Cellular and behavioral effects of altered NaV1.2 sodium channel ion permeability in Scn2aK1422E mice.

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 developmental and epileptic encephalopathy, while loss-of-function variants that reduce neuronal excitability lead to intellectual disability and/or autism spectrum disorder (ASD) with or without co-morbid seizures. One unique case less easily classified using this framework is the de novo missense variant SCN2A-p.K1422E, associated with infant-onset developmental delay, infantile spasms and features of ASD. 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 incorporating variant channels that predicted reductions in peak action potential (AP) speed. We generated Scn2aK1422E mice and characterized effects on neurons and neurological/neurobehavioral phenotypes. Cultured cortical neurons from heterozygous Scn2aK1422E/+ mice exhibited lower current density with a TTX-resistant component and reversal potential consistent with mixed ion permeation. Recordings from Scn2aK1442E/+ cortical slices demonstrated impaired AP initiation and larger Ca2+ transients at the axon initial segment during the rising phase of the AP, suggesting complex effects on channel function. Scn2aK1422E/+ mice exhibited rare spontaneous seizures, interictal electroencephalogram abnormalities, altered induced seizure thresholds, reduced anxiety-like behavior and alterations in olfactory-guided social behavior. Overall, Scn2aK1422E/+ mice present with phenotypes similar yet distinct from other Scn2a models, consistent with complex effects of K1422E on NaV1.2 channel function.

Evaluating the effect of targeting body shape concerns on long-term weight change.

OBJECTIVE: The goal of this follow-up to a randomized proof-of-concept study was to determine if targeting body shape concern (BSC) has a clinically significant impact on long-term weight change among adult women of higher body weight with BSC. A secondary aim was to observe the maintenance of body image improvements during follow-up. METHOD: In the original 4-week trial, women were randomized to behavioral weight loss recommendations alone (control; n = 15) or combined with the evidence-based body project intervention (n = 17). All participants were directed to continue monitoring diet and exercise through Week 8. The current analysis focused on follow-up data collected on weight, BSC, internalized weight bias, internalized thin ideal, and body appreciation at 8 weeks, 6 months, and 12 months. Percent weight change was calculated from baseline and compared against clinical milestones of -2.5% and -5%. An intent-to-treat approach was used for individuals lost to follow-up (n = 11). RESULTS: Body project participants achieved the clinically significant target of -2.5% weight loss by 12 months. Control participants did not reach the milestone and regained lost weight at 12 months. Neither condition reached the 5% clinical target. Both groups experienced improved body image, but body project participants maintained a greater magnitude of improvement in all measures except internalized thin ideal at 12 months. CONCLUSION: The current study provides preliminary evidence that targeting BSC among women with BSC who want to lose weight may improve long-term weight loss. Further intervention development and testing are warranted. PUBLIC SIGNIFICANCE: The results of this study suggest that targeting negative body image among adult women with high BSC might be a pathway to improve long-term weight loss in behavioral weight management. This is aligned with precision medicine priorities to optimize weight-related health care.

Soticlestat, a novel cholesterol 24-hydroxylase inhibitor, reduces seizures and premature death in Dravet syndrome mice.

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.

Targeting body dissatisfaction among women with overweight or obesity: A proof-of-concept pilot study.

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.

The pain of weight-related stigma among women with overweight or obesity.

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<.001) as was internalized stigma. Perceived stigma mediated the relationship between BMI and bodily pain among individuals with a BMI in the overweight range but not among individuals with a BMI in the obese range. Weight-related stigma among women with overweight or obesity appears to be associated with greater experience of physical pain. These results underscore the need to evaluate multiple mechanisms that might explain the relationship between bodily pain and body weight and to determine how the relationship may vary across different subgroups of individuals.

Unique Sensory and Motor Behavior in Thy1-GFP-M Mice before and after Spinal Cord Injury.

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 < 0.01) and was maintained through 42 dpi (p < 0.01). These unexpected locomotor gains were not apparent during grid walking, indicating severe impairment of precise motor control. Thy1 derived mice were hypersensitive to mechanical stimuli at baseline (p < 0.05). After SCI, mechanical hyposensitivity emerged in Thy1 derived groups (p < 0.001), while thermal hyperalgesia occurred in all groups (p < 0.001). Importantly, consistent findings across TG+ and TG- groups suggest that the effects are mediated by the genetic background rather than transgene manipulation itself. Surprisingly, TM training restored mechanical and thermal sensation to baseline levels in TG+ mice with SCI. This behavioral profile and responsiveness to chronic training will be important to consider when choosing models to study the mechanisms underlying sensorimotor recovery after SCI.