Abstract
The mammalian brain is heterogeneous, containing billions of neurons and trillions of synapses forming various neural circuitries, through which sense, movement, thought, and emotion arise. 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.Electronic supplementary materialThe online version of this article (doi:10.1007/s13238-016-0247-8) contains supplementary material, which is available to authorized users.
Highlights
The mammalian brain is a fascinating organ, which breeds wisdom, empathy, and creativity, i.e., features unique to the human mind
While it is known that cells could be pretty much defined by the genes that they express, and that transcriptome analyses have been shown to be useful to delineate molecular features associated with cell type, cell age, and cell physiological or pathological states, transcriptome analyses of brain tissues had not been useful due to the huge cellular heterogeneity of brain tissues and that cells of interest are often rare populations, such as neurons in particular circuitries involved in specific behaviors
These neurons do mature in culture and form synaptic networks, which could be judged anatomically by presynaptic synapsin immunostaining puncta on postsynaptic MAP2-positive dendrites (Fig. 1D), or functionally by the presence of spontaneous excitatory and inhibitory postsynaptic currents (Fig. 1I)
Summary
The mammalian brain is a fascinating organ, which breeds wisdom, empathy, and creativity, i.e., features unique to the human mind. The brain is complex, composed of billions of neurons and trillions of glia including both astrocytes and oligodendrocytes. It is believed that when an individual is conducting a specific task, only a few neurons or specific neural circuitries are engaged in the activity, which means analysis using brain tissues, as a whole will not provide sufficient resolution for dissection of the molecular gene network underlying the particular brain function. While it is known that cells could be pretty much defined by the genes that they express, and that transcriptome analyses have been shown to be useful to delineate molecular features associated with cell type, cell age, and cell physiological or pathological states, transcriptome analyses of brain tissues had not been useful due to the huge cellular heterogeneity of brain tissues and that cells of interest are often rare populations, such as neurons in particular circuitries involved in specific behaviors. There are some bioinformatics tools including WGCNA, which can be used to sort out cell-type specific gene expression signatures from transcriptome of the brain tissue (Miller et al, 2014; Kang et al, 2011; Mirnics 2008), a physical limitation is that transcription signals from rare cells in the tissue will not be captured when the whole tissue is subjected to RNA sequencing
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