Abstracts

Rationale: Recent epidemiologic studies have shown a bidirectional relationship between epilepsy and schizophrenia with patients with schizophrenia at increased risk of developing epilepsy and vice versa. While hallmark features of schizophrenia, such as psychosis, are difficult to model in animals, zebrafish larvae have been shown to be an excellent system for seizure detection and epilepsy modeling. Therefore, we sought to assess available models of genes associated with schizophrenia for features of seizures and epilepsy.

Methods: We obtained mutant zebrafish lines representing 16 unique genes associated with schizophrenia that had been developed in an independent investigation by our collaborators. We evaluated zebrafish larvae at 5 days post fertilization for evidence of seizures (seizure-like swim patterns) using an automated behavioral seizure detection system. We further evaluated for evidence of network hyperexcitability using calcium imaging in larvae bred onto a GCaMP6 background and by direct local field potential recording in larval tectum. We quantified relative numbers of interneurons in the larvae using a transgenic line that labels developing inhibitory interneurons. We compared WT to mutant larvae for all experiments.

Results: We tested 16 schizophrenia-associated genes and, using a high-throughput behavioral screening assay, we identified 5 genes with behavioral patterns suggestive of seizure activity with Stage II seizures. Using conspecific (same clutch) WT controls in a validation experiment, larvae from 4 of the 5 lines displayed seizures: Akt3b, Ambra1, Cacnb2, and Tcf4. Data from assessment of whole brain neuronal activity using calcium imaging, electrophysiology recording by local field potentials (electrophysiology), and quantification of GABAergic neuron populations in the optic tectum are collected and in the process of analysis at the time of abstract submission and will be updated if the abstract is selected for presentation.

Conclusions: Here, we utilize zebrafish as a model organism to observe the effects of mutations in zebrafish orthologs of human genes associated with a risk for schizophrenia. We take advantage of the genetic overlap between epilepsy and schizophrenia risk and establish that a portion of zebrafish models of schizophrenia-associated genes will model features classically associated with epilepsy. While direct modeling of psychosis and other psychiatric features is difficult if not impossible in animal models, the use of seizures and other epilepsy-related features will permit further characterization of genes potentially associated with both schizophrenia and epilepsy. Further, modeling these genes offers the possibility of additional mechanistic studies and pharmacological screening for novel drugs that might address both seizures and psychiatric features in patients.

Funding: Please list any funding that was received in support of this abstract.: BCH Translational Research Program. SCZ: Tommy Fuss Innovation Award.