Signature morpho-electric properties of diverse GABAergic interneurons in the human neocortex

Abstract

Human cortical interneurons have been challenging to study due to high diversity and lack of mature brain tissue platforms and genetic targeting tools. We employed rapid GABAergic neuron viral labeling plus unbiased Patch-seq sampling in brain slices to define the signature morpho-electric properties of GABAergic neurons in the human neocortex. Viral targeting greatly facilitated sampling of the SST subclass, including primate specialized double bouquet cells which mapped to two SST transcriptomic types. Multimodal analysis uncovered an SST neuron type with properties inconsistent with original subclass assignment; we instead propose reclassification into PVALB subclass. Our findings provide novel insights about functional properties of human cortical GABAergic neuron subclasses and types and highlight the essential role of multimodal annotation for refinement of emerging transcriptomic cell type taxonomies.

Neuronal Spike Shapes (NSS): A Straightforward Approach to Investigate Heterogeneity in Neuronal Excitability States

“…Additionally, once comprehensive human patch-seq datasets become available on a larger scale, we plan to extend the validation of the NSS method to include them. In particular, we aim to apply the NSS methodology on the patch-seq dataset analyzed in [39], where the electrophysiological profile of one of the Sst subtypes exhibits similarity to the Pvalb profile, that is, to a fast-spiking excitability state as soon as it will be made publicly available. Future research aims to analyze more datasets containing different neuronal types and potentially from other species.…”

Integrated multimodal cell atlas of Alzheimer’s disease

“…To understand the anatomical and physiological phenotypes of affected supertypes, we reanalyzed a recently published multimodal dataset profiling human cortical interneurons from young donors without AD by Patch-seq 13 , a technique that measures both morpho-electric properties and the transcriptional profile of a cell 13,87,88 . The morphological reconstruction of affected Sst supertypes confirmed their localization to cortical layers 2-4 (L2-L4) and revealed their axons tended to cross laminar boundaries (Fig.…”

“…The current study focused on the middle temporal gyrus (MTG), an area involved in language and semantic memory processing 23 and higher order visual processing 24 . MTG is the human cortical region currently with the best annotated BICCN cell classification 11,17 , including cellular phenotype data available through Patch-seq analysis of neurosurgical specimens 13,16,25 . Perhaps most importantly, pathological and imaging studies demonstrate that MTG is a transition zone between aging-or preclinical AD-related pTau and more advanced stages of AD that are strongly correlated with dementia 4,[26][27][28][29][30][31][32] .…”

“…A subset of donors showed a particularly severe cellular and molecular phenotype, which correlated with steeper cognitive decline. We have created a freely available public resource to explore these data and to accelerate progress in AD research at SEA-AD.org.Recent work catalyzed by the BRAIN Initiative Cell Census Network (BICCN) has firmly established best practices in experimental and quantitative analyses of mouse, non-human primate and human brain using single cell genomics, spatial transcriptomics, and Patch-seq methods to characterize cellular properties and build a knowledge base of brain cell types [10][11][12][13][14][15][16] . Over 100 cell types can be reliably identified using single nucleus RNA-seq in any cortical area 10,11,17,18 , and alignment across species shows strong…”

Long-term human organotypic brain slice cultures: a detailed protocol to provide a comprehensive framework for single-neuron and neuronal network investigations

“…Long-term human organotypic brain slice cultures: a detailed protocol to provide a comprehensive framework for single-neuron and neuronal network investigations 36 or continuing work at the working space. Surgical mask, hair net and surgery clothing can be of advantage as well to avoid possible contaminations.…”