Loss of the Schizophrenia-Linked Furin Protein from Drosophila Mushroom Body Neurons Results in Antipsychotic-Reversible Habituation Deficits

Kyriaki Foka, Eirini-Maria Georganta, Ourania Semelidou, Efthimios M. C. Skoulakis
J. Neurosci.. 2022-08-26; 42(39): 7496-7511
DOI: 10.1523/jneurosci.1055-22.2022

PubMed

Lire sur PubMed

https://www.bordeaux-neurocampus.fr/12086

Foka K(1)(2), Georganta EM(1), Semelidou O(1), Skoulakis EMC(3).

Author information:
(1)Institute for Fundamental Biomedical Research, Biomedical Science Research
Centre « Alexander Fleming, » 16672 Vari, Greece.
(2)Department of Molecular Biology and Genetics, Democritus University of
Thrace, 68100 Alexandroupolis, Greece.
(3)Institute for Fundamental Biomedical Research, Biomedical Science Research
Centre « Alexander Fleming, » 16672 Vari, Greece .

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.