Abstract Fyn-related kinase (FRK) belonging to the Src family of non-receptor protein tyrosine kinases functions during the cell cycle. Here, we reported an autism spectrum disorders (ASD) patient with intragenic mutation of FRK with two other ASD risk genes. Circumventing the barrier of murine model studies, we generated the CRISPR/Cas9-engineered frk−/− zebrafish. We found that frk-knockout led to increased brain sizes. Frk−/− fish exhibited an ASD-like behavior, including impaired social communication, altered anxiety level, and cognitive dysfunction in both larvae and adults, which could be rescued by the transgenic neuron-specific re-expression of frk. GO and KEGG analysis of RNA-sequencing data found that the frk-knockout-induced DEGs were mainly concentrated in processes and functions related to cell metabolisms. PPI network analysis of the detected DEGs suggested that the cyp24a1/tp53 pathway may play a key role in frk-knockout-induced ASD. Furthermore, we found that the numbers of BrdU+ cells were significantly increased in the frk−/− larval brains. Cyp24a1-inhibition or tp53-activation, reduced cell proliferation and partially ameliorated social impairments in frk−/− zebrafish. Overall, our work established an ASD model of frk-knockout with assessable behavior phenotype in zebrafish and provided key insights into cell proliferation and the influence of cyp24a1/tp53 pathway-regulated cell proliferation on frk-knockout-induced ASD-like behaviors.
Abstract Attention deficit/hyperactivity disorder (ADHD) is one of the most common neurodevelopmental disorders, with many gender differences, including attention dimensions. However, the gender differences in eye movements of different attention dimensions and the affecting factors in children with ADHD are still elusive. We enrolled 311 ADHD children who were initially diagnosed and used the combination of computer cancellation test and eye tracking (ET) to examined the eye movement patterns in different attention dimensions and its correlating factors and gender differences in ADHD children. We found that male ADHD children have more severe attention arousal deficits, and careless explorations of the target than females. There are significant gender differences in eye movement in children with ADHD, which are corelated to factors of attention dimensions and the executive function. Moreover, the integration of ET with attention cancellation tests produced a high AUC (1.000) value for identifying ADHD, and a high AUC (0.899) value for identifying ADHD genders. The results indicate that ET during cancellation tests can improve the identification of ADHD, and can effectively identify ADHD genders, which will help improve the clinical diagnosis and intervention of ADHD in different genders.
Abstract Transient receptor potential Melastain2 (TRPM2) ion channel is a non-selective cationic channel that can permeate Ca 2+ and is highly expressed in the brain, especially in the cerebral cortex, hippocampus, and striatum, which are critical for cognitive function. Current research evidence indicates that TRPM2 is closely associated with various neurological diseases such as epilepsy. In this study, TRPM2 gene knockout mice were used to study the effect of TRPM2 on the susceptibility to epilepsy in mice and the specific mechanism of the impact of TRPM2 on epilepsy by affecting neuronal excitability. In PTZ chronic kindling epilepsy model, we have found that TRPM2 knockout mice were more susceptible to epilepsy than WT mice. Furthermore, the neuronal excitability in the hippocampal CA1 region of TRPM2 knockout mice is significantly increased. Compared with WT group, there were no significant differences in the input resistance and afterhyperpolarization of CA1 neurons in TRPM2 knockout mice. Firing adaptation rate of hippocampal CA1 pyramidal neurons of TRPM2 knockout mice is lower than that of WT mice. We found that activation of Kv7 channel by retigabine reduced the firing frequency of action potential in the hippocampal pyramidal neurons of TRPM2 knockout mice. However, inhibiting Kv7 channel increased the firing frequency of action potential in hippocampal pyramidal neurons of WT mice. In animal models, we confirmed that activation of Kv7 channel can effectively reduce epileptic seizures in TRPM2 knockout mice. These results suggest that hippocampal CA1 pyramidal neurons in TRPM2 knockout mice may increase neuronal excitability by inhibiting the Kv7 channel, thus affecting the susceptibility to epilepsy. This study carefully explores the reasons why TRPM2 knockout is more susceptible to epilepsy, which is helpful to understand the occurrence and development of epilepsy, and provides new ideas for the treatment technology and methods of epilepsy.
Transient receptor potential M2 (TRPM2) ion channel is a non-selective cationic channel that can permeate calcium ions, and plays an important role in neuroinflammation, ischemic reperfusion brain injury, neurodegenerative disease, neuropathic pain, epilepsy and other neurological diseases. In ischemic reperfusion brain injury, TRPM2 mediates neuronal death by modulating the different subunits of glutamate N-methyl-D-aspartic acid receptor in response to calcium/zinc signal. In Alzheimer's disease, TRPM2 is activated by reactive oxygen species generated by β-amyloid peptide to form a malignant positive feedback loop that induces neuronal death and is involved in the pathological process of glial cells by promoting inflammatory response and oxidative stress. In epilepsy, the TRPM2-knockout alleviates epilepsy induced neuronal degeneration by inhibiting autophagy and apoptosis related proteins. The roles of TRPM2 channel in the pathogenesis of various central nervous system diseases and its potential drug development and clinical application prospects are summarized in this review.
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