Unity and diversity: Single-cell RNAseq shows it’s all in our head

Cell-type identification, enumeration and classification of heterogeneous brain tissue are essential to understand circuit function and disease.   Current classification is reliant on the expression of select neuropeptides, calcium-binding proteins, neurotransmitters, intrinsic physiological properties, morphology and anatomical location.  Therefore, the determination of neuronal cell-types and their explicit definition becomes controversial and messy.  This problem is further compounded when we attempt to integrate cell-type information with neuronal projections, input selectivity and particularly for GABAergic interneurons, their developmental origin.  In this talk, I will introduce a new conceptual and methodological approach to cortical neuron identity and diversity wherein we embrace neuronal heterogeneity.  I have developed a multiplexed, sensitive and robust RNA sequencing protocol that provides unbiased absolute transcript counts from a single neuron.  Utilizing genetic intersection strategy and innovative reporter mice developed in the Huang lab, populations of GABAergic and Glutamatergic neurons from the neocortex are now being systematically sampled.  To demonstrate the power and resolution of the approach I will present emerging data on one such rare yet highly stereotypical cortical interneuron, the Chandelier cell.  I will discuss on-going and future work and how it may impact disease research and biomarker discovery.

In the second part of my talk I will briefly touch upon some exciting results establishing a novel biological function of MeCP2 that implicates translation regulation in Rett syndrome (RTT) pathogenesis. MeCP2 was identified as a nuclear methyl-CpG DNA binding protein and is best known as a regulator of transcription and chromatin. Mutations in MECP2 are linked to autism spectrum disorders, especially the RTT, but the pathogenic mechanisms remain elusive.