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Transcriptional regulation in synaptic plasticity, learning and memory under normal and pathological situations

Final Activity Report Summary - GENES AND MEMORY (Transcriptional regulation in synaptic plasticity, learning and memory under normal and pathological situations)

Memory is encoded in the form of changes in the strength of specific synaptic connections whose stabilisation requires of de novo gene expression. The CREB family of transcription factors is thought to be one of the core components in the molecular switch that converts short- to long-term memory. The main focus of our research these four years have been to clarify the role of CREB and related proteins in plasticity and memory, both in the normal brain and under pathological situations. To this end we have used a bottom-up approached based on the use of mouse genetics to restrict, both anatomically and temporally, the expression of genetic alteration in the CREB pathway, as well as more conventional genetic tools.

Our research on CREB mutants has revealed that CREB does not only regulate the duration of synaptic plasticity processes, but also modulates intrinsic plasticity in neuronal circuits relevant for learning, a discovery that has critical implication for understanding learning and memory processes. We also demonstrated that both the survival of hippocampal neurons and learning and memory processes require accurate regulation of the CREB pathway, indicating that caution is required in the current effort to produce drugs that increase activity in the CREB pathway because only pharmaceuticals that enhance CREB-mediated gene induction within a reasonable range can restore or enhance memory.

We have made also important advances in our understanding of gene program orchestrated by CREB in neurons (the CREB transcriptome). We recently extended this study to other transcription factors important in synaptic plasticity and memory, such as SRF or Egr1, revealing critical features of activity-driven gene expression programs in neurons. Our research on the CREB binding proteins CBP and p300 has provided novel insight into Rubinstein-Taybi syndrome etiology, a rare mental retardation syndrome, at the same time that highlighted the relevance of epigenetic mechanisms, such as histone acetylation, in normal brain function.

Finally, we have established new models to study the molecular bases of Huntington's disease pathology, a line of research that we hope will produce interesting results in the next years. Overall, this knowledge revealed important cues concerning the role of the CREB pathway in brain function and how its dysfunction can lead to neurological disorders. Furthermore, this Grant has allowed Dr Barco and his interdisciplinary team to establish rapidly as an independent and internationally competitive research group, leading several national and international projects, a goal that, otherwise, would have taken much longer in the current Spanish science framework.