Effects of chronic stress on the local translation and local regulation of actin-binding proteins at dendritic spines in the murine hippocampus

• Applicants: Dr. Jonas Feuge; Professor Dr. Martin Korte
• Subject Area: Biological Psychiatry ; Molecular and Cellular Neurology and Neuropathology
• Term: since 2021
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 467139284

Major depressive disorder (MDD) is the primary major cause of disability worldwide and over the last decades, patient numbers were increasing by up to 50% in all age groups, contributing tremendously to both global disease burden and global health expenditures. Patients suffering from MDD commonly show feelings of sadness, anxiety, loss of interest in typically enjoyable activities, suicidal thoughts and memory deficits. While the underlying neuropathological mechanisms are not completely understood, it is suggested that MDD develops mainly under chronic psychological stress conditions and that MDD is predominantly a disease of the synapse. Especially affected are brain regions linked to emotional regulation where synaptic phenotypes are manifested by changes in synaptic plasticity, dendritic spine density and synapse structure. Based on research of the last decades, it is considered that a dysregulation of protein synthesis pathways is at the fundamental core of MDD and, as a result, most antidepressants available as treatment options for MDD directly or indirectly aim at interfering with these pathways. Although the significance of synaptic protein synthesis for general neuronal function, learning and memory and ultimately behavior is increasingly clear, it is surprising that very little effort has been put on deciphering the potential importance of local protein translation on synapse dysfunction in MDD. Intriguingly, it is still unknown how exactly psychosocial stress induces changes in the function and structure of synapses and how stress affects the activity-dependent, local translation of synaptic proteins.Synapse structure as well as function (both altered in MDD) are crucially dependent on the synaptic actin-cytoskeleton and recent work – among others, from our lab - showed that actin-binding proteins (ABPs) are locally translated in an activity-dependent manner in a time-window crucial for the proper induction of synaptic plasticity. Hence, in this project, we aim at studying the potential neuropathological role of ABP dysregulations for MDD. We plan to specifically focus on two ABPs which are directly competing for F-actin binding, have a counteracting function on F-actin stabilization at the synapse and in addition, were shown to be specifically regulated in response to stress: cofilin 1 and caldesmon. By analyzing the local translation as well as the local mRNA and protein regulation of these ABPs at the synapse, this project will help to understand the spatial and temporal regulations of synaptically localized ABPs. This will allow us to directly link synapse phenotypes in MDD to alterations in the local regulation of synaptic actin and will help to gain a more detailed perception of the molecular mechanisms mediating stress-dependent modifications of synapses. Moreover, our data will offer novel knowledge needed to develop more targeted treatment possibilities for MDD in the future.

• DFG Programme: Research Grants