Prof. Gräff Lab : Davide Coda - CRISPR-based epigenetic editing of engram cells in fear memories

Hybrid - By invitation only

EXCEPTIONALLY AT 16:00!

The experience of traumatic, life-threatening events gives rise to some of the most enduring forms of fear memories, which can degenerate into a devastating pathological state known as post-traumatic stress disorder (PTSD). Nevertheless, surprisingly little is known about how long-lasting memories are formed and stored. Over the past decade, engram cells have emerged as a plausible physiological substrate of the memory trace, but the molecular mechanisms therein to encode memories remain incompletely understood. In my research I combine c-Fos driven engram tagging technologies with in vivo epigenetic editing tools to assess whether and the extent to which epigenetic modifications within the memory trace cells contribute to memory encoding. First, I will show that in transgenic c-Fos::tTA mice overexpressing the histone acetyl transferase CREB binding protein (CBP) in engram cells of the dentate gyrus increases whole-genome H3K27ac levels and the ability to recall fear memories, while overexpressing of HDAC8 has the opposite effects. Then, I will go on to show that epigenetic editing of a single site on the genome – using CRISPR-dCas9 coupled to transcriptional activators or repressors – is sufficient to alter memory performances. Engram-specific, dCas9-VPR mediated upregulation of a master regulator of synaptic plasticity improves recent fear memory, whilst expression of dCas9-KRAB-MeCP2 in the same cells at the same locus impairs fear memory recall. Overall, these findings show how the modulation of epigenetic marks in a cell type and locus-specific manner can impact neuronal function and memory capacity; at the same time, they deepen our understanding of the molecular mechanisms of traumatic memory storage.