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

• Main Authors: Jacob M. Hull, Heather A. O’Malley, Chunling Chen, Yukun Yuan, Nicholas Denomme, Alexandra A. Bouza, Charles Anumonwo, Luis F. Lopez‐Santiago, Lori L. Isom
• Format: Article
• Language: English
• Published: Wiley 2020-11-01
• Series: Annals of Clinical and Translational Neurology
• Online Access: https://doi.org/10.1002/acn3.51205

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 (INa) and pyramidal neuron hyperexcitability. In contrast, Scn1a‐linked DEE variants, in general, are loss‐of‐function, resulting in decreased INa 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 Scn1bFL/FL mice to delete Scn1b in specific neuronal populations. Results Scn1b−/− cortical PV + interneurons were hypoexcitable, with reduced INa density. Scn1b−/− cortical pyramidal neurons had population‐specific changes in excitability and impaired INa 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.