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Dryad

Drugs prescribed in Phelan-McDermid Syndrome differentially impact sensory behaviors in shank3 zebrafish models

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Jan 02, 2023 version files 7.65 GB
Jan 05, 2023 version files 7.65 GB

Abstract

Altered sensory processing is a pervasive symptom in individuals with Autism Spectrum Disorders (ASD). Especially in cases of profound autism, individuals are often medicated to manage behaviors like aggression and/or self-harm and/or epilepsy, and it remains unclear how these medications might impact perception/sensory processing. To test this, we screened three medications, risperidone, Lithium Chloride (LiCl), and carbamazepine (CBZ), prescribed to individuals with Phelan-McDermid Syndrome (PMS) and one drug, 2-Methyl-6-(phenylethynyl) pyridine (MPEP) tested in rodent models of PMS, for their effects on a sensory-induced behavior in two zebrafish PMS models with frameshift mutations in the N- or C- termini. PMS is caused by deletions of the terminal end of chromosome 22 or point mutations in Shank3. People with PMS can present with an array of symptoms including ASD, epilepsy, gastrointestinal distress, and reduced responses to sensory stimuli. Our zebrafish mutant shank3ab models likewise show reduced responses in a Visual Motor Response (VMR) assay, in which increased locomotion is triggered by light-to-dark transitions. To test how pharmacological treatments affect the VMR, we exposed larvae to selected drugs for twenty-four hours and then quantified their locomotion during four ten-minute cycles of lights on-to-off stimuli. We found that risperidone normalized the VMR in shank3 models, LiCl and CBZ had no effect on the VMR in any of the three genotypes. MPEP reduced the VMR in WT to levels seen in shank3 models but caused no changes in either shank3 model. Our work shows that the effects of drugs on sensory processing is varied in a way that can be highly genotype- and drug-dependent.