The overall aim of my research is to understand how the organisation of the synapse, with particular reference to the postsynaptic proteome (PSP) of excitatory synapses in the brain, informs the fundamental mechanisms of learning, memory and behaviour and how these mechanisms go awry in neurological dysfunction. The PSP indeed bears a remarkable burden of disease, with components being disrupted in disorders (synaptopathies) including schizophrenia, depression, autism and intellectual disability. Our work has been fundamental in revealing and then characterising the unprecedented complexity (>1000 highly conserved proteins) of the PSP in terms of the subsynaptic architecture of postsynaptic proteins such as PSD95 and how these proteins assemble into complexes and supercomplexes in different neurons and regions of the brain. Characterising the PSPs in multiple species, including human and mouse, has revealed differences in key sets of functionally important proteins, correlates with brain imaging and connectome data, and a differential distribution of disease-relevant proteins and pathways. Such studies have also provided important insight into synapse evolution, establishing that vertebrate behavioural complexity is a product of the evolutionary expansion in synapse proteomes that occurred ~500 million years ago. My lab has identified many mutations causing cognitive impairments in mice before they were found to cause human disorders. Our proteomic studies revealed that >130 brain diseases are caused by mutations affecting postsynaptic proteins. We uncovered mechanisms that explain the polygenic basis and age of onset of schizophrenia, with postsynaptic proteins, including PSD95 supercomplexes, carrying much of the polygenic burden. We discovered the “Genetic Lifespan Calendar”, a genomic programme controlling when genes are regulated. We showed that this could explain how schizophrenia susceptibility genes are timed to exert their effects in young adults. The Genes to Cognition programme is the largest genetic study so far undertaken into the synaptic molecular mechanisms underlying behaviour and physiology. We made important conceptual advances that inform how the repertoire of both innate and learned behaviours is built from unique combinations of postsynaptic proteins that either amplify or attenuate the behavioural response. This constitutes a key advance in understanding how the brain decodes information inherent in patterns of nerve impulses, and provides insight into why the PSP has evolved to be so complex, and consequently why the phenotypes of synaptopathies are so diverse. Our most recent work has opened a new phase, and scale, in understanding synapses with the first synaptome maps of the brain. We have developed next-generation methods (SYNMAP) that enable single-synapse resolution molecular mapping across the whole mouse brain and extensive regions of the human brain, revealing the molecular and morphological features of a billion synapses. This has already uncovered unprecedented spatiotemporal synapse diversity organised into an architecture that correlates with the structural and functional connectomes, and shown how mutations that cause cognitive disorders reorganise these synaptome maps; for example, by detecting vulnerable synapse subtypes and synapse loss in Alzheimer’s disease. This innovative synaptome mapping technology has huge potential to help characterise how the brain changes during normal development, including in specific cell types, and with degeneration, facilitating novel pathways to diagnosis and therapy.

Microglia are implicated in a variety of functions in the central nervous system, ranging from shaping neural circuits during early brain development, to surveying the brain parenchyma, and providing trophic support to neurons across the entire lifespan. In neurodegeneration, microglia have been considered for long time mere bystanders, accompanying and worsening neuronal damage. However, recent evidence indicates that microglia can causally contribute to neurodegenerative diseases, and that their dysfunction can even be at the origin of the pathology. In fact, the broad range of physiological roles microglia play in the healthy brain suggest that faulty microglia can initiate neurodegeneration through several possible mechanisms. In particular, in this seminar, we will discuss how dysfunctional microglia can affect synaptic function leading to pathological synapse loss, thus putting microglia center stage in the pathogenesis of brain disorders.

Alzheimer’s Disease is characterised by the accumulation of misfolded proteins, namely amyloid and tau, however it is synapse loss which leads to the cognitive impairments associated with the disease. Many studies have focussed on single time points to determine the effects of pathology on synapses however this does not inform on the plasticity of the synapses, that is how they behave in vivo as the pathology progresses. Here we used in vivo two-photon microscopy to assess the temporal dynamics of axonal boutons and dendritic spines in mouse models of tauopathy[1] (rTg4510) and amyloidopathy[2] (J20). This revealed that pre- and post-synaptic components are differentially affected in both AD models in response to pathology. In the Tg4510 model, differences in the stability and turnover of axonal boutons and dendritic spines immediately prior to neurite degeneration was revealed. Moreover, the dystrophic neurites could be partially rescued by transgene suppression. Understanding the imbalance in the response of pre- and post-synaptic components is crucial for drug discovery studies targeting the synapse in Alzheimer’s Disease. To investigate how sub-types of synapses are affected in human tissue, the Multi-‘omics Atlas Project, a UKDRI initiative to comprehensively map the pathology in human AD, will determine the synaptome changes using imaging and synaptic proteomics in human post mortem AD tissue. The use of multiple brain regions and multiple stages of disease will enable a pseudotemporal profile of pathology and the associated synapse alterations to be determined. These data will be compared to data from preclinical models to determine the functional implications of the human findings, to better inform preclinical drug discovery studies and to develop a therapeutic strategy to target synapses in Alzheimer’s Disease[3].

Genome-wide association studies implicate microglia in Alzheimer’s disease (AD) pathogenesis, but how microglia contribute to cognitive decline in AD is unclear. Emerging research suggests microglia, the resident macrophages of the central nervous system, to be active participants in brain wiring. One mechanism by which microglia help eliminate synapses is through the classical complement pathway (C1q, CR3/C3). Data from multiple laboratories collectively suggest that there may be an aberrant reactivation of the complement-dependent pruning pathway in multiple models of neurologic diseases including AD. These data altogether suggest that microglia participate in synaptic pathology. However, how and which synapses are targeted are unknown. Furthermore, whether microglia directly impair synaptic function is unknown. Primary goals of my laboratory are to understand how higher cognitive functions such as learning and memory involve microglial biology in the healthy adult brain and dissect immune mechanisms behind the region-specific vulnerability of synapse loss and neuronal dysfunction during disease. Mechanistic insight into local signals that regulate neuroglia interactions will be key to developing potential therapeutic avenues to target in disease.