A02
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.
Principal Investigators
Dr. Anna Karpova
Dr. Michael R. Kreutz
Co-Workers
Dr. Guilherme Gomes
Dr. Katarzyna Grochowska
Dr. Anja Oelschlegel
Sebastian Samer
Dr. Pingan Yuanxiang
Fabian Zmiskol
What are synapto-nuclear
protein messengers?
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.
