Characterization of the zebrafish SLC6A1 KO mutant line and identification of new pharmacological treatments in SLC6A1-associated neurodevelopment disorders

SLC6A1-related disorders are a spectrum of genetic conditions characterized by mild-to-severe symptoms, including epilepsy and neurodevelopmental disabilities like autism, schizophrenia as well as intellectual delay. The disease-onset typically occurs during childhood, and it persists throughout life. The common cause of all the disorder has been identified in the mutation of the SLC6A1 gene, which encodes for a transporter named GAT-1 able to control the activity of the major inhibitory neurotransmitter in the brain. In pathological conditions, the balance of excitation/inhibition is thus impaired even though the underlying pathological mechanisms are still not fully understood.The identification of new therapeutic options and the whole comprehension of the pathogenetic mechanism are closely interrelated and rely on the availability of experimental models. Since zebrafish (Danio rerio) has become an important model for studying epilepsy both in basic research and in drug discovery, we have recently generated a new animal model of SLAC6A1-related disorders, using this small freshwater fish. The application of different approaches we will allow us to: i) fully characterize our animal model from a phenotypical point of view; ii) perform in our disease model a target-driven screening of selected chemical compounds named HDACi. Therefore, the present study has the great potential of generating findings that on one side will shed light on the correlation between mutation and clinical manifestation, while on the other side will allow the identification of a small number of antiepileptic drugs ready to be tested in the future in other disease models.