ZEBRAFISH KCNA3 AND RBFOX1 MUTANTS PROVIDE NEW INSIGHTS INTO ATTENTION-DEFICIT/HYPERACTIVITY DISORDER

The attention-deficit/hyperactivity disorder (ADHD) is a neurodevelopmental disorder, with a prevalence of 6.3% in children and adolescent population of China. The main clinical manifestations of ADHD patients are commonly known as the inattention and/or hyperactivity and impulsivity, the so-called core diagnostic symptom (DSM-V, 2013), but mounting evidence have also indicated that the learning deficiency is another key feature of ADHD. ADHD is a complex disorder with varied phenotypes, complex etiology and wide-ranging heterogeneity. The genetic risks for ADHD are thus associated with numerous candidate genes with a wide spectrum of biological functions. Furthermore, ADHD is often a comorbidity of many psychiatric disorders including the autism spectrum disorder. The complexity of the disorder and variety of ADHD genetic status apparently have made ADHD diagnosis and treatment quite challenging. Therefore, identifying some common features of cognition, memory, behavior, candidate gene SNPs or expression profiles of ADHD patients is of great importance for the therapeutic purpose.
Here, we proposed to investigate whether two genetic risk genes KCNA3 and RBFOX1 share some ADHD pathologies because the two distinct human genes have been thought to be ADHD risk genes through the genome-wide association studies (GWAS), whereas KCNA3 encodes a potassium voltage-gated channel protein and RBFOX1 encodes an RNA binding protein that regulates both RNA splicing and RNA stability. In order to identify the shared features of ADHD individuals with distinct genemutations, we chose to study zebrafish kcna3 and rbfox1 mutants because zebrafish has become a reliable model to analyze the large-scale phenotypic and neuropsychiatric studies. After initially knocking down kcna3 or rbfox1, and generating the respective F0 mutants, inattention and learning disabilities were identified to be the common deficits. At the transcriptional level, kcna3 and rbfox1 mutants also shared significant expression profiles and signaling transduction and/or neurobiological pathways related to ADHD pathology. At individual gene level, snap25a, whose product is involved in regulating both presynaptic and postsynaptic functions, was found to be one of many common downstream genes of Kcna3 and Rbfox1. Furthermore, as one of the endjoining points of two seemingly unrelated genes, snap25a has also been labeled as the ADHD risk gene and is likely responsible for the shared neurobiological and behavioral phenotypes including acoustic/visual stimulated hyperactivities defined by our study. Finally, by specific cell/tissue ablation experiments/chemical treatments/behavioral tests in zebrafish, we tend to believe that acoustic and/or vestibular organs (inner ear and lateral line) may be indispensable from some CNS (central nervous system)-PSS (peripheral sensory system)-based neural circuit(s) that is responsible for ADHD. Though ADHD is often thought to be exclusively due to aberrant central nervous system (CNS) function(s). In summary, our study highlights a few promising strategies to explore the mechanisms underlying molecular pathology of ADHD, a psychiatric disease with high heredity.

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