The formation of an engram in a neuronal ensemble critically requires activity-dependent gene expression. A pivotal role is played in this regard by the transcription factor cAMP-responsive element binding protein (CREB), whose transcriptional activity has a major impact on synaptic function and network activity. In our project, we are addressing the hypothesis that protein transport from synapse to nucleus stabilises CREB transcriptional complexes and may therefore be involved in both memory allocation and memory consolidation following learning. We are investigating how one can employ the signalling principles of the synapto-nuclear protein messenger Jacob to optimise neuronal engram ensemble formation with particular emphasis on healthy ageing.
Dr. Anna Karpova
Anna Karpova is a senior researcher and a Co-PI with Michael Kreutz at Leibniz Institute for Neurobiology (LIN), Research Group Neurplasticity, as well as PI in CBBS, Magdeburg. She is a program coordinator Molecular Biology / Cell Biology at the Leibniz Institute for Neurobiology. She runs research on the role of long-distance protein and membrane trafficking in neuronal function. Her main expertise is in molecular and cellular neuroscience including structural and functional organization of the chemical synapse, synaptic plasticity, time-lapse and super resolution imaging.
Dr. Michael R. Kreutz
Michael R. Kreutz is head of the Neuroplasticity research group at the Leibniz Institute for Neurobiology and he has a second affiliation at the Center for Molecular Neurobiology (ZMNH) in Hamburg where he is heading the Leibniz Group ‘Dendritic Organelles and Synaptic Function’. His research interest is in synapse biology. His work is concerned with fundamental questions on how synapses communicate with the nucleus, how gene activity-dependent gene expression feeds back to synaptic function and how this is related to the formation of a cellular engram and last but not least how the nanoscale organization of the synapse determines functional properties in the context of learning and memory.
Dr. Guilherme Gomes
I am a Brazilian neuroscientist member of the Research Group Neuroplasticity (LIN). I am interested on the molecular players that give rise to complex behaviors., and over the past 10 years I have been focusing on how NMDAR signaling controls the expression of plasticity-related genes, both in health and disease. As a member of the CRC1436 I am part of project A02, A04 and Z01, and my goal is to provide state-of-the-art methods for engram detection and manipulation to the CRC community
Dr. Katarzyna Grochowska
Dr. rer. nat Katarzyna M. Grochowska obtained her M.Sc. degree in Biotechnology at Warsaw University of Life Sciences, Warsaw, Poland. Afterward, she performed her PhD studies at the Leibniz Institute for Neurobiology (LIN) within a Marie Sklodowska-Curie ITN Programme under the supervision of Dr. Michael Kreutz. During her PhD research, she focused on the molecular mechanisms of neurodegenerative diseases, especially Alzheimer’s disease. Currently, she studies the mechanisms of neurodegeneration, especially in the context of excitation-transcription coupling, endolysosomal degradative pathway, and neuroinflammatory signaling.
Dr. Pingan Yuanxiang
My name is PingAn YuanXiang and graduated from Shanghai, China. I studied in the major of Neurobiology at the Fudan University in Shanghai and completed my Ph.D. thesis in 2012.
Since 2013 I work as a research scientist in Nplast at the LIN. My expertise is electrophysiology including field recordings and single-cell patch clamp and also combines with cell biological techniques. My main interest is related to molecular mechanisms of synaptic plasticity and aging regulator in brain function.
What are synapto-nuclear
Neurons express more genes than any other cell type and it is therefore unlikely that synapto–nuclear Ca2+ signaling alone can explain the specific genomic response to the plethora of extracellular stimuli that control gene expression. Possible candidates for encoding of signals at the origin and later decoding at a nuclear destination are synapto–nuclear protein messenger. These proteins translocate from synapses to the nucleus in a stimulus-dependent manner, where they can regulate via their nuclear target interactions very specific aspects of gene expression.
Why is excitation transcription coupling important for engram formation and memory consolidation?
In a given neuronal network, activity at excitatory synapses will differ between neurons. Intrinsic excitability refers to the propensity of neurons to fire action potentials in response to a defined input. De novo transcription of DNA is a fundamental requirement for the formation of long-term memory, where it is instrumental in memory consolidation. The biological mechanisms underlying consolidation start with a rapid phase of gene expression, known as molecular consolidation. Although there is consensus about this conceptual framework, the underlying neurobiological mechanisms still remain elusive. A paradigmatic transcription factor, whose activation has been associated with long-term memory formation, is CREB. Several studies have shown that CREB is at a central converging point of pathways and mechanisms activated during the processes of synaptic strengthening and memory formation.
The goals of our project
Within the framework of this CRC, it is important to note that regulation of neuronal excitability can also be a potential molecular mechanism underlying CREB-dependent neuronal selection. Previous research has shown that neurons with increased CREB are selectively recruited to a memory trace. CREB-mediated global changes in neuronal excitability ensure effective linking of events with temporal proximity and promote cell-assembly formation during the memory consolidation phase. Memory formation depends on both input-specific modifications of synaptic strength and cell-specific increases in excitability. Both increased excitability and generation of more plastic synapses by CREB could increase the probability of neurons with higher active CREB levels being allocated to a memory trace and, most importantly, to the subsequent process of molecular consolidation.
We will test the hypothesis that protein transport from synapse to nucleus stabilizes CREB transcriptional complex and is thereby involved in molecular memory allocation or subsequent molecular memory consolidation, or both. The second aim is to harness the molecular principles of Jacob-induced excitation-transcription coupling as a neural resource in CA1 pyramidal neurons. To this end, we will bridge mouse transgenesis, viral interventions, analysis of synaptic function and neural circuitry as well as behavioral analysis with the ultimate goal of mobilizing and enhancing resources and unlocking hidden potential.
Publications of the project A02
Integration of nuclear Ca2+ transients and subnuclear protein shuttling provides a novel mechanism for the regulation of CREB-dependent gene expression
Karpova A, Samer S, Turacak R, Yuanxiang P, Kreutz MR. Cell Mol Life Sci (2023)
Jacob-induced transcriptional inactivation of CREB promotes Aβ-induced synapse loss in Alzheimer’s disease
K. M Grochowska, G. M Gomes, R. Raman, R. Kaushik, L. Sosulina, H. Kaneko, A. M Oelschlegel, P. Yuanxiang, I. Reyes-Resina, G. Bayraktar, S. Samer, C. Spilker, M. S Woo, M. Morawski, J. Goldschmidt, M. A Friese, S. Rossner, G. Navarro, S….
Katarzyna M Grochowska, Maria Andres-Alonso, Anna Karpova, Michael R Kreutz EMBO J (2022)
Neddylation-dependent protein degradation is a nexus between synaptic insulin resistance, neuroinflammation and Alzheimer’s disease
Alessandro Dario Confettura, Eleonora Cuboni, Mohamed Rafeet Ammar, Shaobo Jia, Guilherme M Gomes, PingAn Yuanxiang, Rajeev Raman, Tingting Li , Katarzyna M Grochowska, Robert Ahrends, Anna Karpova, Alexander Dityatev, Michael R Kreutz Translational Neurodegeneration (2022)
Jacob, a Synapto-Nuclear Protein Messenger Linking N-methyl-D-aspartate Receptor Activation to Nuclear Gene Expression
Katarzyna M Grochowska, Julia Bär, Guilherme M Gomes, Michael R Kreutz, Anna Karpova Front. Synaptic Neurosci (2021)
Irene Reyes-Resina, Sebastian Samer, Michael R Kreutz, Anja M Oelschlegel Front Mol Neurosci (2021)
Multiomics of synaptic junctions reveals altered lipid metabolism and signaling following environmental enrichment
Maximilian Borgmeyer, Cristina Coman, Canan Has, Hans-Frieder Schött, Tingting Li, Philipp Westhoff, Yam F H Cheung, Nils Hoffmann, PingAn Yuanxiang, Thomas Behnisch, Guilherme M Gomes, Mael Dumenieu, Michaela Schweizer, Michaela Chocholoušková, Michal Holčapek, Marina Mikhaylova, Michael R Kreutz, Robert Ahrends Cell Rep (2021)
Autism-associated SHANK3 missense point mutations impact conformational fluctuations and protein turnover at synapses
Michael Bucher, Stephan Niebling, Yuhao Han, Dmitry Molodenskiy, Fatemeh Hassani Nia, Hans-Jürgen Kreienkamp, Dmitri Svergun, Eunjoon Kim, Alla S Kostyukova, Michael R Kreutz, Marina Mikhaylova Elife (2021)
Sebastian Samer, Rajeev Raman, Gregor Laube, Michael R. Kreutz & Anna Karpova Molecular Brain (2021)