Biology subjects

Bien, E.

Publications and source records attributed to Bien, E..

3 recordsLinked to original sources

bioRxiv2020

CUB and Sushi Multiple Domains 1 (CSMD1) opposes the complement cascade in neural tissues

Schizophrenia risk is associated with increased gene copy number and brain expression of complement component 4 (C4). Because the complement system facilitates synaptic pruning, the C4 association has renewed interest in a hypothesis that excessive pruning contributes to schizophrenia pathogenesis. However, little is known about complement regulation in neural tissues or whether such regulation could be relevant to psychiatric illness. Intriguingly, common variation within CSMD1, which encodes a putative complement inhibitor, has consistently associated with schizophrenia at genome-wide significance. We found that Csmd1 is predominantly expressed in the brain by neurons, and is enriched at synapses; that human stem cell-derived neurons lacking CSMD1 are more vulnerable to complement deposition; and that mice lacking Csmd1 have increased brain complement activity, fewer synapses, aberrant complement-dependent development of a neural circuit, and synaptic elements that are preferentially engulfed by cultured microglia. These data suggest that CSMD1 opposes the complement cascade in neural tissues. O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=168 SRC="FIGDIR/small/291427v1_ufig1.gif" ALT="Figure 1"> View larger version (30K): org.highwire.dtl.DTLVardef@172c857org.highwire.dtl.DTLVardef@bee84corg.highwire.dtl.DTLVardef@184da10org.highwire.dtl.DTLVardef@10867c8_HPS_FORMAT_FIGEXP M_FIG Graphic Abstract.Our findings support a model in which CSMD1 opposes actions of the complement cascade in neural tissues (top left). We investigated two models in which Csmd1 was genetically ablated: human cortical neurons derived from embryonic stem cells, and a back-crossed C57bl6-Tac mouse line (top right). Csmd1 is normally expressed by neurons and present at synapses where it can protect them from complement (bottom left); in the absence of Csmd1 (bottom right), we find more deposition of complement (on cultured human cortical neurons and in the mouse visual system), reduced numbers of synapses (in the mouse visual system), and synaptic fractions that are more readily engulfed by microglia (ex vivo). Created with BioRender.com. C_FIG

neuroscience↗

bioRxiv2019

Innovations in Primate Interneuron Repertoire

Primates and rodents, which descended from a common ancestor more than 90 million years ago, exhibit profound differences in behavior and cognitive capacity. Modifications, specializations, and innovations to brain cell types may have occurred along each lineage. We used Drop-seq to profile RNA expression in more than 184,000 individual telencephalic interneurons from humans, macaques, marmosets, and mice. Conserved interneuron types varied significantly in abundance and RNA expression between mice and primates, but varied much more modestly among primates. In adult primates, the expression patterns of dozens of genes exhibited spatial expression gradients among neocortical interneurons, suggesting that adult neocortical interneurons are imprinted by their local cortical context. In addition, we found that an interneuron type previously associated with the mouse hippocampus--the \"ivy cell\", which has neurogliaform characteristics--has become abundant across the neocortex of humans, macaques, and marmosets. The most striking innovation was subcortical: we identified an abundant striatal interneuron type in primates that had no molecularly homologous cell population in mouse striatum, cortex, thalamus, or hippocampus. These interneurons, which expressed a unique combination of transcription factors, receptors, and neuropeptides, including the neuropeptide TAC3, constituted almost 30% of striatal interneurons in marmosets and humans. Understanding how gene and cell-type attributes changed or persisted over the evolutionary divergence of primates and rodents will guide the choice of models for human brain disorders and mutations and help to identify the cellular substrates of expanded cognition in humans and other primates.

neuroscience↗

bioRxiv2018

A Single-Cell Atlas of Cell Types, States, and Other Transcriptional Patterns from Nine Regions of the Adult Mouse Brain

The mammalian brain is composed of diverse, specialized cell populations, few of which we fully understand. To more systematically ascertain and learn from cellular specializations in the brain, we used Drop-seq to perform single-cell RNA sequencing of 690,000 cells sampled from nine regions of the adult mouse brain: frontal and posterior cortex (156,000 and 99,000 cells, respectively), hippocampus (113,000), thalamus (89,000), cerebellum (26,000), and all of the basal ganglia - the striatum (77,000), globus pallidus externus/nucleus basalis (66,000), entopeduncular/subthalamic nuclei (19,000), and the substantia nigra/ventral tegmental area (44,000). We developed computational approaches to distinguish biological from technical signals in single-cell data, then identified 565 transcriptionally distinct groups of cells, which we annotate and present through interactive online software we developed for visualizing and re-analyzing these data (DropViz). Comparison of cell classes and types across regions revealed features of brain organization. These included a neuronal gene-expression module for synthesizing axonal and presynaptic components; widely shared patterns in the combinatorial co-deployment of voltage-gated ion channels by diverse neuronal populations; functional distinctions among cells of the brain vasculature; and specialization of glutamatergic neurons across cortical regions to a degree not observed in other neuronal or non-neuronal populations. We describe systematic neuronal classifications for two complex, understudied regions of the basal ganglia, the globus pallidus externus and substantia nigra reticulata. In the striatum, where neuron types have been intensely researched, our data reveal a previously undescribed population of striatal spiny projection neurons (SPNs) comprising 4% of SPNs. The adult mouse brain cell atlas can serve as a reference for analyses of development, disease, and evolution.

neuroscience↗