EASTBIO: The role of synapse protein lifetime in memory

Understanding the mechanisms of memory formation and how these change across the lifespan remains a major scientific question, impacting language acquisition in children to cognitive decline in old age. Modification of synapse proteins is central to learning and it is imperative to understand the molecular properties of synapses at different ages. Using our world-leading synaptome mapping technology (Zhu et al, Neuron 2018; doi:10.1016/j.neuron.2018.07.007) we delivered the first analysis of the molecular composition of individual synapses across the whole mouse brain and lifespan (Cizeron et al, Science 2020; doi:10.1126/science.aba3163), revealing an unprecedented diversity of synapse types and subtypes with unique spatiotemporal distributions.

Our current work addresses the contribution of protein turnover to this diversity. Synapse protein turnover is known to be important in brain development, aging, memory and disease. We developed HaloTag-based methods that systematically quantify endogenous protein (PSD95) turnover in individual excitatory synapses, revealing a diversity of protein lifetimes differentially distributed in dendrites, neuron types, circuits and functional regions across the brain and lifespan (Bulovaite et al, Neuron 2022, in press). For example, long-protein-lifetime synapses are enriched in circuits storing long-term memories, accumulate during postnatal development and are preferentially retained in old age. This characteristic spatiotemporal distribution of synapses with long and short protein lifetimes led to the central hypothesis of this project: that synaptic protein lifetime is a correlate, potentially even a causal mechanism, of memory duration.

We will combine synaptome imaging technology with optogenetic and behavioural approaches for labelling ‘engram neurons’ to explore the colocalisation of synaptic changes with memory retention in the hippocampus and frontal cortex. Using the HaloTag system in combination with genetic mouse models, we will double label for PSD95 and cells activated by memory retrieval (Finnie et al, Curr Biol 2018; doi:10.1016/j.cub.2018.07.037) or plasticity-related proteins (Fernández et al, Cell Rep 2017; doi:10.1016/j.celrep.2017.09.045) to investigate whether colocalisation at the cellular level changes with memory duration and with ageing. We can also directly manipulate PSD95 turnover rates to uncover the impact on long-term memory; for example, by exploiting the PSD95-HaloTag to deliver a photoactivatable toxin for selective damage of synapses with long protein lifetimes. These studies will provide the first demonstration of a direct causal link between synaptic protein lifetime and memory duration.

Research techniques and training will include Home Office license training, in vivo behaviour, surgery optogenetics, perfusion and tissue processing, mouse genetics, transgenic mouse and viral transduction technology, high-resolution microscopy, computational image analysis, experimental design, data analysis, statistics.

How to Apply

Please refer to UKRI website and Annex B of the UKRI Training Grant Terms and Conditions for full eligibility criteria

EASTBIO Application and Reference Forms can be downloaded via  http://www.eastscotbiodtp.ac.uk/how-apply-0 

Please send your completed EASTBIO Application Form along with a copy of your academic transcripts to [Email Address Removed] by the deadline of 5 December 2022

You should also ensure that two references have been sent to [Email Address Removed] by the deadline using the EASTBIO Reference Form