Linking molecular pathways to affective symptomatology is essential to identify novel clinical treatments. An emerging target in this context is the enzyme dimethylarginine dimethylamino hydrolase-1 (DDAH1), which metabolises asymmetric dimethylarginine (ADMA), a key regulator of the nitric oxide (NO) synthesis. DDAH1 is highly expressed in the brain, and several studies reported systemic alterations of the ADMA/NO axis in patients with affective disorders and psychosis. However, evidence for causality of these associations and brain region-specific roles of DDAH1 activity are lacking. Addressing fundamental molecular mechanisms in animal models by using sophisticated tools to control gene expression offers a powerful means to fill these gaps in our knowledge. To do so, this project will use mice that systemically express human DDAH1 (DDAH1-tg), resulting in increased NO bioavailability and behavioural hyperactivity, a measure for mania and a key feature of bipolar disorder. We will combine in-depth mapping of the onset and progression of abnormal behavioral phenotypes in the model with common and translational directly comparable endpoints, including neuroimaging. We will then integrate the brain and behavioural data utilizing multivariate analysis tools that allow for correlations with analogous data in humans to facilitate bi-directional translational research between basic science and the clinic. Furthermore, retroviral approaches controlling DDAH1 expression will be implemented to disentangle brain-specific from systemic effects. Finally, we will test state-of-the-art and selective new pharmacological interventions to reduce behavioural abnormalities. The project builds on the complementary expertise from King’s and TUD and provides an exceptional possibility to train in a broad range of preclinical research methods.
- Kozlova AA, Ragavan VN, Jarzebska N, Lukianova I, Anastasia B, Rubets E, Suzuki-Yamamoto Kimoto M, Mangoni AA, Gainetdinov RR, Weiss N, Bauer M, Markov A, Rodionov RN, Bernhardt N. Divergent dimethylarginine dimethylaminohydrolase isoenzyme expression in the central nervous system. Cellular and Molecular Neurobiology 2021; doi:10.1007/s10571-021-01101-7
- Mueller FS, Scarborough J, Schalbetter SM, Richetto J, Kim E, Couch A, Yee Y, Lerch JP, Vernon AC, Weber-Stadlbauer U, Meyer U. Behavioral, neuroanatomical, and molecular correlates of resilience and susceptibility to maternal immune activation. Molecular Psychiatry 2021;26(2), 396–410. Doi:10.1038/s41380-020-00952-8
- Onwordi EC, Halff EF, Whitehurst T, Mansur A, Cotel MC, Wells L, Creeney H, Bonsall D, Rogdaki M, Shatalina E, Reis Marques T, Rabiner EA, Gunn RN, Natesan S, Vernon AC, Howes OD. Synaptic density marker SV2A is reduced in schizophrenia patients and unaffected by antipsychotics in rats. Nat Commun 2020;11:246. doi:10.1038/s41467-019-14122-0
Skills/qualities required especially for this project:
- Biological, biomedical and neuroscientific interest. Enthusiasm to work with animal models of psychopathology and sophisticated data analysis