Neurogenetische Analyse eines visuellen Arbeitsgedächtnisses bei Drosophila melanogaster
Biochemie und Physiologie der Tiere
Biologie des Verhaltens und der Sinne
Zusammenfassung der Projektergebnisse
Walking "Drosophila" flies can recall the position of an attractive landmark for a few seconds after their target disappeared from sight. A working memory for visual orientation stabilizes their course and prevents zigzagging behaviour. The overarching goal of the project has been the identification of molecular components and neuronal networks that encode this memory. Mutant analysis of different genes and cell-specific rescue experiments revealed that this orientation memory is built in the ellipsoid body within the fly’s central complex, specifically in the ring neurons type 3. We identified a signalling cascade of several protein kinases, which ultimately results in the phosphorylation of dCREB2, a transcriptional activator required for synaptic plasticity. Moreover, we identified a critical role of two neuronal gasotransmitters nitric oxide (NO) and hydrogen sulphide (H2S) for the visual working memory that jointly elevate cGMP levels in R3 neurons to induce dCREB2 activation. Besides this permissive role, short-lived NO-cGMP signalling seems to represent the memory trace for the vanished landmark by stimulating cGMP-regulated ion channels in R3 neurons. Next, we addressed the role of cAMP/PKA signalling for the visual working memory and could identify an essential function of PKA activity in phosphorylating the presynaptic, vesicle-associated, Synapsin protein. Synapsins in vertebrates and invertebrates orchestrate the transition of neurotransmitter-releasing vesicles in the presynapse from the reserve pool to the readily-releasable pool. Therefore, Synapsin is an integral part of neuronal plasticity and loss of Synapsin function results in learning and memory deficiencies. We find Synapsin in R3 neurons to be jointly regulated by another protein kinase, Calcium/calmodulin-dependent protein kinase type II (CaMKII), and the dual regulation to be controlled through pre-RNA editing by ADAR (adenosine deaminase acting on RNA). Editing of the conserved PKA phosphorylation site of Synapsin strongly reduces PKA-dependent phosphorylation but does not affect CaMKII-dependent activation of Synapsin. Therefore, the fly uses pre-mRNA editing to shift the activity-dependent control of Synapsin phosphorylation from cAMP/PKA to Ca2+/CaMKII signalling. Finally yet importantly, we could show that cleavage of the fly orthologue to the human Amyloid Precursor Protein, APPL, increases with age resulting in age-related memory impairment (AMI) and a complete loss of visual working memory at mid age of the flies. Reducing the expression levels of either three secretases cleaving APPL mitigated AMI. We could show that full-length APPL is required to inhibit the function of the neural cell adhesion molecule Fasciclin 2 (FASII) in R3 neurons and moderate expression of a secretion-defective variant of APPL in aging flies (up to 6 weeks) mitigates AMI. This part of our work has been covered in 3sat nano.
Projektbezogene Publikationen (Auswahl)
- (2017) Visual Working Memory Requires Permissive and Instructive NO/cGMP Signaling at Presynapses in the Drosophila Central Brain. Curr. Biol. 27(5): 613-623
Kuntz, S., Poeck, B., Strauss, R.
(Siehe online unter https://doi.org/10.1016/j.cub.2016.12.056) - (2018) Drosophila Full-Length Amyloid Precursor Protein is Required for Visual Working Memory and Prevents Age-Related Memory Impairment. Curr. Biol. 28: 817–823
Rieche, F., Carmine-Simmen, K, Poeck, B., Kretzschmar, D., Strauss, R.
(Siehe online unter https://doi.org/10.1016/j.cub.2018.01.077) - (2018) The PKA-C3 Catalytic Subunit is Required in Two Pairs of Interneurons for Successful Mating of Drosophila. Sci. Rep. 8:2458
Cassar, M., Sunderhaus, E., Wentzell, J.S., Kuntz, S., Strauss, R., and Kretzschmar, D.
(Siehe online unter https://doi.org/10.1038/s41598-018-20697-3)
