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

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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.