Coupled electrophysiological recording and single-cell transcriptome analyses revealed molecular mechanisms underlying neuronal maturation

The mammalian brain is heterogeneous, containing billions of neurons and trillions of synapses forming various neural circuitries, through which sense, movement, thought, and emotion are generated. The cellular heterogeneity of the brain has made it difficult to study the molecular logic of neural circuitry wiring, pruning, activation, and plasticity, until recently, transcriptome analyses with single-cell resolution makes decoding of gene regulatory networks underlying aforementioned circuitry properties possible. Here, we report success in performing both electrophysiological and whole-genome transcriptome analyses on single human neurons in culture. Using Weighted Gene Coexpression Network Analyses (WGCNA), we identified gene clusters highly correlated with neuronal maturation judged by electrophysiological characteristics. A tight link between neuronal maturation and genes involved in ubiquitination and mitochondrial function was revealed. Moreover, we identified a list of candidate genes, which could potentially serve as biomarkers for neuronal maturation. Coupled electrophysiological recording and single-cell transcriptome analysis will serve as powerful tools in the future to unveil molecular logics for neural circuitry functions. Overall design: Patch-Seq of 20 hESC/hiPSC-derived neurons.