Palmitoylation of neuronal and glial 5-HT1A receptors: physiological functions and implication in mood disorders.

• Applicants: Dr. Nataliya Gorinski; Professor Dr. Evgeni Ponimaskin
• Subject Area: Molecular Biology and Physiology of Neurons and Glial Cells
• Term: since 2020
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 445387974

Dysregulation of the serotonin system has long been considered central to the etiology of mood disorders, including major depression disorder (MDD) and bipolar disorder (BD), and the main inhibitory serotonin receptor 5-HT1A (5-HT1AR) seems to play a key role in neuropathology. Despite much effort, the molecular routes impairing the 5-HT1AR-mediated signaling in MDD and BD remain largely enigmatic.The 5-HT1AR undergoes palmitoylation and non-palmitoylated mutants reduces Gi-protein receptor-mediated signaling via mis-localization of receptor outside of lipid rafts. Within the initial DFG-funded project PO732/14-1, we identified DHHC-5, -9 and -21 as major palmitoyl-transferases, whose depletion reduced palmitoylation and signaling functions of 5-HT1AR. We also found reduced DHHC21 expression and decreased 5-HT1AR palmitoylation in the prefrontal cortex of MDD victims died by suicide. More importantly, selective knock-down of DHHC21 in murine forebrain by itself sufficed to provoke depressive symptoms, demonstrating a causal relationship between 5-HT1AR palmitoylation and depression. Searching for the mechanisms tuning DHHC21 expression, we identified microRNAs miR-30a and miR-30e as important expression regulators. Suggesting downregulation of 5-HT1AR palmitoylation as a novel mechanism involved in MDD, these results however do not distinguish between the functional role of 5-HT1AR palmitoylation in neurons and astrocytes. On the other hand, astrocytes have been considered to play an important role in the etiology of MDD.One important goal of the present proposal is thus to molecularly define the mechanisms regulating 5-HT1AR palmitoylation in astrocytes and to analyze involvement of receptor palmitoylation in astrocytes for modulation of astrocytic properties and neuron-glia interaction under physiological conditions. The second major goal is to elucidate and compare an impact of 5-HT1AR palmitoylation in astrocytes and neurons for the developing, maintaining and pathogenesis of depressive phenotype. This also implies a potential neuroprotective role of astrocytic receptor palmitoylation against the neuronal degeneration. Finally, we will evaluate 5-HT1AR palmitoylation as a diagnostic marker and potential therapeutic target for the treatment of MDD.To achieve these goals we will apply combination of innovative techniques presented in our lab, including analysis of 5-HT1AR palmitoylation in vitro, in vivo and in human post mortem brain samples, application of biosensors, electrophysiological recordings, usage of depression models in rodents, and behavioral analysis. The combined outcomes of these investigations will greatly advance our fundamental knowledge about the impact of palmitoylation for regulation of neuronal and astrocytic functions under physiological and pathological conditions, providing information about the possible therapeutic role of 5-HT1AR palmitoylation for treating neurodegenerative and mood disorders.

• DFG Programme: Research Grants