Figure 1

Cross-species presynaptic event comparison in cerebral cortex using a learning-based algorithm is minimally impacted by technical confounders. (A) Public available SynTOF data collected on synaptosome preparations from three species: human (Hu), non-human primate cynomolgus macaques (Macaca fascicularis, NHP), and C57Bl6 mouse (Mu) from different brain regions was leveraged in our study¹⁷. A region-specific machine-learning pipeline was developed to compare these more than 4 M pre-synapses between species from three different brain regions: cerebral cortex (CTX, isocortical organization) from all three species (Brodmann area 9 for Hu and frontal cortex for NHP); neostriatum (NSTR) from Hu and NHP (Mu NSTR was not collected); and hippocampus (HIPP; allocortical organization) from Hu (at the level of the lateral geniculate nucleus) and Mu (NHP HIPP was unavailable because of commitments to other projects). (B) Mean species cross-reactive protein expression levels for Hu, NHP and Mu in cerebral cortex. One-way ANOVA test revealed no significant differences between the three species’ mean levels (P-value > 0.05). Lines represent mean value for each species. (C) Coefficient of variation computed on mono-species (Hu) and multi-species dataset per protein for three brain regions. (CTX, cortex; STR, Striatum; HIPP, Hippocampus). (D) Proportion of subject-specific synaptic events per cluster stratified by species. Presynaptic events across samples group together based on clustering assignment, no clusters were clearly segregated by subjects or sex, suggesting that our method is unaltered by intra-species or sex variation. (E) Nearest-neighbor graph built using the mean expression of single events from 11 primate-specific clusters (P1–P11) and one multi-species cluster (A1) (nodes). Edges correspond to the inter and intra-species one minus the normalized Euclidean distances between two subjects. Only edges superior to the mean distance value are shown. The model derives a latent space that brings closer events from the same nature regardless of the species origin. Node positions are computed based on the Fruchterman-Reingold algorithm. (AS, alpha-synuclein).