Dataset Information

Morphological pseudotime ordering and fate mapping reveal diversification of cerebellar inhibitory interneurons.

ABSTRACT: Understanding how diverse neurons are assembled into circuits requires a framework for describing cell types and their developmental trajectories. Here we combine genetic fate-mapping, pseudotemporal profiling of morphogenesis, and dual morphology and RNA labeling to resolve the diversification of mouse cerebellar inhibitory interneurons. Molecular layer interneurons (MLIs) derive from a common progenitor population but comprise diverse dendritic-, somatic-, and axon initial segment-targeting interneurons. Using quantitative morphology from 79 mature MLIs, we identify two discrete morphological types and presence of extensive within-class heterogeneity. Pseudotime trajectory inference using 732 developmental morphologies indicate the emergence of distinct MLI types during migration, before reaching their final positions. By comparing MLI identities from morphological and transcriptomic signatures, we demonstrate the dissociation between these modalities and that subtype divergence can be resolved from axonal morphogenesis prior to marker gene expression. Our study illustrates the utility of applying single-cell methods to quantify morphology for defining neuronal diversification.

SUBMITTER: Wang WX

PROVIDER: S-EPMC9197879 | biostudies-literature | 2022 Jun

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Morphological pseudotime ordering and fate mapping reveal diversification of cerebellar inhibitory interneurons.

Wang Wendy Xueyi WX Lefebvre Julie L JL

Nature communications 20220614 1

Understanding how diverse neurons are assembled into circuits requires a framework for describing cell types and their developmental trajectories. Here we combine genetic fate-mapping, pseudotemporal profiling of morphogenesis, and dual morphology and RNA labeling to resolve the diversification of mouse cerebellar inhibitory interneurons. Molecular layer interneurons (MLIs) derive from a common progenitor population but comprise diverse dendritic-, somatic-, and axon initial segment-targeting in ...[more]

PMID: 35701402

Similar Datasets

Project description:Nitric oxide (NO) is an important signaling molecule that fulfills diverse functional roles as a neurotransmitter or diffusible second messenger in the developing and adult CNS. Although the impact of NO on different behaviors such as movement, sleep, learning, and memory has been well documented, the identity of its molecular and cellular targets is still an area of ongoing investigation. Here, we identify a novel role for NO in strengthening inhibitory GABAA receptor-mediated transmission in molecular layer interneurons of the mouse cerebellum. NO levels are elevated by the activity of neuronal NO synthase (nNOS) following Ca2+ entry through extrasynaptic NMDA-type ionotropic glutamate receptors (NMDARs). NO activates protein kinase G with the subsequent production of cGMP, which prompts the stimulation of NADPH oxidase and protein kinase C (PKC). The activation of PKC promotes the selective strengthening of α3-containing GABAARs synapses through a GΑΒΑ receptor-associated protein-dependent mechanism. Given the widespread but cell type-specific expression of the NMDAR/nNOS complex in the mammalian brain, our data suggest that NMDARs may uniquely strengthen inhibitory GABAergic transmission in these cells through a novel NO-mediated pathway.SIGNIFICANCE STATEMENT Long-term changes in the efficacy of GABAergic transmission is mediated by multiple presynaptic and postsynaptic mechanisms. A prominent pathway involves crosstalk between excitatory and inhibitory synapses whereby Ca2+-entering through postsynaptic NMDARs promotes the recruitment and strengthening of GABAA receptor synapses via Ca2+/calmodulin-dependent protein kinase II. Although Ca2+ transport by NMDARs is also tightly coupled to nNOS activity and NO production, it has yet to be determined whether this pathway affects inhibitory synapses. Here, we show that activation of NMDARs trigger a NO-dependent pathway that strengthens inhibitory GABAergic synapses of cerebellar molecular layer interneurons. Given the widespread expression of NMDARs and nNOS in the mammalian brain, we speculate that NO control of GABAergic synapse efficacy may be more widespread than has been appreciated.

Dataset Information

Morphological pseudotime ordering and fate mapping reveal diversification of cerebellar inhibitory interneurons.

Publications

Morphological pseudotime ordering and fate mapping reveal diversification of cerebellar inhibitory interneurons.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets