Dysregulation of Ca2+-activated K+ channel signalling by reduced dosage of the psychiatric risk gene CACNA1C

最近的人类遗传学研究发现，精神分裂症和双相情感障碍等精神疾病存在复杂的遗传风险。这些发现表明，脑细胞功能的改变以及它们相互沟通的方式导致了精神病中常见的症状。特别是，钙通道的遗传变异与精神病的风险密切相关。钙通道是控制钙离子进入脑细胞的蛋白质。现在迫切需要将这些进展转化为更有效的治疗方法。对精神病的人类和临床前动物研究都一致发现，大脑中被称为海马体的部分发生了变化。这个区域是了解大脑如何形成和处理记忆的门户。海马细胞包含所谓的BK和SK通道。它们被钙激活，并调节脑细胞对信息储存的贡献。钙通道变化与海马细胞功能通过BK和SK通道调节之间的联系尚不清楚。在这个项目中，我们首次直接解决了这个问题。我们将测试改变BK和SK通道功能的药物如何在脑钙通道蛋白CaV1.2水平改变的大鼠（Cacna1c+/-大鼠）中拯救行为和海马细胞功能缺陷。我们将使用卡迪夫大学的活体生理学和显微镜记录来详细研究Cacna1c+/-大鼠的海马细胞如何无法整合和传递来自其他大脑区域的信息。这将有助于我们了解BK和SK通道在这种损伤中的作用。我们还将研究通过靶向大脑中的胆碱能受体来挽救这些缺陷的可能性。这些是调节BK和SK通道功能的先天脑机制的一部分。我们将把行为测试和药物应用直接结合在海马体上。我们的总体目标是了解BK和SK通道及其胆碱能调节的潜力，以便在精神病中使用更有效的治疗靶点。

Recent studies in human genetics have found a complex genetic risk in psychiatric illness such as schizophrenia and bipolar disorder. These discoveries indicate that alterations in the function of brain cells and how they communicate with each other result in common symptoms found in psychoses. In particular, genetic variation in calcium channels is strongly associated with risk of psychoses. Calcium channels are proteins that control the entry of calcium ions in brain cells. There is now an urgent need to translate these advances into more effective therapies.Both human and preclinical animal studies in psychoses have consistently found alterations in a part of the brain called the hippocampus. This region is a gateway into how the brain forms and processes memories. Hippocampal cells contain so-called BK and SK channels. These are activated by calcium and regulate the way in which brain cells contribute to information storage.The link between calcium channel variation and the regulation of hippocampal cell functions by BK and SK channels is not understood. In this project we directly address this problem for the first time. We will test how drugs that modify the function of BK and SK channels can rescue the behavioural and hippocampal cell function deficits in rats with altered levels of the calcium channel protein CaV1.2 in the brain (Cacna1c+/- rats). We will use live physiology and microscopy recordings at Cardiff University to study in detail how the hippocampal cells in Cacna1c+/- rats fail to integrate and convey information from other brain regions. This will help us understand the role of BK and SK channels in this impairment.We will also investigate the potential to rescue these deficits by targeting cholinergic receptors in the brain. These are part of an innate brain mechanism that modulates the function of BK and SK channels. We will combine behavioural testing with drug applications directly in the hippocampus.Our overall aim is to understand the potential of BK and SK channels, and of their cholinergic modulation, for use a more effective therapeutic targets in psychoses.