epileptic encephalopathy (EE) is a severe epilepsy syndrome resulting from mutations in the voltage-gated sodium channel Na 1.6, encoded by the gene . Na 1.

Targeted therapy improves cellular dysfunction, ataxia, and seizure susceptibility in a model of a progressive myoclonus epilepsy.

The recurrent variant KCNC1-p.Arg320His causes progressive myoclonus epilepsy (EPM) type 7, defined by progressive myoclonus, epilepsy, and ataxia, and is without effective treatment. KCNC1 encodes the voltage-gated potassium channel subunit Kv3.

Developmentally regulated impairment of parvalbumin interneuron synaptic transmission in an experimental model of Dravet syndrome.

Dravet syndrome is a neurodevelopmental disorder characterized by epilepsy, intellectual disability, and sudden death due to pathogenic variants in SCN1A with loss of function of the sodium channel subunit Nav1.1. Nav1.

Targeted Augmentation of Nuclear Gene Output (TANGO) of Scn1a rescues parvalbumin interneuron excitability and reduces seizures in a mouse model of Dravet Syndrome.

Dravet Syndrome (DS) is a severe developmental and epileptic encephalopathy typically caused by loss-of-function de novo mutations in the SCN1A gene which encodes the voltage-gated sodium channel isoform Na1.1. Decreased Na1.

Astrocyte reactivity in a mouse model of SCN8A epileptic encephalopathy.

Objective: SCN8A epileptic encephalopathy is caused predominantly by de novo gain-of-function mutations in the voltage-gated sodium channel Na 1.6. The disorder is characterized by early onset of seizures and developmental delay.

Somatostatin-Positive Interneurons Contribute to Seizures in Epileptic Encephalopathy.

epileptic encephalopathy is a devastating epilepsy syndrome caused by mutant , which encodes the voltage-gated sodium channel Na1.6. To date, it is unclear if and how inhibitory interneurons, which express Na1.

Adrenergic Mechanisms of Audiogenic Seizure-Induced Death in a Mouse Model of Encephalopathy.

Sudden unexpected death in epilepsy (SUDEP) is the leading cause of death amongst patients whose seizures are not adequately controlled by current therapies. Patients with encephalopathy have an elevated risk for SUDEP. While transgenic mouse models have provided insight into the molecular mechanisms of encephalopathy etiology, our understanding of seizure-induced death has been hampered by the inability to reliably trigger both seizures and seizure-induced death in these mice.

Postictal Death Is Associated with Tonic Phase Apnea in a Mouse Model of Sudden Unexpected Death in Epilepsy.

Objective: Sudden unexpected death in epilepsy (SUDEP) is an unpredictable and devastating comorbidity of epilepsy that is believed to be due to cardiorespiratory failure immediately after generalized convulsive seizures.

Methods: We performed cardiorespiratory monitoring of seizure-induced death in mice carrying either a p.Arg1872Trp or p.

The Role of the Persistent Sodium Current in Epilepsy.

Voltage-gated sodium channels (VGSCs) are foundational to excitable cell function: Their coordinated passage of sodium ions into the cell is critical for the generation and propagation of action potentials throughout the nervous system. The classical paradigm of action potential physiology states that sodium passes through the membrane only transiently (1-2 milliseconds), before the channels inactivate and cease to conduct sodium ions. However, in reality, a small fraction of the total sodium current (1%-2%) remains at steady state despite prolonged depolarization.

Biallelic inherited SCN8A variants, a rare cause of SCN8A-related developmental and epileptic encephalopathy.

Objective: Monoallelic de novo gain-of-function variants in the voltage-gated sodium channel SCN8A are one of the recurrent causes of severe developmental and epileptic encephalopathy (DEE). In addition, a small number of de novo or inherited monoallelic loss-of-function variants have been found in patients with intellectual disability, autism spectrum disorder, or movement disorders. Inherited monoallelic variants causing either gain or loss-of-function are also associated with less severe conditions such as benign familial infantile seizures and isolated movement disorders.

Prax330 reduces persistent and resurgent sodium channel currents and neuronal hyperexcitability of subiculum neurons in a mouse model of SCN8A epileptic encephalopathy.

SCN8A epileptic encephalopathy is a severe genetic epilepsy syndrome caused by de novo gain-of-function mutations of SCN8A encoding the voltage-gated sodium (Na) channel (VGSC) Na1.6. Therapeutic management is difficult in many patients, leading to uncontrolled seizures and risk of sudden unexpected death in epilepsy (SUDEP).

Prominent role of forebrain excitatory neurons in SCN8A encephalopathy.

De novo mutations of the sodium channel gene SCN8A result in an epileptic encephalopathy with refractory seizures, developmental delay, and elevated risk of sudden death. p.Arg1872Trp is a recurrent de novo SCN8A mutation reported in 14 unrelated individuals with epileptic encephalopathy that included seizure onset in the prenatal or infantile period and severe verbal and ambulatory comorbidities.

The novel sodium channel modulator GS-458967 (GS967) is an effective treatment in a mouse model of SCN8A encephalopathy.

Objective: De novo mutations of SCN8A, encoding the voltage-gated sodium channel Na 1.6, have been associated with a severe infant onset epileptic encephalopathy. Individuals with SCN8A encephalopathy have a mean age of seizure onset of 4-5 months, with multiple seizure types that are often refractory to treatment with available drugs.

Partial loss-of-function of sodium channel SCN8A in familial isolated myoclonus.

Variants in the neuronal sodium channel gene SCN8A have been implicated in several neurological disorders. Early infantile epileptic encephalopathy type 13 results from de novo gain-of-function mutations that alter the biophysical properties of the channel. Complete loss-of-function variants of SCN8A have been identified in cases of isolated intellectual disability.