Serotonergic mechanisms and therapeutic relevance of neuron (re)generation in the adult brain

• Applicant: Privatdozentin Dr. Friederike C. Klempin
• Subject Area: Molecular Biology and Physiology of Neurons and Glial Cells
• Term: from 2014 to 2016
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 251471665

Dolor animi multo gravior est quam corporis (Publilius Syrus, 42 A.D.). Major depression is becoming an increasing cause of drastically impaired quality of life, especially in woman, and only 25% of patients get adequate medication. Antidepressants are thought to target the serotonin system alongside positive modulation of adult hippocampal neurogenesis. Recent studies however challenge the monoamine hypothesis by suggesting a more direct change in cellular plasticity such as spine density or the ceramide system as target for antidepressants. My data accrued in Tph2-deficient mice indicates that serotonin is not required for steady state neurogenesis, but instead, I demonstrated a novel link between exercise and the transmission of neurogenic signals through serotonergic fibers in the brain. The genetic loss-of-function models used in this proposal are uniquely suited for testing serotonergic mechanisms in adult hippocampal neurogenesis per se, illuminating its role in physical activity, and serve as control to define the functional targets of antidepressants. It is of potential therapeutic significance to better understand if the lack of serotonin has a direct and acute effect on the hippocampal niche or leads to an enduring compensation at cell and receptor levels, or altered neurotrophic signaling. Together with a novel 3-D mouse brain imaging approach, CLARITY, and treatment of selected drugs altered levels of serotonin transporter, and receptor subtypes can be analyzed. The findings of this study will characterize a pathway that could potentially yield new preventive and clinical targets for managing depression or other neurological disorders.

• DFG Programme: Research Grants