TY - JOUR T1 - Loss of the Schizophrenia-Linked Furin Protein from <em>Drosophila</em> Mushroom Body Neurons Results in Antipsychotic-Reversible Habituation Deficits JF - The Journal of Neuroscience JO - J. Neurosci. SP - 7496 LP - 7511 DO - 10.1523/JNEUROSCI.1055-22.2022 VL - 42 IS - 39 AU - Kyriaki Foka AU - Eirini-Maria Georganta AU - Ourania Semelidou AU - Efthimios M. C. Skoulakis Y1 - 2022/09/28 UR - http://www.jneurosci.org/content/42/39/7496.abstract N2 - Habituation is a conserved adaptive process essential for incoming information assessment, which drives the behavioral response decrement to recurrent inconsequential stimuli and does not involve sensory adaptation or fatigue. Although the molecular mechanisms underlying the process are not well understood, habituation has been reported to be defective in a number of disorders including schizophrenia. We demonstrate that loss of furin1, the Drosophila homolog of a gene whose transcriptional downregulation has been linked to schizophrenia, results in defective habituation to recurrent footshocks in mixed sex populations. The deficit is reversible by transgenic expression of the Drosophila or human Furin in adult α′/β′ mushroom body neurons and by acute oral delivery of the typical antipsychotic haloperidol and the atypical clozapine, which are commonly used to treat schizophrenic patients. The results validate the proposed contribution of Furin downregulation in schizophrenia and suggest that defective footshock habituation is a Drosophila protophenotype of the human disorder.SIGNIFICANCE STATEMENT Genome-wide association studies have revealed a number of loci linked to schizophrenia, but most have not been verified experimentally in a relevant behavioral task. Habituation deficits constitute a schizophrenia endophenotype. Drosophila with attenuated expression of the schizophrenia-linked highly conserved Furin gene present delayed habituation reversible with acute exposure to antipsychotics. This strongly suggests that footshock habituation defects constitute a schizophrenia protophenotype in Drosophila. Furthermore, determination of the neurons whose regulated activity is required for footshock habituation provides a facile metazoan system to expediently validate putative schizophrenia genes and variants in a well understood simple brain. ER -