Dataset Information

Integrated Morphoelectric and Transcriptomic Classification of Cortical GABAergic Cells.

ABSTRACT: Neurons are frequently classified into distinct types on the basis of structural, physiological, or genetic attributes. To better constrain the definition of neuronal cell types, we characterized the transcriptomes and intrinsic physiological properties of over 4,200 mouse visual cortical GABAergic interneurons and reconstructed the local morphologies of 517 of those neurons. We find that most transcriptomic types (t-types) occupy specific laminar positions within visual cortex, and, for most types, the cells mapping to a t-type exhibit consistent electrophysiological and morphological properties. These properties display both discrete and continuous variation among t-types. Through multimodal integrated analysis, we define 28 met-types that have congruent morphological, electrophysiological, and transcriptomic properties and robust mutual predictability. We identify layer-specific axon innervation pattern as a defining feature distinguishing different met-types. These met-types represent a unified definition of cortical GABAergic interneuron types, providing a systematic framework to capture existing knowledge and bridge future analyses across different modalities.

SUBMITTER: Gouwens NW

PROVIDER: S-EPMC7781065 | biostudies-literature | 2020 Nov

REPOSITORIES: biostudies-literature

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Integrated Morphoelectric and Transcriptomic Classification of Cortical GABAergic Cells.

Gouwens Nathan W NW Sorensen Staci A SA Baftizadeh Fahimeh F Budzillo Agata A Lee Brian R BR Jarsky Tim T Alfiler Lauren L Baker Katherine K Barkan Eliza E Berry Kyla K Bertagnolli Darren D Bickley Kris K Bomben Jasmine J Braun Thomas T Brouner Krissy K Casper Tamara T Crichton Kirsten K Daigle Tanya L TL Dalley Rachel R de Frates Rebecca A RA Dee Nick N Desta Tsega T Lee Samuel Dingman SD Dotson Nadezhda N Egdorf Tom T Ellingwood Lauren L Enstrom Rachel R Esposito Luke L Farrell Colin C Feng David D Fong Olivia O Gala Rohan R Gamlin Clare C Gary Amanda A Glandon Alexandra A Goldy Jeff J Gorham Melissa M Graybuck Lucas L Gu Hong H Hadley Kristen K Hawrylycz Michael J MJ Henry Alex M AM Hill DiJon D Hupp Madie M Kebede Sara S Kim Tae Kyung TK Kim Lisa L Kroll Matthew M Lee Changkyu C Link Katherine E KE Mallory Matthew M Mann Rusty R Maxwell Michelle M McGraw Medea M McMillen Delissa D Mukora Alice A Ng Lindsay L Ng Lydia L Ngo Kiet K Nicovich Philip R PR Oldre Aaron A Park Daniel D Peng Hanchuan H Penn Osnat O Pham Thanh T Pom Alice A Popović Zoran Z Potekhina Lydia L Rajanbabu Ramkumar R Ransford Shea S Reid David D Rimorin Christine C Robertson Miranda M Ronellenfitch Kara K Ruiz Augustin A Sandman David D Smith Kimberly K Sulc Josef J Sunkin Susan M SM Szafer Aaron A Tieu Michael M Torkelson Amy A Trinh Jessica J Tung Herman H Wakeman Wayne W Ward Katelyn K Williams Grace G Zhou Zhi Z Ting Jonathan T JT Arkhipov Anton A Sümbül Uygar U Lein Ed S ES Koch Christof C Yao Zizhen Z Tasic Bosiljka B Berg Jim J Murphy Gabe J GJ Zeng Hongkui H

Cell 20201101 4

Neurons are frequently classified into distinct types on the basis of structural, physiological, or genetic attributes. To better constrain the definition of neuronal cell types, we characterized the transcriptomes and intrinsic physiological properties of over 4,200 mouse visual cortical GABAergic interneurons and reconstructed the local morphologies of 517 of those neurons. We find that most transcriptomic types (t-types) occupy specific laminar positions within visual cortex, and, for most ty ...[more]

PMID: 33186530

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Project description:The clinical syndromes caused by frontotemporal lobar degeneration are heterogeneous, including the behavioural variant frontotemporal dementia (bvFTD) and progressive supranuclear palsy. Although pathologically distinct, they share many behavioural, cognitive and physiological features, which may in part arise from common deficits of major neurotransmitters such as γ-aminobutyric acid (GABA). Here, we quantify the GABAergic impairment and its restoration with dynamic causal modelling of a double-blind placebo-controlled crossover pharmaco-magnetoencephalography study. We analysed 17 patients with bvFTD, 15 patients with progressive supranuclear palsy, and 20 healthy age- and gender-matched controls. In addition to neuropsychological assessment and structural MRI, participants undertook two magnetoencephalography sessions using a roving auditory oddball paradigm: once on placebo and once on 10 mg of the oral GABA reuptake inhibitor tiagabine. A subgroup underwent ultrahigh-field magnetic resonance spectroscopy measurement of GABA concentration, which was reduced among patients. We identified deficits in frontotemporal processing using conductance-based biophysical models of local and global neuronal networks. The clinical relevance of this physiological deficit is indicated by the correlation between top-down connectivity from frontal to temporal cortex and clinical measures of cognitive and behavioural change. A critical validation of the biophysical modelling approach was evidence from parametric empirical Bayes analysis that GABA levels in patients, measured by spectroscopy, were related to posterior estimates of patients' GABAergic synaptic connectivity. Further evidence for the role of GABA in frontotemporal lobar degeneration came from confirmation that the effects of tiagabine on local circuits depended not only on participant group, but also on individual baseline GABA levels. Specifically, the phasic inhibition of deep cortico-cortical pyramidal neurons following tiagabine, but not placebo, was a function of GABA concentration. The study provides proof-of-concept for the potential of dynamic causal modelling to elucidate mechanisms of human neurodegenerative disease, and explains the variation in response to candidate therapies among patients. The laminar- and neurotransmitter-specific features of the modelling framework, can be used to study other treatment approaches and disorders. In the context of frontotemporal lobar degeneration, we suggest that neurophysiological restoration in selected patients, by targeting neurotransmitter deficits, could be used to bridge between clinical and preclinical models of disease, and inform the personalized selection of drugs and stratification of patients for future clinical trials.

Dataset Information

Integrated Morphoelectric and Transcriptomic Classification of Cortical GABAergic Cells.

Publications

Integrated Morphoelectric and Transcriptomic Classification of Cortical GABAergic Cells.

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