Identification of novel functional and post-transcriptional regulatory mechanisms during homeostatic synaptic downscaling
Final Report Abstract
Information processing in the brain is achieved by communication within extensive networks of neurons. In order to function properly, neural networks have inbuilt homeostatic mechanisms that allow them to adapt to alterations in the environment, such as extremely low or high levels of stimulation. One such mechanism is synaptic scaling, which scales the strength of synaptic connections between individual neurons in the direction opposite to the stimulus. Synaptic scaling plays important roles in brain physiology (e.g. development of the visual system) as well as pathophysiology (e.g. epilepsy). In this project, we have uncovered a new molecular mechanism that is important for the scaling down of excitatory synapses in the brain in response to chronically high levels of extracellular stimulation. This mechanism involves the small non-coding RNA miR-129-5p, a member of the microRNA family, and its targets Atp2b4 (calcium pump) and Doublecortin (Dcx, part of the microtubule cytoskeleton). If miR-129- 5p is blocked, synaptic scaling and the downstream regulation of Atp2b4 and Dcx no longer takes place. Importantly, this newly identified molecular pathway is also relevant for epilepsy, since blocking miR-129-5p in the mouse brain strongly improves epileptic phenotypes, such as seizures, induced by strong pharmacological stimulation of neural networks. Moreover, miR-129-5p levels are increased in brain tissue obtained from human temporal lobe epilepsy patients compared to healthy control subjects and anticorrelate with Atp2b4 and Dcx levels. Taken together, the results from this project suggest that miR-129-5p and its downstream targets Atp2b4 and Dcx could represent promising new targets for the treatment of epilepsy and potential new biomarkers for the diagnosis of human temporal lobe epilepsy.
Publications
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A microRNA-129-5p/Rbfox crosstalk coordinates homeostatic downscaling of excitatory synapses. EMBO J. 2017 Jun 14;36(12):1770-1787
Rajman M, Metge F, Fiore R, Khudayberdiev S, Aksoy-Aksel A, Bicker S, Ruedell Reschke C, Raoof R, Brennan GP, Delanty N, Farrell MA, O'Brien DF, Bauer S, Norwood B, Veno MT, Krüger M, Braun T, Kjems J, Rosenow F, Henshall DC, Dieterich C, Schratt G
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Personalized translational epilepsy research - Novel approaches and future perspectives: Part I: Clinical and network analysis approaches. Epilepsy Behav. 2017 Nov;76:13-18
Rosenow F, van Alphen N, Becker A, Chiocchetti A, Deichmann R, Deller T, Freiman T, Freitag CM, Gehrig J, Hermsen AM, Jedlicka P, Kell C, Klein KM, Knake S, Kullmann DM, Liebner S, Norwood BA, Omigie D, Plate K, Reif A, Reif PS, Reiss Y, Roeper J, Ronellenfitsch MW, Schorge S, Schratt G, Schwarzacher SW, Steinbach JP, Strzelczyk A, Triesch J, Wagner M, Walker MC, von Wegner F, Bauer S
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Personalized translational epilepsy research - Novel approaches and future perspectives: Part II: Experimental and translational approaches. Epilepsy Behav. 2017 Nov;76:7-12
Bauer S, van Alphen N, Becker A, Chiocchetti A, Deichmann R, Deller T, Freiman T, Freitag CM, Gehrig J, Hermsen AM, Jedlicka P, Kell C, Klein KM, Knake S, Kullmann DM, Liebner S, Norwood BA, Omigie D, Plate K, Reif A, Reif PS, Reiss Y, Roeper J, Ronellenfitsch MW, Schorge S, Schratt G, Schwarzacher SW, Steinbach JP, Strzelczyk A, Triesch J, Wagner M, Walker MC, von Wegner F, Rosenow F
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Electrical stimulation of the ventral hippocampal commissure delays experimental epilepsy and is associated with altered microRNA expression. Brain Stimul. 2019 Nov - Dec;12(6):1390-1401
Costard LS, Neubert V, Venø MT, Su J, Kjems J, Connolly NMC, Prehn JHM, Schratt G, Henshall DC, Rosenow F, Bauer S
