Foka Kyriaki, Georganta Eirini-Maria, Semelidou Ourania, Skoulakis Efthimios M C
Institute for Fundamental Biomedical Research, Biomedical Science Research Centre "Alexander Fleming," 16672 Vari, Greece.
Department of Molecular Biology and Genetics, Democritus University of Thrace, 68100 Alexandroupolis, Greece.
J Neurosci. 2022 Sep 28;42(39):7496-7511. doi: 10.1523/JNEUROSCI.1055-22.2022.
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 , the 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 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 protophenotype of the human disorder. 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. 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 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.
习惯化是一种保守的适应性过程，对传入信息评估至关重要，它促使对反复出现的无关紧要刺激的行为反应减弱，且不涉及感觉适应或疲劳。尽管该过程的分子机制尚未完全了解，但据报道，习惯化在包括精神分裂症在内的多种疾病中存在缺陷。我们证明，基因（其转录下调与精神分裂症有关）的同源物缺失，会导致混合性别群体对反复出现的足部电击的习惯化出现缺陷。通过在成年α'/β'蘑菇体神经元中转基因表达该基因或人类弗林蛋白酶，以及通过急性口服常用治疗精神分裂症患者的典型抗精神病药物氟哌啶醇和非典型抗精神病药物氯氮平，这种缺陷是可逆的。这些结果证实了弗林蛋白酶下调在精神分裂症中的作用，并表明足部电击习惯化缺陷是人类疾病的一种原代表型。全基因组关联研究已经揭示了许多与精神分裂症相关的基因座，但大多数尚未在相关行为任务中通过实验验证。习惯化缺陷构成了精神分裂症的一种内表型。精神分裂症相关的高度保守的弗林蛋白酶基因表达减弱的小鼠表现出延迟的习惯化，急性暴露于抗精神病药物后可恢复。这强烈表明，足部电击习惯化缺陷在小鼠中构成了精神分裂症的一种原代表型。此外，确定足部电击习惯化所需调节活性的神经元，提供了一个简便的后生动物系统，以便在一个易于理解的简单大脑中快速验证假定的精神分裂症基因和变体。
