School of Physiology, Pharmacology and Neuroscience, Faculty of Life Science, University of Bristol, UK; Departamento de Biología Celular y Molecular, Facultad de Ciencias Biológicas, Pontificia Universidad Católica de Chile, Chile.
Departamento de Biología Celular y Molecular, Facultad de Ciencias Biológicas, Pontificia Universidad Católica de Chile, Chile.
Neurobiol Dis. 2021 Jul;155:105394. doi: 10.1016/j.nbd.2021.105394. Epub 2021 May 18.
Schizophrenia exhibits up to 80% heritability. A number of genome wide association studies (GWAS) have repeatedly shown common variants in voltage-gated calcium (Ca) channel genes CACNA1C, CACNA1I and CACNA1G have a major contribution to the risk of the disease. More recently, studies using whole exome sequencing have also found that CACNA1B (Ca2.2 N-type) deletions and rare disruptive variants in CACNA1A (Ca2.1 P/Q-type) are associated with schizophrenia. The negative symptoms of schizophrenia include behavioural defects such as impaired memory, sleep and circadian rhythms. It is not known how variants in schizophrenia-associated genes contribute to cognitive and behavioural symptoms, thus hampering the development of treatment for schizophrenia symptoms. In order to address this knowledge gap, we studied behavioural phenotypes in a number of loss of function mutants for the Drosophila ortholog of the Ca2 gene family called cacophony (cac). cac mutants showed several behavioural features including decreased night-time sleep and hyperactivity similar to those reported in human patients. The change in timing of sleep-wake cycles suggested disrupted circadian rhythms, with the loss of night-time sleep being caused by loss of cac just in the circadian clock neurons. These animals also showed a reduction in rhythmic circadian behaviour a phenotype that also could be mapped to the central clock. Furthermore, reduction of cac just in the clock resulted in a lengthening of the 24 h period. In order to understand how loss of Ca2 function may lead to cognitive deficits and underlying cellular pathophysiology we targeted loss of function of cac to the memory centre of the fly, called the mushroom bodies (MB). This manipulation was sufficient to cause reduction in both short- and intermediate-term associative memory. Memory impairment was accompanied by a decrease in Ca transients in response to a depolarizing stimulus, imaged in the MB presynaptic terminals. This work shows loss of cac Ca2 channel function alone causes a number of cognitive and behavioural deficits and underlying reduced neuronal Ca transients, establishing Drosophila as a high-throughput in vivo genetic model to study the Ca channel pathophysiology related to schizophrenia.
精神分裂症的遗传率高达 80%。许多全基因组关联研究（GWAS）反复表明，电压门控钙（Ca）通道基因 CACNA1C、CACNA1I 和 CACNA1G 中的常见变异对疾病风险有重大贡献。最近，使用全外显子组测序的研究还发现 CACNA1B（Ca2.2 N 型）缺失和 CACNA1A（Ca2.1 P/Q 型）中的罕见破坏变异与精神分裂症有关。精神分裂症的阴性症状包括记忆、睡眠和昼夜节律受损等行为缺陷。目前尚不清楚精神分裂症相关基因的变异如何导致认知和行为症状，从而阻碍了针对精神分裂症症状的治疗方法的开发。为了填补这一知识空白，我们研究了果蝇 CACNA1 基因家族同源物 cac 功能丧失突变体的多种行为表型。 cac 突变体表现出几种行为特征，包括夜间睡眠时间减少和过度活跃，与人类患者报告的类似。睡眠-觉醒周期时间的变化表明昼夜节律紊乱，由于仅在昼夜节律神经元中丧失 cac，导致夜间睡眠时间减少。这些动物还表现出节律性昼夜行为减少的表型，该表型也可以映射到中央时钟。此外，仅在时钟中减少 cac 会导致 24 小时周期延长。为了了解 Ca2 功能丧失如何导致认知缺陷和潜在的细胞病理生理学，我们将 cac 的功能丧失靶向到果蝇的记忆中心，称为蘑菇体（MB）。这种操作足以导致短期和中期联想记忆减少。记忆损伤伴随着对去极化刺激的 Ca 瞬变减少，在 MB 突触前末梢中成像。这项工作表明，仅丧失 cac Ca2 通道功能就会导致多种认知和行为缺陷以及潜在的神经元 Ca 瞬变减少，使果蝇成为研究与精神分裂症相关的 Ca 通道病理生理学的高通量体内遗传模型。
