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Mapping age-related dysregulation of in vivo synaptic plasticity to molecular synaptic diversity

Reference	BB/X010171/1
Principal Investigator / Supervisor	Ms Kjara Pilch
Co-Investigators / Co-Supervisors
Institution	Imperial College London
Department	Brain Sciences
Funding type	Research
Value (£)	406,515
Status	Current
Type	Fellowships
Start date	01/03/2023
End date	28/02/2026
Duration	36 months

Abstract

How the molecular diversity of synapses maps to healthy synaptic function and plasticity remains unclear. Recently, the Barnes lab have used functional calcium imaging to estimate the synaptic activity of dendritic spines in the intact brain. This work has found discrete clusters of plastic and non-plastic dendritic spines in the visual cortex and a dysregulation of synaptic plasticity in the aging brain (Radulescu et al., under review). One of the central challenges is to understand how discrete functional clusters of synapses with common plasticity properties map to their molecular composition and how a dysregulation of molecular processes contributes to synaptic dysfunction during ageing. During this project I will first determine functionally defined clusters of plastic dendritic spines using 2-P in vivo calcium imaging in the visual cortex of mice subjected to multimodal sensory stimuli to induce plasticity. To do this I will use dimensionality reduction approaches to reveal how plasticity maps to functional clusters. Second, I will map functional clusters of plastic spines to their molecular identity. To do this, I will induce plasticity in brain slices using pharmacology and electrophysiology and then determine the molecular identity of functional clusters of discrete spine populations with proteomics. Moreover, I will map synaptic plasticity induced in vivo to ex vivo proteomic measures using established mapping approaches. Finally, I will test for age-related changes in identified spine clusters. Plasticity will be induced in vivo and ex vivo in brains from aged mice and changes in protein composition of spine populations assessed. Super-resolution microscopy will complement findings on alterations in spine clusters. In addition to substantially advancing our understanding of synaptic function and brain homeostasis, this research may open pathways to targeting molecularly defined populations of synapses with known function/dysfunction in the aged brain.

Summary

Synapses are highly specialised structures consisting of a presynaptic (sender) and postsynaptic (receiver) site to connect neuronal cells and enable communication. In the cortex, most connections are mediated via small membranous protrusions called dendritic spines, which make up the postsynaptic site. Synapses exhibit a high degree of diversity in their function and protein composition. Moreover, protein levels can be dynamically altered, for example during synaptic plasticity. During synaptic plasticity, adjustments in synaptic strength underlie the encoding of new information during learning and memory. To avoid excessive or insufficient firing rates, homeostatic mechanisms are in place. A dysregulation of plastic adaptations is thought to underly pathological levels of brain activity and has also been observed in early stages of dementia in the ageing brain. A fundamental challenge is to understand how different protein compositions of spines relate to healthy synapse function and plastic adaptations. Recently, the Barnes laboratory has found discrete clusters of plastic and non-plastic spines in the visual cortex of mice. They also revealed, that in the aged brain, some forms of synaptic plasticity at dendritic spines are changed. However, how synaptic function relates to molecular diversity remains unclear. In this project I hypothesize that discrete populations of molecularly defined synapses map to specific classes of synaptic function and plasticity in vivo. I will establish how a dysregulation of these synaptic clusters leads to synaptic dysfunction in the ageing brain. I will first demonstrate different functional clusters of dendritic spines in vivo. For this, I will perform calcium imaging experiments of dendritic spines in awake mice during normal behaviour and after the induction of plasticity to determine functional spine clusters. To map functional clusters to their protein composition, I will induce plasticity in brain slices and assess protein levels with multiplexed proteomics. Finally, to assess changes in spine plasticity in the ageing brain, calcium imaging experiments, proteomics and follow-up super resolution microscopy will reveal changes in different spine populations in older mice. This research will be crucial for our understanding of synaptic function and spine dynamics in the ageing brain. Particularly the possibility to correlate functional clusters from in vivo experiments to their molecular composition at the single synapse level makes these findings so valuable. This research is highly relevant with important implications for further translational research. Identifying the molecular basis of changes that drive synaptic dysfunction in the ageing brain may open new avenues for clinical interventions in cognitive decline and dementia.

Committee	Research Committee D (Molecules, cells and industrial biotechnology)
Research Topics	X – not assigned to a current Research Topic
Research Priority	X – Research Priority information not available
Research Initiative	Fellowship - David Phillips Fellowship (DF) [1995-2015]
Funding Scheme	X – not Funded via a specific Funding Scheme

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