Search

Objective Dravet syndrome is a severe developmental and epileptic encephalopathy (DEE) most often caused by de novo pathogenic variants in SCN1A. Individuals with Dravet syndrome rarely achieve seizure control and have significantly elevated risk for sudden unexplained death in epilepsy (SUDEP). Heterozygous deletion of Scn1a in mice (Scn1a+/- ) recapitulates several core phenotypes, including temperature-dependent and spontaneous seizures, SUDEP, and behavioral abnormalities. Furthermore, Scn1a+/- mice exhibit a similar clinical response to standard anticonvulsants. Cholesterol 24-hydroxlase (CH24H) is a brain-specific enzyme responsible for cholesterol catabolism. Recent research has indicated the therapeutic potential of CH24H inhibition for diseases associated with neural excitation, including seizures. Methods In this study, the novel compound soticlestat, a CH24H inhibitor, was administered to Scn1a+/- mice to investigate its ability to improve Dravet-like phenotypes in this preclinical model. Results Soticlestat treatment reduced seizure burden, protected against hyperthermia-induced seizures, and completely prevented SUDEP in Scn1a+/- mice. Video-electroencephalography (EEG) analysis confirmed the ability of soticlestat to reduce occurrence of electroclinical seizures. Significance This study demonstrates that soticlestat-mediated inhibition of CH24H provides therapeutic benefit for the treatment of Dravet syndrome in mice and has the potential for treatment of DEEs.

Genetic variants in SCN2A, encoding the NaV1.2 voltage-gated sodium channel, are associated with a range of neurodevelopmental disorders with overlapping phenotypes. Some variants fit into a framework wherein gain-of-function missense variants that increase neuronal excitability lead to infantile epileptic encephalopathy, while loss-of-function variants that reduce neuronal excitability lead to developmental delay and/or autism spectrum disorder with or without co- morbid seizures. One unique case less easily classified using this binary paradigm is the de novo missense variant SCN2A p.K1422E, associated with infant-onset developmental delay, infantile spasms, and features of autism spectrum disorder. Prior structure-function studies demonstrated that K1422E substitution alters ion selectivity of NaV1.2, conferring Ca2+ permeability, lowering overall conductance, and conferring resistance to tetrodotoxin (TTX). Based on heterologous expression of K1422E, we developed a compartmental neuron model that predicted mixed effects on channel function and neuronal activity. We also generated Scn2aK1422E mice and characterized effects on neurons and neurological/neurobehavioral phenotypes. Dissociated neurons from heterozygous Scn2aK1422E/+ mice exhibited a novel TTX-resistant current with a reversal potential consistent with mixed ion permeation. Cortical slice recordings from Scn2aK1442E/+ tissue demonstrated impaired action potential initiation and larger Ca2+ transients at the axon initial segment during the rising phase of the action potential, suggesting mixed effects on channel function. Scn2aK1422E/+ mice exhibited rare spontaneous seizures, interictal EEG abnormalities, altered response to induced seizures, reduced anxiety-like behavior and alterations in olfactory-guided social behavior. Overall, Scn2aK1422E/+ mice present with phenotypes similar yet distinct from Scn2a knockout models, consistent with mixed effects of K1422E on NaV1.2 channel function.Significance StatementThe early-onset epilepsy variant SCN2A-p.K1422E displays unique biophysical properties in vitro. To model the impact of this rare variant, we generated Scn2aK1422E mice. Neurons from heterozygous Scn2aK1422E/+ mice showed functional deficits similar to the loss-of-function effects observed in the Scn2a haploinsufficiency model, as well as gain-of-function effects specific to the K1422E variant. There is also some overlap in neurobehavioral phenotypes between Scn2aK1422E/+ and Scn2a haploinsufficient mice. However, Scn2aK1422E/+ mice exhibited unique epilepsy-related phenotypes, including epileptiform events and seizures. Scn2aK1422E/+ mice serve as a useful platform to investigate phenotypic complexity of SCN2A-associated disorders.

Pain is prevalent among individuals with overweight or obesity but few studies have examined the mechanism linking pain with excess body weight. Because there is evidence that social and physical pain may be processed through similar physiological mechanisms, weight-stigma may potentiate the experience of physical pain through shared neuroanatomical pathways. This study evaluated the relationship between perceived weight stigma and self-reported bodily pain in a sample of overweight and obese adult women. Sixty-one women with a body mass index (BMI) between 25–35 completed self-report questionnaires assessing perceived stigma, internalized weight stigma, and self-reported pain. Height and weight were measured and participants completed a demographic and health history questionnaire. Hierarchical regression analyses were utilized to predict self-reported pain from perceived stigma, adjusting for demographic variables associated with self-reported pain as well as pain-related conditions. Perceived stigma was associated with pain F(6, 54)=6.10, p

Sensorimotor recovery after spinal cord injury (SCI) is of utmost importance to injured individuals and will rely on improved understanding of SCI pathology and recovery. Novel transgenic mouse lines facilitate discovery, but must be understood to be effective. The purpose of this study was to characterize the sensory and motor behavior of a common transgenic mouse line (Thy1-GFP-M) before and after SCI. Thy1-GFP-M positive (TG+) mice and their transgene negative littermates (TG-) were acquired from two sources (in-house colony, n = 32, Jackson Laboratories, n = 4). C57BL/6J wild-type (WT) mice (Jackson Laboratories, n = 10) were strain controls. Moderate-severe T9 contusion (SCI) or transection (TX) occurred in TG+ (SCI, n = 25, TX, n = 5), TG- (SCI, n = 5), and WT (SCI, n = 10) mice. To determine responsiveness to rehabilitation, a cohort of TG+ mice with SCI (n = 4) had flat treadmill (TM) training 42–49 days post-injury (dpi). To characterize recovery, we performed Basso Mouse Scale, Grid Walk, von Frey Hair, and Plantar Heat Testing before and out to day 42 post-SCI. Open field locomotion was significantly better in the Thy1 SCI groups (TG+ and TG-) compared with WT by 7 dpi (p

Objective This proof-of-concept study was designed to replicate the effects of the empirically-supported Body Project intervention on body dissatisfaction when combined with behavioral recommendations for weight loss among women with overweight or obesity. Method Women with overweight or obesity who reported body dissatisfaction and a desire to lose weight were randomized to one of two 4-week treatment conditions. Individuals assigned to the standard group (n = 15) were directed to track diet and activity level daily. Body project (n = 17) participants tracked daily diet and activity, in addition to attending four weekly, group-based body project intervention sessions. Body mass index, body dissatisfaction, body appreciation, and internalization of thin ideal and weight stigma were evaluated before and after the treatment period. Results Feasibility data suggest the Body Project can be implemented with this novel sample. Preliminary estimates suggest greater effects on body appreciation in the Body Project group than in the standard group (ES = 0.43), but no group effects for other body image variables. Conclusions With minor modifications, the Body Project was successfully implemented among women with overweight or obesity. The effect on body appreciation is encouraging and worthy of further investigation. Modification to the intervention may be necessary to enhance treatment effects on other body image variables.