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

Periodic Reporting for period 2 - SYNNOVATE (Molecular organization and dynamics of synapse diversity: novel genetic, imaging and computational approaches)

Reporting period: 2018-02-01 to 2019-07-31

Synapses – the connections between neurons – can contain many different proteins in many different combinations, leading to vast potential synaptic diversity in the vertebrate brain. This has led to the recognition that ‘synaptome mapping’ needs to be developed, whereby the expression level of these various proteins is measured in individual synapses throughout the brain. We developed a novel ‘synaptome discovery and imaging platform’ that enables routine and rapid quantification of multiple proteins in almost a billion synapses in hundreds of brain regions, generating statistically robust molecular synaptome maps that have revealed remarkable new neuroanatomical features of the vertebrate brain and indications as to how synaptic architecture is altered in brain disease. Our goals are to understand how these maps develop and are reorganised in cognitive disorders such as schizophrenia, intellectual disability and autism, and to examine how they change during development following learning and stimulation in normal animals and those carrying cognitive disorder mutations. We also plan to develop computational approaches based on synaptome maps and to freely distribute genetic and image analysis tools to promote synaptome mapping in the community. These findings will provide important new insight into the molecular, genetic and physiological basis of learning, memory and the disorders of cognition – a major objective of neuroscience.
We have made substantial progress in mapping synapse diversity and the distribution of synapse types and subtypes across the mouse brain. Using high-speed microscopy to examine the molecular composition of individual synapses and their size and shape parameters, we have developed the first synapse catalogue based on data across the whole brain (Zhu et al., 2018. Architecture of the mouse brain synaptome. Neuron 99, 781-799). This shows that from two key postsynaptic proteins it is possible to identify 37 synapse subtypes. Each of these subtypes shows a unique anatomical distribution. Some subtypes are restricted to subregions of the hippocampus and striatum; some show graded distributions within regions, and others reveal boundaries between distinct areas of the brain (see Figure).
We have also been able to use these data to examine the relationship between the connectome (the ‘wiring diagram’ of neural connections in the brain) and the synaptome maps. We find that anatomical projections between brain regions are associated with specific synapse subtype distributions and that the architecture of the synaptome and connectome are correlated. This implies that there is a ‘synaptic molecular code’ that is associated with the large-scale organisation of brain circuitry.
The remarkable synapse diversity that is evident from our findings implies that the different synapse types and their spatial distribution contribute functional properties to the synaptome maps. We have used quantitative modelling approaches (in collaboration with Prof. Erik Fransén, KTH, Stockholm, Sweden) to study how synaptome maps respond to patterns of neuronal activity. These results show that synapse diversity combined with synaptic plasticity can be used to store and recall information from the nervous system. We are presently studying how neural activity and behavioural changes modify synaptome maps and thus act as a memory mechanism.
These synaptome maps provide an entirely new way to examine the architecture of the brain and represent progress beyond the state of the art, with major collaborative potential. The potential impact is significant, leading to new ways to understand how information is stored and recalled from the brain. Our current view is that the synaptome maps are a template for information storage and that this is genetically programmed; thus, genetic disorders of behaviour could arise by gene mutations that reorganise synaptome maps (Grant, 2019a. The synaptomic theory of behavior and brain disease. Cold Spring Harb. Symp. Quant. Biol. 83, doi:10.1101/sqb.2018.83.037887; Grant, 2019b. Synapse diversity and synaptome architecture in human genetic disorders. Hum. Mol. Genet. pii: ddz178, doi: 10.1093/hmg/ddz178). This view would enable us to directly connect the genome with the organisation of the brain via synaptome maps. We anticipate that this could lead to new understandings of brain disease and cognitive disorders and create potential for new diagnostic applications.
Coronal sections of mouse brain showing the distribution of 37 different synapse subtypes