Cell adhesion molecules play subclass-specific roles in electrophysiological response and Schizophrenia risk

Multimodal assays such as Patch-seq that simultaneously profile molecular and cellular phenotypes of cells enable the identification of molecular underpinnings of electrophysiological response patterns in neurons. Here we analyzed Patch-seq measurements of thousands of mouse interneurons to identify subclass-specific genes associated with different electrophysiological features. We found extensive subclass specificity: even for the same ephys feature, largely unique sets of genes are associated with that feature in different subclasses. Well established ephys genes such as Reln demonstrated subclass specificity that was previously not reported. Surprisingly, we found that ion channels explained significantly less variation in ephys response across interneurons compared to other genes; in particular, gene sets enriched in cell adhesion genes were amongst the most associated. We found our gene sets associated with action potential dV/dt measurements explained significant heritability of Schizophrenia risk, suggesting a novel role of single neuron electrophysiology in Schizophrenia risk. Finally, we observed significant ephys function switching of cell adhesion molecules across subclasses; the same adhesion molecule was observed to associate with different functional ephys measurements in distinct subclasses and co-express with different genes, suggesting re-purposing of adhesion molecules in different subclasses. Overall, our results yield novel insight into the specificity of roles that individual genes and adhesion molecules play in both single neuron ephys response and Schizophrenia risk.