SCN1A

We have identified a homeostatic response in a Scn1a+/- mouse model of Dravet syndrome (DS), a developmental and epileptic encephalopathy caused by genetic variants of the SCN1A gene, leading to loss of function of the NaV1.1 sodium channel and consequent hypoexcitability of GABAergic neurons. Strikingly, we observed that cholecystokinin (CCK)-positive basket cells are hyperexcitable, unlike other GABAergic neurons, leading to increased release of CCK, which is a neuromodulator that can increase the excitability of other GABAergic interneurons. We have boosted this homeostatic response in a th

Mutations in the sodium channel NaV1.1, encoded by SCN1A, are associated with a range of epileptic disorders in which febrile seizures with varying rates of severity are involved, such as Dravet syndrome (DS), generalised epilepsy with febrile seizures plus (GEFS+) and familial febrile seizures (FS). It is thought that NaV1.1 deficiency leads to a reduction in firing of GABAergic inhibitory interneurons which causes an imbalance between excitation and inhibition, resulting in a hyperactive network. Alternatively, a hyperactive network can also result from an increase in excitatory signalling,

…is caused by haploinsufficiency of SCN1A gene, encoding the alpha subunit of the voltage-gated sodium channel Nav1.1. While DS onset is triggered by interneuron (IN) hypoexcitability, alterations in glutamatergic neurons contribute to its progression. Current gene therapy strategies aim to boost SCN1A gene expression in INs, prompting this study to investigate whether targeting them alone at various disease stages is suffici

…of DS is haploinsufficiency of the SCN1A gene, which encodes the voltage-gated sodium channel Nav1.1. In current mouse models of DS, the epileptic phenotype is strictly dependent on the genetic background and most mouse models exhibit drastically higher SUDEP rates than patients. Therefore, we sought to develop an alternative animal

…due to loss of function variants in SCN1A, the disease mostly manifests because of the impairment of the functionality of inhibitory interneurons. Trying to address the unmet clinical needs of patients carrying missense variants, we used a transgenic mouse model carrying the recurrent variant p.(Ala1783Val) in Scn1a. This mouse closely recapitulates the clinical phenotype, allowing to more deeply explore the epileptogenesis and find new precision medicine approaches.We carried ou

Voltage-gated sodium channels (Navs) play an integral role in brain function and development, enabling the generation and transmission of electrical signals with implications for neuronal excitability, synapse formation, and circuit establishment. Despite the distinct spatiotemporal expression of Navs, the understanding of their regulation in the developing brain is limited. Here we investigated the involvement of microRNAs (miRNAs), short non-coding RNAs, in the post-transcriptional regulation of sodium channel subunit expression. We carried out Argonaute sequencing on mouse hippocampal tissu

The long-term goal of our research is to understand the mechanisms of SUDEP, defined as Sudden, Unexpected, witnessed or unwitnessed, nontraumatic and non-drowning Death in patients with EPilepsy, excluding cases of documented status epilepticus. The majority of SUDEP patients die during sleep. SUDEP is the most devastating consequence of epilepsy, yet little is understood about its causes and no biomarkers exist to identify at risk patients. While SUDEP accounts for 7.5-20% of all epilepsy deaths, SUDEP risk in the genetic epilepsies varies with affected genes. Patients with ion channel gene

…loss-of-function mutations in the SCN1A gene, which encodes for the alpha-subunit of the voltage-gated sodium channel (Nav1.1) and is responsible mainly of GABAergic interneuron excitability. While different therapies based on the upregulation of the healthy allele of the gene are being developed, the dynamics of reversibility of the pathology are still unclear. In fact, whether and to which extent the

Genetic mutations of the SCN1A gene, the voltage gated sodium channel NaV1.1, cause well-defined epilepsies, including the severe developmental and epileptic encephalopathy Dravet syndrome and genetic epilepsy with febrile seizures plus (GEFS+), as well as a severe form of migraine with aura, familial hemiplegic migraine (FHM). More recently, they have been identified in an extremely severe early infantile encephalopathy. Functional studies and animal models have contributed to disclose pathological mechanisms, which can be often linked to a straightforward loss- vs gain- of channel function.

…loss-of-function of the gene SCN1A encoding the voltage-gated sodium channel subunit Nav1.1, and is defined by treatment-resistant epilepsy, intellectual impairment, and sudden death. However, disease mechanisms remain unclear, as previously-identified deficiency in action potential generation of Nav1.1-expressing parvalbumin-positive fast-spiking GABAergic interneurons (PV-INs) in DS (Scn1a+/-) mice normalizes during development. We used a novel approach that facilitated the assessment of PV-IN function at both early

…loss-of-function mutation of the gene SCN1A, which encodes the type 1 neuronal voltage gated sodium (Na+) channel alpha-subunit Nav1.1. Prior studies in mouse models of Dravet syndrome (Scn1a+/- mice) at early developmental time points indicate that, in cerebral cortex, Nav1.1 is predominantly expressed in GABAergic interneurons (INs) and, in particular, in parvalbumin-positive fast-spiking basket cells (PV-INs). This has led to a model of Dravet syndrome pathogenesis whereby Nav1.1 mutation leads to preferential IN dysfunction