Glial regulation of synapse numbers in schizophrenia – an integrated multimodal experimental and clinical approach to identify new targets

This proposal builds on multi-disciplinary data describing abnormal synaptic pruning as a mechanism in schizophrenia (SZ).

So far, increased expression of the SZ risk gene coding for complement component 4A (C4A) has been shown to contribute to excessive microglial engulfment of synaptic structures in patient-derived SZ models, while protein levels of C 4A are elevated in first-episode SZ patients.

However, the mechanistic understanding of the molecular events that leads to activity-dependent synapse elimination by microglia, and other glia cells, is largely incomplete due to the lack of adequate experimental models.

This has complicated the identification of suitable drug targets and stalled the highly needed clinical studies using novel or repurposed compounds in SZ.

Here, we propose a novel and unique integrated experimental and clinical approach - linked on subject level and supported by humanized in vivo models - to identify suitable drug targets for modifying glial synapse elimination in SZ.

Using state-of-the-art organoid models combined with high-resolution single cell transcriptomic profiling we aim to identify cell types and mechanisms contributing to excessive pruning in SZ.

By perturbing these mechanisms in our models, we select a set of candidate mechanisms that are validated in vivo and in a clincial context (CSF and longitudinal MRI imaging) using within-subjects analyses followed by case versus control analyses utilizing a cohort consisting of >200 subjects.