Reduced dendritic arborization and hyperexcitability of pyramidal neurons in a Scn1b-based model of Dravet syndrome

Reid, Christopher A.; Leaw, Bryan; Richards, Kay; Richardson, Robert J.; Wimmer, Verena C.; Yu, Christiaan; Hill‐Yardin, Elisa L.; Lerche, Holger; Scheffer, Ingrid E.; Berkovic, Samuel F.; Petrou, Steven

doi:10.1093/brain/awu077

Cited by 50 publications

(79 citation statements)

References 49 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…Mutations in VGSC genes are associated with multiple genetic epilepsies, including genetic epilepsy with febrile seizures plus (GEFSϩ) (Scheffer and Berkovic, 1997;Wallace et al, 1998;Singh et al, 1999) and Dravet syndrome (Patino et al, 2009). Autosomal-dominant mutations in SCN1B, encoding VGSC ␤1 and ␤1B, are associated with GEFSϩ (Wallace et al, 1998;Wal-lace et al, 2002;Scheffer et al, 2007).…”

Section: Introductionmentioning

confidence: 99%

“…Autosomal-dominant mutations in SCN1B, encoding VGSC ␤1 and ␤1B, are associated with GEFSϩ (Wallace et al, 1998;Wal-lace et al, 2002;Scheffer et al, 2007). SCN1B-C121W, the first reported GEFSϩ mutation, disrupts a critical, intramolecular disulfide bond within the extracellular ␤1 Ig loop domain (Wallace et al, 1998;Audenaert et al, 2003;Barbieri et al, 2012).…”

Section: Introductionmentioning

confidence: 99%

“…The effects of mutant ␤1-C121W subunit expression on VGSC function have been investigated extensively in heterologous systems, but results are cell-type and VGSC ␣-subunit specific (Moran and Conti, 2001;Meadows et al, 2002;Tammaro et al, 2002;Lucas et al, 2005;Aman et al, 2009;Egri et al, 2012;Baroni et al, 2013). Ex vivo studies of brain slices from the heterozygous Scn1b ϩ/W GEFSϩ knock-in mouse model showed temperature-sensitive changes in AP threshold and firing (Wimmer et al, 2010;Reid et al, 2014). In addition, Scn1b ϩ/W mice showed differences in dendritic branching in subicular neurons that may be consistent with defects in ␤1-mediated cell-cell adhesion (Wimmer et al, 2010;Reid et al, 2014).…”

Section: Introductionmentioning

confidence: 99%

“…Ex vivo studies of brain slices from the heterozygous Scn1b ϩ/W GEFSϩ knock-in mouse model showed temperature-sensitive changes in AP threshold and firing (Wimmer et al, 2010;Reid et al, 2014). In addition, Scn1b ϩ/W mice showed differences in dendritic branching in subicular neurons that may be consistent with defects in ␤1-mediated cell-cell adhesion (Wimmer et al, 2010;Reid et al, 2014). Although multiple in vitro studies have demonstrated ␤1-C121W polypeptide expression at the surface of heterologous cells in which cDNA was overexpressed (Meadows et al, 2002;Tammaro et al, 2002;Patino et al, 2011), viral transduction of mouse neurons predicted that ␤1-C121W may be retained inside the cell and thus is nonfunctional (Wimmer et al, 2010).…”

Section: Introductionmentioning

confidence: 99%

“…Although multiple in vitro studies have demonstrated ␤1-C121W polypeptide expression at the surface of heterologous cells in which cDNA was overexpressed (Meadows et al, 2002;Tammaro et al, 2002;Patino et al, 2011), viral transduction of mouse neurons predicted that ␤1-C121W may be retained inside the cell and thus is nonfunctional (Wimmer et al, 2010). Studies of homozygous Scn1b W/W knock-in mice, which have a severe phenotype similar to the epileptic encephalopathy Dravet syndrome, showed differences in dendritic branching consistent with defects in ␤1-mediated cell-cell adhesion (Wimmer et al, 2010;Reid et al, 2014). ␤1-C121W subunits failed to localize at axon initial segments (AISs) of subicular neurons in these mice; however, whether the mutant ␤1 polypeptides were expressed at the neuronal cell surface was not addressed (Wimmer et al, 2015).…”

Section: Introductionmentioning

confidence: 99%

See 4 more Smart Citations

β1-C121W Is Down But Not Out: Epilepsy-AssociatedScn1b-C121WResults in a Deleterious Gain-of-Function

Kruger¹,

O’Malley²,

Hull

et al. 2016

J. Neurosci.

View full text Add to dashboard Cite

Voltage-gated sodium channel (VGSC) ␤ subunits signal through multiple pathways on multiple time scales. In addition to modulating sodium and potassium currents, ␤ subunits play nonconducting roles as cell adhesion molecules, which allow them to function in cell-cell communication, neuronal migration, neurite outgrowth, neuronal pathfinding, and axonal fasciculation. Mutations in SCN1B, encoding VGSC ␤1 and ␤1B, are associated with epilepsy. Autosomal-dominant SCN1B-C121W, the first epilepsy-associated VGSC mutation identified, results in genetic epilepsy with febrile seizures plus (GEFSϩ). This mutation has been shown to disrupt both the sodium-current-modulatory and cell-adhesive functions of ␤1 subunits expressed in heterologous systems. The goal of this study was to compare mice heterozygous for Scn1b-C121W (Scn1b ϩ/W ) with mice heterozygous for the Scn1b-null allele (Scn1b ϩ/ Ϫ ) to determine whether the C121W mutation results in loss-of-function in vivo. We found that Scn1b ϩ/W mice were more susceptible than Scn1b ϩ/ Ϫ and Scn1b ϩ/ϩ mice to hyperthermia-induced convulsions, a model of pediatric febrile seizures. ␤1-C121W subunits are expressed at the neuronal cell surface in vivo. However, despite this, ␤1-C121W polypeptides are incompletely glycosylated and do not associate with VGSC ␣ subunits in the brain. ␤1-C121W subcellular localization is restricted to neuronal cell bodies and is not detected at axon initial segments in the cortex or cerebellum or at optic nerve nodes of Ranvier of Scn1b W/W mice. These data, together with our previous results showing that ␤1-C121W cannot participate in trans-homophilic cell adhesion, lead to the hypothesis that SCN1B-C121W confers a deleterious gain-of-function in human GEFSϩ patients.

show abstract

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 3 more Smart Citations

β1-C121W Is Down But Not Out: Epilepsy-AssociatedScn1b-C121WResults in a Deleterious Gain-of-Function

Kruger¹,

O’Malley²,

Hull

et al. 2016

J. Neurosci.

View full text Add to dashboard Cite

show abstract

Excitatory and inhibitory neuron defects in a mouse model of Scn1b‐linked EIEE52

Hull

O’Malley²,

Chen

et al. 2020

Ann Clin Transl Neurol

View full text Add to dashboard Cite

Objective: Human variants in voltage-gated sodium channel (VGSC) α and β subunit genes are linked to developmental and epileptic encephalopathies (DEEs). Inherited, biallelic, loss-of-function variants in SCN1B, encoding the β1/β1B subunits, are linked to early infantile DEE (EIEE52). De novo, monoallelic variants in SCN1A (Nav1.1), SCN2A (Nav1.2), SCN3A (Nav1.3), and SCN8A (Nav1.6) are also linked to DEEs. While these VGSC-linked DEEs have similar presentations, they have diverse mechanisms of altered neuronal excitability. Mouse models have suggested that Scn2a-, Scn3a-, and Scn8a-linked DEE variants are, in general, gain of function, resulting in increased persistent or resurgent sodium current (I Na) and pyramidal neuron hyperexcitability. In contrast, Scn1a-linked DEE variants, in general, are loss-of-function, resulting in decreased I Na and hypoexcitability of fast-spiking interneurons. VGSC β1 subunits associate with Nav1.1, Nav1.2, Nav1.3, and Nav1.6 and are expressed throughout the brain, raising the possibility that insults to both pyramidal and interneuron excitability may drive EIEE52 pathophysiology. Methods: We investigated excitability defects in pyramidal and parvalbumin-positive (PV +) interneurons in the Scn1b −/− model of EIEE52. We also used Scn1b FL/FL mice to delete Scn1b in specific neuronal populations. Results: Scn1b −/− cortical PV + interneurons were hypoexcitable, with reduced I Na density. Scn1b −/− cortical pyramidal neurons had population-specific changes in excitability and impaired I Na density. Scn1b deletion in PV + neurons resulted in 100% lethality, whereas deletion in Emx1 + or Camk2a + neurons did not affect survival. Interpretation: This work suggests that SCN1B-linked DEE variants impact both excitatory and inhibitory neurons, leading to the increased severity of EIEE52 relative to other DEEs.

show abstract

Exome‐based analysis of cardiac arrhythmia, respiratory control, and epilepsy genes in sudden unexpected death in epilepsy

Bagnall

Crompton

Petrovski

et al. 2016

Annals of Neurology

Self Cite

231

238

View full text Add to dashboard Cite

show abstract

Reduced dendritic arborization and hyperexcitability of pyramidal neurons in a Scn1b-based model of Dravet syndrome

Cited by 50 publications

References 49 publications

β1-C121W Is Down But Not Out: Epilepsy-AssociatedScn1b-C121WResults in a Deleterious Gain-of-Function

β1-C121W Is Down But Not Out: Epilepsy-AssociatedScn1b-C121WResults in a Deleterious Gain-of-Function

Excitatory and inhibitory neuron defects in a mouse model of Scn1b‐linked EIEE52

Exome‐based analysis of cardiac arrhythmia, respiratory control, and epilepsy genes in sudden unexpected death in epilepsy

Contact Info

Product

Resources

About