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Molecular organization and dynamics of synapse diversity: novel genetic, imaging and computational approaches

Periodic Reporting for period 3 - SYNNOVATE (Molecular organization and dynamics of synapse diversity: novel genetic, imaging and computational approaches)

Reporting period: 2019-08-01 to 2021-07-31

Synapses – the connections between neurons – can contain many different proteins in many different combinations, leading to potentially vast synaptic diversity in the brain. Characterising this diversity is key to understanding its significance for brain function. We have developed ‘synaptome mapping’, a method that can map almost a billion individual synapses throughout the many hundreds of regions of the mammalian brain. Using synaptome mapping we have shown that these synapse diversity maps can be used to store and recall information, that they are not fixed but change during normal development and ageing, adjust in response to sensory stimulations, and are impacted by drugs (olanzapine) and brain disease. These findings provide important new insight into how learning and memory work in the brain and why it goes awry in conditions such as schizophrenia and autism.
We have made substantial progress towards characterising and unlocking the functional significance of synapse diversity in the mammalian brain. A key finding in the context of learning and memory is that synaptome maps can be used as a mechanism for storing information. Disease mutations, such as those seen in schizophrenia and autism, alter these maps, potentially affecting information storage/recall and how the external world is represented. Olanzapine, a commonly prescribed antipsychotic medication, can also change the synaptome maps, opening up opportunities of using synaptome mapping for drug development to treat brain disease. A second key finding is that synaptome maps are not fixed even in normal life, but change (‘plasticity’) throughout the lifespan (see figure) and in a characteristic way that mirrors natural changes in cognitive ability during development and ageing. These lifespan changes may also help to explain why we are susceptible to certain brain disorders at particular ages. A third key finding is that synaptome maps may help us to understood how and where memories of different durations are stored and why this capacity changes throughout life and in brain diseases. The synapse protein PSD95, which is required to write and store memories, seems to last longest in synapse types found in areas of the brain that store long-term memories. Sleep deprivation causes a decrease in short-protein-lifetime synapses, consistent with its effect on short-term memory. The schizophrenia mutation alters how long PSD95 lasts, which might contribute to the cognitive dysfunction of this condition. All the data that we have gathered during the project have been made freely available to the research community through online databases, together with tools that facilitate data discovery and analysis in order to maximise the reuse and potential health impact of our data.
In this project we have shown that brain synapses are much more diverse and subject to change than previously thought. Synaptome maps provide an entirely new way to examine the architecture of the brain, with potential impacts in the understanding, diagnosis, monitoring and treatment of brain disease and cognitive disorders.

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