CaMKK2 control of neuronal function and complex behaviour in health and disease

Mental illnesses such as anxiety, bipolar disorder, and schizophrenia are among the most prevalent health problems in Australia, highlighting the need to gain a better understanding of the molecular processes in brain that control emotional and complex behaviour. This multidisciplinary project will identify the key role of the enzyme, CaMKK2, in the regulation of mouse brain function and behaviour, and provide novel insights into the cause and treatment of clinical psychiatric disorders.

Our research has revealed that Ca2+-calmodulin dependent protein kinase kinase-2 (CaMKK2) is a key regulator of neuronal function and associated complex behaviour. Mutations that reduce CaMKK2 expression or activity display a strong association with a spectrum of human psychiatric disorders, including anxiety, bipolar disorder and schizophrenia, indicating that optimal CaMKK2 activity is essential for normal, healthy brain development and function. Notably, the mood-stabilising drug, lithium, a major therapy for multiple psychiatric illnesses, activates CaMKK2. Therefore, understanding central CaMKK2 signalling is of significant translational interest.

However, the neurobiology of CaMKK2, including its upstream regulatory inputs, and its downstream signalling and neural network effects in brain are not fully understood. In this project, we will study the behavioural profile of mice with targeted mutations of a regulatory site in CaMKK2 in a range of validated behavioural assays, as well as the responsiveness of these mice to lithium. We will also determine the neuroanatomical distribution of CaMKK2 within specific types of neurons and neural circuits, and the impact of altered CaMKK2 signalling on specific downstream targets.

These studies will provide an improved mechanistic understanding of CaMKK2 function, which is essential to advance our fundamental biological knowledge of this key neuronal enzyme system, and to inform novel treatment strategies for multiple psychiatric conditions.