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Landscape of ribosome-engaged alternative transcript isoforms across neuronal cell classes

ABSTRACT: The goal of this project was to assess how alternative splicing programs are arrayed across neuronal cells types. We systematically mapped ribosome-associated transcript isoforms in genetically-defined neuron types of the mouse forebrain. The endogenous ribosomal protein Rpl22 was conditionally HA-tagged in glutamatergic neurons (using CamK2-cre for most neocortical pyramidal cells and Scnn1a-cre for spiny stellate and star pyramid layer 4 cells), and GABAergic interneurons [with somatostatin-cre (SST), parvalbumin-cre (PV) and vasointestinal peptide-cre (VIP)]. Within the hippocampus, we further targeted Cornu ammonis 1 (CA1) neurons (CamK2-cre), CA3 neurons (Grik4-cre), and SST-positive interneurons (SST-cre). Four replicates were deep sequenced (~100 million reads) using an Illumina platform. We find that neuronal transcript isoform profiles reliably distinguish even closely-related classes of pyramidal cells and inhibitory interneurons in the mouse hippocampus and neocortex, positing transcript diversification by alternative splicing as a central mechanism for the functional specification of neuronal cell types and circuits.

ORGANISM(S): Mus musculus

PROVIDER: GSE133291 | GEO | 2019/07/01

REPOSITORIES: GEO

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Discrete hippocampal projections are differentially regulated by parvalbumin and somatostatin interneurons

Project description:People with schizophrenia show hyperactivity in the ventral hippocampus (vHipp) and we have previously demonstrated distinct behavioral roles for vHipp cell populations. Here, we test the hypothesis that parvalbumin (PV) and somatostatin (SST) interneurons differentially innervate and regulate hippocampal pyramidal neurons based on their projection target. First, we use eGRASP to show that PV-positive interneurons form a similar number of synaptic connections with pyramidal cells regardless of their projection target while SST-positive interneurons preferentially target nucleus accumbens (NAc) projections. To determine if these anatomical differences result in functional changes, we used in vivo opto-electrophysiology to show that SST cells also preferentially regulate the activity of NAc-projecting cells. These results suggest vHipp interneurons differentially regulate that vHipp neurons that project to the medial prefrontal cortex (mPFC) and NAc. Characterization of these cell populations may provide potential molecular targets for the treatment schizophrenia and other psychiatric disorders associated with vHipp dysfunction.

2023-11-09 | GSE244159 | GEO

Chronic nicotine differentially affects murine transcriptome profiling in isolated cortical interneurons and pyramidal neurons

Project description:Nicotine differentially affected subset of genes in Sst- and Thy1- neurons, which might contribute to the distinct effect of nicotine on interneuron and pyramidal neuron activities. Meanwhile, the altered transcripts associated with mitochondrial activity were found between interneurons and pyramidal neurons after chronic nicotine.

2017-06-12 | GSE89899 | GEO

Cortical somatostatin long-range projection neurons and interneurons exhibit divergent developmental trajectories

Project description:The mammalian cerebral cortex contains an extraordinary diversity of cell types that emerge through the implementation of different developmental programs. Delineating when and how cellular diversification occurs is particularly challenging for cortical inhibitory neurons, as they represent a relatively small proportion of all cortical cells, migrate tangentially from their embryonic origin to the cerebral cortex, and have a protracted development. Here we combine single-cell RNA sequencing and spatial transcriptomics to characterize the emergence of neuronal diversity among somatostatin-expressing (SST+) cells, the most diverse subclass of inhibitory neurons in the mouse cerebral cortex. We found that SST+ inhibitory neurons segregate during embryonic stages into long-range projection (LRP) neurons and two types of interneurons, Martinotti cells and non-Martinotti cells, following distinct developmental trajectories. Two main subtypes of LRP neurons and several subtypes of interneurons are readily distinguishable in the embryo, although interneuron diversity is further refined during early postanal life. Our results suggest that the timing for cellular diversification is unique for different subtypes of SST+ neurons and particularly divergent for LRP neurons and interneurons. Thus, the diversification of SST+ inhibitory neurons involves a temporal cascade of unique molecular programs driving their divergent developmental trajectories.

2023-11-01 | GSE217065 | GEO

Sensory experience restricts cortical plasticity by inducing IGF-1 in VIP neurons

Project description:RNA-seq libraries purified from the visual cortices of neurons expressing Emx-, GAD2-, PV-, SST-, or VIP-Cre using the Ribotag allele. Seq libraries are provided from mice raised in standard housing, or housed in the dark for two weeks (dark-housed), or dark-housed and then exposed to light for 1, 3, or 7.5 hours. These seq libraries represent the genetic response of distinct types of cortical interneurons to altered sensory experience. To explore how sensory experience affects gene expression, we examined this process in the visual cortex of adult mice that were housed in standard conditions, in complete darkness (i.e. dark-housed), or dark-housed and then exposed to light for increasing amounts of time. We generated mice that were heterozygous for alleles of either Emx-,Gad2-,Sst-,Vip- or Pv-Cre, and were also heterozygous for the Rpl22-HA (RiboTag) allele, which expresses an HA-tagged ribosomal protein specifically in Cre-expressing neurons. We performed RNA-Seq on RNA isolated from the dark-housed/light-exposed RiboTag-mice; Experiments were done in 3 biological replicates and the visual cortices of 3 mice were pooled per sample at each time-point and for each Cre line.

2016-03-17 | E-GEOD-77243 | biostudies-arrayexpress

bacTRAP profiling of seven different types of neurons , vulnerable and resistant to Alzheimer's disease (AD) across the lifetime of the mouse

Project description:We report here the bacTRAP (bacterial artificial chromosome , translating ribosome affinity purification) profiling of 7 different types of neurons in the mouse, at three different ages: two neuron types very vulnerable to AD (principal cells of entorhinal cortex layer II - ECII), pyramidal cells of hippocampus CA1, and 5 types of neurons more resistant to AD (pyramidal cells of hippocampus CA2 and CA3, granule neurons of the dentate gyrus, pyramidal cells from layer IV of primary visual cortex V1, and pyramidal cells from layer II/III and V of primary somatosensory cortex S1). Using these profiles we generated molecular signatures for each of these cell types, proved that the molecular identity of these cell types is very well conserved across mouse and humans, and constructed functional networks for each cell type that allowed us to identify genes and pathways associated with selective neuronal vulnerability in AD. We also report the profiling of ECII neurons in APP/PS1 mice (a mouse model of Abeta accumulation) at 6 months of age.

2020-05-30 | GSE151460 | GEO

Sensory experience restricts cortical plasticity by inducing IGF-1 in VIP neurons

2016-03-17 | GSE77243 | GEO

Transcriptional maintenance of cortical somatostatin interneuron subtype identity during migration

Project description:Cortical interneuron diversity arises from the interplay of intrinsic developmental patterning and local extrinsic cues. While individual genetic programs underlying cardinal cell type identity are established in immature neurons prior to integration into cortical circuits, it remains unclear whether distinct interneuron subtype identities are pre-established, and if so, how their identity is maintained prior to circuit integration. Sox6 is a transcription factor with an established role in the maturation of interneurons derived from the medial ganglionic eminence and cell-type specification in other neuronal and non-neuronal cells. To determine a possible role in maintaining cortical somatostatin-expressing (Sst+) interneuron subtype identity, we conditionally removed Sox6 (Sox6-cKO) in migrating Sst+ interneurons and assessed the effects on their mature identity. In adolescent animals, five of eight molecular Sst+ subtypes were nearly absent in the cortex of Sox6-cKO mice. This reduced subtype diversity was not due to a decrease in the overall number of Sst+ interneurons and cells displayed electrophysiological maturity and expressed genes enriched within the broad class of Sst+ interneurons. Furthermore, we show that at embryonic day 18.5, prior to cortical integration, mature Sst+ cell subtype identity could already be inferred in both control and Sox6-cKO cortices, suggesting that the loss in subtype diversity observed in the mature cortex is due to a disrupted subtype maintenance. Importantly, Sox6 removal at postnatal day 7, after Sst+ interneurons have finished migrating and begun integration into the network, did not disrupt marker expression of Sst+ subtypes in the mature cortex. Therefore, Sox6 is necessary during this migratory phase for maintenance of Sst+ subtypes identity, indicating that subtype maintenance requires active transcriptional programs during migration.

2023-08-25 | GSE233791 | GEO

Neocortical layer 4 in adult mouse differs in major cell types and circuit organization between primary sensory areas

Project description:Layer 4 (L4) of mammalian neocortex plays a crucial role in cortical information processing, yet a complete census of its cell types and connectivity remains elusive. Using whole-cell recordings with morphological recovery, we identified one major excitatory and seven inhibitory types of neurons in L4 of adult mouse visual cortex (V1). Nearly all excitatory neurons were pyramidal and all somatostatin-positive (SOM+) non-fast-spiking interneurons were Martinotti cells. In contrast, in somatosensory cortex (S1), excitatory neurons were mostly stellate and SOM+ interneurons were non-Martinotti. These morphologically distinct SOM+ interneurons corresponded to different transcriptomic cell types and were differentially integrated into the local circuit with only S1 neurons receiving local excitatory input. We propose that cell type specific circuit motifs, such as the Martinotti/pyramidal and non-Martinotti/stellate pairs, are used across the cortex as building blocks to assemble cortical circuits.

2019-08-06 | GSE134378 | GEO

Epigenomic Signatures of Neuronal Diversity in the Mammalian Brain

Project description:We developed an affinity purification approach to isolate tagged nuclei in mice (similar to INTACT; [Deal R.B. and Henikoff S. A simple method for gene expression and chromatin profiling of individual cell types within a tissue. Dev. Cell 18,1030-1040. (2010)]) and used it to characterize genome-wide patterns of transcription, DNA methylation, and chromatin accessibility in 3 major neuron classes of the neocortex (excitatory pyramidal neurons, parvalbumin (PV)-positive GABAergic interneurons, and vasoactive intestinal peptide (VIP)-positive GABAergic interneurons). By combining cell purification and integrative analysis, our findings relate the phenotypic and functional complexity of neocortical neurons to their underlying transcriptional and epigenetic diversity. RNA-seq, MethylC-seq, ATAC-seq, and ChIP-seq for histone modifications using INTACT-purified nuclei from the mouse neocortex

2015-06-17 | E-GEOD-63137 | biostudies-arrayexpress

The relative contributions of cell-dependent cortical microcircuit aging to cognition and anxiety

Project description:Background: Aging is accompanied by altered thinking (cognition) and feeling (mood) functions that depend to some extent on information processing by brain cortical cell microcircuits. We hypothesized that age-associated long-term functional and biological changes are mediated by gene transcriptomic changes within neuronal cell-types forming cortical microcircuits, namely excitatory pyramidal cells (PYC) and inhibitory GABAergic neurons expressing vasoactive intestinal peptide (Vip), somatostatin (Sst) and parvalbumin (Pvalb). Methods: To test this hypothesis, we assessed locomotor, anxiety-like and cognitive behavioral changes between young (2 months, n=9) and old (22 months, n=12) male C57BL/6 mice, and performed frontal cortex cell-type specific molecular profiling, using laser-capture microscopy and RNA sequencing. Results: Old-mice displayed increased anxiety and reduced working memory. The four cell-types displayed distinct age-related transcriptomes and biological pathway profiles, affecting metabolic and cell signaling pathways, and selective markers of neuronal vulnerability (Ryr3), resilience (Oxr1), and mitochondrial dynamics (Opa1), suggesting high age-related vulnerability of PYCs, and variable degree of adaptation in GABAergic neurons. Correlations between gene expression and behaviors suggest that changes in cognition and anxiety associated with age are partly mediated by normal age-related cell changes, and that additional age-independent decreases in synaptic and signaling pathways, notably in PYC and SST-neurons further contribute to behavioral changes. Conclusions: Our study demonstrates cell-dependent differential vulnerability and coordinated cell-specific cortical microcircuit molecular changes with age. Collectively, the results suggest intrinsic molecular links between aging, cognition and mood-related behaviors with SST-neurons contributing evenly to both behavioral conditions.

2018-08-30 | GSE119183 | GEO

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