No abstract

RBFOX3 mutations are linked to epilepsy and cognitive impairments, but the underlying pathophysiology of these disorders is poorly understood. Here we report replication of human symptoms in a mouse model with disrupted Rbfox3. Rbfox3 knockout mice displayed increased seizure susceptibility and decreased anxiety-related behaviors. Focusing on hippocampal phenotypes, we found Rbfox3 knockout mice showed increased expression of plasticity genes Egr4 and Arc, and the synaptic transmission and plasticity were defective in the mutant perforant pathway. The mutant dentate granules cells exhibited an increased frequency, but normal amplitude, of excitatory synaptic events, and this change was associated with an increase in the neurotransmitter release probability and dendritic spine density. Together, our results demonstrate anatomical and functional abnormality in Rbfox3 knockout mice, and may provide mechanistic insights for RBFOX3-related human brain disorders.

■ PURPOSE: To compare the effectiveness of high-intensity aerobic interval training (AIT) with active recovery and continuous moderate-intensity exercise (CME) on exercise capacity and metabolic risk factors in adults with cardiometabolic disorders through a systematic review and meta-analysis.■ METHODS: Studies were selected from 5 electronic databases (PubMed, MEDLINE, CINAHL, Physiotherapy Evidence Database [PEDro] and Cochrane Library Register of Controlled Trials). Randomized controlled trials (RCTs), published in English, that compared the effects of AIT with CME on exercise capacity and metabolic risk factors in adults with cardiometabolic disorders were included. Aerobic interval training was defined as high-intensity training separated by active recovery periods; CME incurred identical energy expenditure as AIT. Each trial was evaluated using the PEDro scale. Weighted mean difference (WMD) and 95% CIs were used to determine the effect size for each outcome.■ RESULTS: Six RCTs with 153 participants (40 overweight/obesity, 19 with metabolic syndrome, and 94 with heart disease) were included. The mean value on the PEDro scale for these studies was 5.0. Aerobic interval training significantly increased peak oxygen consumption (WMD, 3.6 mL·kg Ϫ1 ·min Ϫ1 ; 95% CI, 2.3-4.9) with a trend of decreasing fasting glucose (WMD, Ϫ0.4 mmol/L; 95% CI, Ϫ0.9 to 0.2, P ϭ .18) compared with CME. The effects on other metabolic risk factors were similar between AIT and CME.■ CONCLUSION: Analysis of a limited number of studies with small sample sizes indicates that AIT is superior to CME in terms of improving exercise capacity. Further high quality studies with larger sample size are required to confirm this finding in adults with cardiometabolic disorders.

Dysfunction of RBFOX3 has been identified in neurodevelopmental disorders such as autism spectrum disorder, cognitive impairments and epilepsy and a causal relationship with these diseases has been previously demonstrated with Rbfox3 homozygous knockout mice. Despite the importance of RBFOX3 during neurodevelopment, the function of RBFOX3 regarding neurogenesis and synaptogenesis remains unclear. To address this critical question, we profiled the developmental expression pattern of Rbfox3 in the brain of wild-type mice and analyzed brain volume, disease-relevant behaviors, neurogenesis, synaptic plasticity, and synaptogenesis in Rbfox3 homozygous knockout mice and their corresponding wild-type counterparts. Here we report that expression of Rbfox3 differs developmentally for distinct brain regions. Moreover, Rbfox3 homozygous knockout mice exhibited cold hyperalgesia and impaired cognitive abilities. Focusing on hippocampal phenotypes, we found Rbfox3 homozygous knockout mice displayed deficits in neurogenesis, which was correlated with cognitive impairments. Furthermore, RBFOX3 regulates the exons of genes with synapse-related function. Synaptic plasticity and density, which are related to cognitive behaviors, were altered in the hippocampal dentate gyrus of Rbfox3 homozygous knockout mice; synaptic plasticity decreased and the density of synapses increased. Taken together, our results demonstrate the important role of RBFOX3 during neural development and maturation. In addition, abnormalities in synaptic structure and function occur in Rbfox3 homozygous knockout mice. Our findings may offer mechanistic explanations for human brain diseases associated with dysfunctional RBFOX3.

Visual system development is light-experience dependent, which strongly implicates epigenetic mechanisms in light-regulated maturation. Among many epigenetic processes, genomic imprinting is an epigenetic mechanism through which monoallelic gene expression occurs in a parent-of-origin-specific manner. It is unknown if genomic imprinting contributes to visual system development. We profiled the transcriptome and imprintome during critical periods of mouse visual system development under normal- and dark-rearing conditions using B6/CAST F1 hybrid mice. We identified experience-regulated, isoform-specific and brain-region-specific imprinted genes. We also found imprinted microRNAs were predominantly clustered into the Dlk1-Dio3 imprinted locus with light experience affecting some imprinted miRNA expression. Our findings provide the first comprehensive analysis of light-experience regulation of the transcriptome and imprintome during critical periods of visual system development. Our results may contribute to therapeutic strategies for visual impairments and circadian rhythm disorders resulting from a dysfunctional imprintome.