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

Abstract

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.

Sodium channel β1 subunits participate in regulated intramembrane proteolysis-excitation coupling

“…In addition to their canonical roles in modulating the cell-surface localization, gating, and kinetics of sodium channel pore-forming α subunits ( 3 , 4 ), β1 subunits modulate potassium currents and participate in cell-cell and cell-matrix adhesion as CAMs ( 5 – 8 ). Scn1b -null mice, which model DEE52, have cell type–specific alterations in sodium current ( 9 – 13 ), multiple deficits in neuronal migration and pathfinding in the cerebellum ( 14 ), fewer nodes of Ranvier in the optic nerve ( 15 ), aberrant neuronal pathfinding and fasciculation in the corticospinal tract ( 16 ), delayed maturation of GABAergic signaling in the brain ( 17 ), abnormal formation of cardiac intercalated discs ( 18 ), and altered calcium signaling in cardiac ventricular myocytes ( 12 ). Finally, sodium channel β1 subunits are essential for normal development: Scn1b -null mice have severe seizures, ataxia, and cardiac arrhythmia, with 100% mortality by postnatal day 21 ( 10 , 15 ).…”

Regulation of the voltage-dependent sodium channel NaV1.1 by AKT1

“…All these models support the idea that the loss-of-function mutations of Na V 1.1 reduce the electrical excitability of GABAergic interneurons, which would imbalance the ratio of excitation and inhibition in neural circuits throughout the brain and lead to general hyperexcitability (Liautard et al, 2013;Ogiwara et al, 2007;Tran et al, 2020;Yu et al, 2006). The function of Na V 1.1 in vivo also depends on SCN1B, as evidenced in experiments in which the selective deletion of this gene in PV + neurons caused their hypoexcitability, accompanied by hyperexcitability of the network (Hull et al, 2020).…”

Complex synaptic and intrinsic interactions disrupt input/output functions in the hippocampus ofScn1bknockout mice

“…-/mice in our colony had spontaneous seizures and stunted growth beginning around P10 and exhibited 100% mortality by P22 (Chen et al, 2004;Hull et al, 2020).…”