Dissecting the phenotypes of Dravet syndrome by gene deletion

Abstract

*These authors contributed equally to this work.Neurological and psychiatric syndromes often have multiple disease traits, yet it is unknown how such multi-faceted deficits arise from single mutations. Haploinsufficiency of the voltage-gated sodium channel Na v 1.1 causes Dravet syndrome, an intractable childhood-onset epilepsy with hyperactivity, cognitive deficit, autistic-like behaviours, and premature death. Deletion of Na v 1.1 channels selectively impairs excitability of GABAergic interneurons. We studied mice having selective deletion of Na v 1.1 in parvalbumin-or somatostatin-expressing interneurons. In brain slices, these deletions cause increased threshold for action potential generation, impaired action potential firing in trains, and reduced amplification of postsynaptic potentials in those interneurons. Selective deletion of Na v 1.1 in parvalbumin-or somatostatin-expressing interneurons increases susceptibility to thermally-induced seizures, which are strikingly prolonged when Na v 1.1 is deleted in both interneuron types. Mice with global haploinsufficiency of Na v 1.1 display autistic-like behaviours, hyperactivity and cognitive impairment. Haploinsufficiency of Na v 1.1 in parvalbuminexpressing interneurons causes autistic-like behaviours, but not hyperactivity, whereas haploinsufficiency in somatostatin-expressing interneurons causes hyperactivity without autistic-like behaviours. Heterozygous deletion in both interneuron types is required to impair long-term spatial memory in context-dependent fear conditioning, without affecting short-term spatial learning or memory. Thus, the multi-faceted phenotypes of Dravet syndrome can be genetically dissected, revealing synergy in causing epilepsy, premature death and deficits in long-term spatial memory, but interneuron-specific effects on hyperactivity and autistic-like behaviours. These results show that multiple disease traits can arise from similar functional deficits in specific interneuron types.

Forty Years of Sodium Channels: Structure, Function, Pharmacology, and Epilepsy

“…We used the Cre-Lox method to delete Na V 1.1 channels specifically in each of these interneuron classes [82]. We found that these interneurons are selectively involved in the different DS phenotypes (Table 1; [82]).…”

“…We used the Cre-Lox method to delete Na V 1.1 channels specifically in each of these interneuron classes [82]. We found that these interneurons are selectively involved in the different DS phenotypes (Table 1; [82]). Deletion in PV interneurons causes pro-epileptic effects and autistic-like behavior, but not other phenotypes [82].…”

“…We found that these interneurons are selectively involved in the different DS phenotypes (Table 1; [82]). Deletion in PV interneurons causes pro-epileptic effects and autistic-like behavior, but not other phenotypes [82]. Deletion in SST interneurons causes pro-epileptic effects and hyperactivity, but not other phenotypes [82].…”

“…Deletion in PV interneurons causes pro-epileptic effects and autistic-like behavior, but not other phenotypes [82]. Deletion in SST interneurons causes pro-epileptic effects and hyperactivity, but not other phenotypes [82]. Deletion in both PV and SST interneurons causes synergistic effects on the severity of epilepsy and on cognitive deficit [82].…”

“…Deletion in SST interneurons causes pro-epileptic effects and hyperactivity, but not other phenotypes [82]. Deletion in both PV and SST interneurons causes synergistic effects on the severity of epilepsy and on cognitive deficit [82]. Deletion in 5-HT3aR interneurons causes only autistic-like effects without epilepsy or cognitive deficit (Cheah et al, unpublished).…”