Investigating the role of diacylglycerol kinase eta in bipolar disorder and lithium response

• Applicant: Rhiannon McNeill, Ph.D.
• Subject Area: Biological Psychiatry
• Term: since 2024
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 552667893

Bipolar disorder (BD) is a chronic mental disorder affecting 1-2% of the world’s population. Not only does it significantly impact quality of life, , but it is also associated with premature death. Unfortunately, only ~50% patients can be satisfactorily treated with currently available drugs such as lithium. This is mostly because we do not understand the causes of the disorder, and therefore do not know what we should be targetting in the brain with novel drugs. Genetics have been shown to play a large role in the development of BD, and studies have highlighted a specific gene, DGKH, that is thought to be involved in both BD and whether a patient can be succesfully treated with lithium. This gene makes a receptor, DGKη, that is important for transmitting signals inside the cell. There are changes (‘variants’) in the DNA sequence of this gene which have specifically been linked to BD and lithium response, called ‘GAT’. However, data showing the effects of the GAT variant in this gene in BD and lithium responsiveness is lacking, especially in humans. We are now able to generate living brain cells (neurons) from humans, which are specific to the human from which they come from, containing the same unique DNA. This process involves the reprogramming of skin cells into stem cells, which can differentiate into any part of the body. We have already made stem cells from many healthy control donors and BD patient donors, and for each donor we know whether they have the GAT variant in their DNA. In this project, we firstly aim to make even more of these stem cells from donors, to make sure that the results we obtain are reliable. We will then make neurons from these stem cells, and investigate whether there are differences in the amount and activity of the DGKη receptor in the cells, depending on whether the neurons are from a human with the GAT variant. We will also assess assess neuronal signalling. We will then treat the neurons with lithium, to see whether treatment can change the amount and activity of the receptor and neuronal signalling, and if this differs depending on whether the neurons are from a human with the GAT variant. Lastly we will use cutting-edge technology to look at changes in the amount of all genes within a single cell. This means that we can assess whether the GAT variant, and lithium treatment, changes the amount of other genes within a certain neuronal subtype. This will give us a much deeper understanding of the processes potentially involved. In summary, we plan to use living human neurons from healthy controls and BD patients to investigate the role of a risk gene for BD, and to help us understand why some BD patients can be successfully treated with current medications and others cannot. The results of our project could help us to identify new targets for novel drug development, to be able to treat all patients with BD, improving their quality of life.

• DFG Programme: Research Grants
• International Connection: Ireland
• Cooperation Partner: Professorin Dr. Sarah Kittel-Schneider