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Notman, B.

Publications and source records attributed to Notman, B..

3 recordsLinked to original sources

Experiences are encoded by brainwide reprogramming of synaptome architecture

Synaptome architecture describes the spatiotemporal distribution of highly diverse excitatory synapses throughout the brain. Whether and how this architecture is impacted by experience is key to understanding its role in learning and memory. We found that environmental enrichment and monocular visual deprivation drive large-scale, type-and subtype-specific reorganisation of excitatory synapses in more than one hundred brain regions. Each experience modifies distinct subsets of synapses, with patterns aligned with protein turnover rates and connectome architecture. These reorganisations occur during development and adulthood, revealing a conserved mechanism of synaptome plasticity across the lifespan. Our findings support a population-selection model in which experience drives adaptation by selectively modifying synapse varieties, generating a distributed trace of past experiences. Our results also point to synaptome architecture as a shared framework integrating experience, lifespan changes, sleep, genetic variation and disease.

neuroscience↗

A synaptic-astrocytic proteomic signature associated with synaptopathy in Alzheimer's Disease

Synapse loss is the greatest correlate of cognitive impairment in Alzheimers Disease (AD) and offers a therapeutic avenue alongside disease-modifying therapies. However, the events preceding synapse loss in the human condition have not been well characterised. In this study, we describe a pseudotemporal profile of alterations in the synaptic proteome prior to excitatory synapse loss in human post-mortem brain AD tissue using synapse proteomics and synaptome mapping techniques. In a region with early-stage disease pathology, the most predominant changes were pre-synaptic and featured changes in metabolism and exocytosis. In a mid-stage disease state, alongside initial synapse loss, there was a dominance of inhibitory synaptic changes. In a region with late-stage disease pathology and profound synapse loss, post-synaptic changes were most prevalent with a range of canonical synaptic transmission pathways reduced and differential excitatory synapse subtype pathology. Synapse loss was associated with changes in astrocytic proteins which were enriched for those at peri-synaptic astrocytic processes, including an upregulation of complement activation and endocytosis; a signature that differed from the astrocyte cytosolic proteome. Taken together, this provides evidence of a cascade of events leading to synapse loss with multiple points for therapeutic intervention to alleviate cognitive decline in AD. Data are available via ProteomeXchange with identifier PXD056052.

neuroscience↗

SV2A is expressed in synapse subpopulations in mouse and human brain: implications for PET radiotracer studies

Synapse pathology is a feature of most brain diseases and there is a pressing need to monitor the onset and progression of this pathology using brain imaging in living patients. A major step toward this goal has been the development of small-molecule radiotracers that bind to synaptic vesicle glycoprotein 2A (SV2A) for use in positron emission tomography (PET). Changes in SV2A radiotracer binding in PET are widely interpreted to report differences in the density of all synapses throughout brain regions. Here, we analyse the expression of SV2A at single-synapse resolution across regions of adult mouse and human brain. We find that SV2A is expressed in fewer than 50% of excitatory and inhibitory synapses and that the density of SV2A-positive synapses differs between brain regions. Furthermore, individual synapses differ in their amounts of SV2A. These findings have important implications for the interpretation of PET imaging studies in a clinical setting and point to the need for a detailed understanding of SV2A synaptome architecture in both healthy brain and disease cases where PET imaging is being applied.

neuroscience↗