¹University of Edinburgh, Institute for Neuroscience and Cardiovascular Research, Edinburgh, United Kingdom, ²University of Edinburgh, Simons Initiative for the Developing Brain, Edinburgh, United Kingdom, ³University of Edinburgh, Centre for Clinical Brain Sciences, Edinburgh, United Kingdom, ⁴University of Strathclyde, Biomedical Engineering, Glasgow, United Kingdom

Background: Excitatory synapses are highly diverse, differing in their proteome composition, nanoscale organisation, and protein turnover. This enables the classification of synapses into types and subtypes, each with a distinct spatial distribution, thus creating the synaptome architecture. Genetic studies have identified synaptic dysfunction as a hallmark of schizophrenia and bipolar disorder. However, the impact of genetic risk for schizophrenia and bipolar disorder, as well as the influence of antipsychotic drug treatment on excitatory synapses is poorly characterised.

Aims & Objectives: We hypothesised that a risk gene of schizophrenia and bipolar disorder could alter the excitatory synaptome architecture and that olanzapine, a D2 and 5-HT2A/C receptor antagonist widely prescribed to treat such conditions, could modify these changes. To test this, we administered olanzapine by oral gavage daily for 28 days to adult mice (9.5-11.5 months old) carrying a heterozygous knockout mutation in Dlg2, a schizophrenia and bipolar disorder risk gene.

Method: We examined four experimental groups: vehicle-treated wild-type mice (n=10, 3F), vehicle-treated Dlg2^+/- mice (n=9, 5F), olanzapine-treated wild-type mice (n=10, 3F), and olanzapine-treated Dlg2^+/- mice (n=10, 7F). For each experimental group, we mapped the synaptome architecture of PSD95 and SAP102, two postsynaptic scaffolding proteins widely expressed in excitatory synapses, at single-synapse resolution across 113 brain regions. We used machine-learning algorithms developed in-house to detect, colocalise, and classify excitatory synapses into three types and 37 subtypes.

Results: We observed global alterations in synapse subtype densities in Dlg2^+/- mice, with increases in the total density of excitatory postsynaptic puncta in forebrain regions. Conversely, olanzapine globally reduced the total density of excitatory postsynaptic puncta in Dlg2^+/-mice, acting as a partial reversal to the mutation effect in a region-dependent manner. In addition, the synaptome architecture of wild-type mice was modified by olanzapine in a way that differed from Dlg2^+/- mice in most subregions. This suggests that the reorganization of the synaptome architecture by olanzapine depends on genetic background, and that genotype–drug interactions determine synaptome response.

Discussion & Conclusions: These results are the first evidence of pharmacological modulation of the synaptome architecture and demonstrate the potential to detect and reverse synaptic pathology in models of psychiatric disorders.