Table 1.
Pharmacological targets for clinical phenotypes revealed by genetic models of Dravet syndrome.
| Phenotype | DEE Model | Molecular Mechanism | Reference |
|---|---|---|---|
| Seizures | Scn1a−/− and +/− mice | Reduced Na currents in GABA interneurons led to hyperexcitability of glutamatergic neurons in the hippocampus | Yu 2006 [29] |
| Zebrafish scn1Lab model of Dravet syndrome | Epileptiform activity occurred with reduced neural serotonin expression | Sourbron 2016 [30] | |
| scn1lab−/− zebrafish model of Dravet syndrome | GABAergic neuronal loss and astrogliosis (attenuated by fenfluramine) were noted | Tiraboschi 2020 [28] | |
| Neurodegeneration, cognitive deficits | Scn1a−/− mice | Cortical necrosis with cognitive deficits was evident in Scn1a−/− mice (rescued by liraglutide, a GLP-1 analogue) | Liu 2020 [31] |
| Cognitive defects, learning and memory | Cre-Lox Scn1a deletion localized to hippocampus in mice | Local loss of Nav1.1 function in the hippocampus selectively reduced inhibitory neurotransmission, resulting in thermally evoked seizures and spatial learning deficits | Stein 2019 [32] |
| Scn1a−/− and +/− mice | Reduced sodium currents in forebrain GABAergic neurons led to context-dependent spatial memory (rescued by clonazepam, a positive allosteric modulator of GABAA receptors) | Han 2017 [33] | |
| Hyperactive behavior | Zebrafish scn1a mutant model of Dravet syndrome | Sigma1R agonists abolished FFA-mediated inhibition and hyperlocomotion | Sourbron 2017 [23] |
| Autistic-like behavior | Scn1a−/− and +/− mice | Reduced sodium currents in forebrain GABAergic neurons led to social interaction deficits and stereotyped behaviors (rescued by clonazepam, a positive allosteric modulator of GABAA receptors) | Han 2017 [33] |
| Scn1a−/− and +/− mice | Reduced sodium currents in forebrain GABAergic neurons led to autistic-like social interaction deficits (rescued by CBD by antagonism at lipid-activated GPR55) | Kaplan Catterall 2017 [34] | |
| Motor: Ataxia |
Scn1a−/− and +/− mice | Reduced sodium currents in Purkinje cerebellar neurons led to ataxia | Kalume 2007 [35] |
| Emotional regulation | Scn1a +/− mice | Anxiety-related thigmotactic behavior and atypical fear expression were noted | Bahceci 2020 [36] |
| Disrupted sleep architecture | Scn1a−/− and +/− mice | Reduced sodium currents in the GABAergic reticular nucleus of the thalamus resulted in disrupted sleep architecture | Kalume 2015 [37] |
| SUDEP | Scn1a +/− mice and conditional brain- and cardiac-specific KO mice | SUDEP following GTCs in Scn1a+/− mice was caused by parasympathetic CNS hyperactivity, leading to lethal bradycardia | Kalume 2013 [38] |
| Mouse SUDEP model | Seizure-induced respiratory arrest (attenuated by fluoxetine at 5-HT3 without affecting seizures) occurred | Faingold 2016 [25] | |
| In vivo mouse DBA-1 model of SUDEP | Seizure-induced respiratory arrest (inhibited by FFA activity at 5-HT4) occurred | Faingold 2019 [26] |
Pharmacological or functional activity has not been reported at 5-HT3, 5-HT5, 5-HT6, or 5-HT7 receptors. 5-HT, serotonin; CBD, cannabidiol; CNS, central nervous system; DEE, developmental and epileptic encephalopathy; FFA, fenfluramine; GABA, γ-aminobutyric acid; GLP, glucagon-like peptide; GPR55, G-protein-coupled receptor 55; GTC, generalized tonic-clonic seizure; KO, knockout; Sigma1R, sigma-1 receptor; SUDEP, sudden unexpected death in epilepsy.