Transcriptomic signature of L5 pyramidal neuron subpopulations during early steps of inhibitory synapse formation
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ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE237311 | GEO | 2025/03/01
REPOSITORIES: GEO
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Project description:Transcriptomic signature of L5 pyramidal neuron subpopulations during early steps of inhibitory synapse formation
| PRJNA994556 | ENA
Project description:How neuronal connections are established and organized in functional networks determines brain function. In the mouse cerebral cortex, different classes of GABAergic interneurons exhibit specific connectivity patterns that underlie their ability to shape temporal dynamics and information processing. Much progress has been made parsing interneuron diversity, yet the molecular mechanisms by which interneuron subtype-specific connectivity motifs emerge remain unclear. Here we investigate transcriptional dynamics in different classes of interneurons during the formation of cortical inhibitory circuits. We found that whether the interneurons synapse with pyramidal neurons on their dendrites, soma, or axon initial segment is determined by synaptic molecules that are expressed in a subtype-specific manner. Thus cell-specific molecular programs that unfold during early postnatal development underlie the connectivity patterns of cortical interneurons.
2019-01-25 | GSE120161 | GEO
Project description:Cortical layer 5 (L5) intratelencephalic (IT) and pyramidal tract (PT) neurons are embedded in distinct information processing pathways. The morphology, connectivity, electrophysiological properties, and role in behavior of these neurons have been extensively analyzed. However, the molecular composition of their synapses remains largely uncharacterized. Here, we dissect the protein composition of the excitatory postsynaptic compartment of L5 neurons in intact somatosensory circuits, using an optimized proximity biotinylation workflow with subsynaptic resolution. We find distinct synaptic signatures of L5 IT and PT neurons that are defined by proteins regulating synaptic organization and transmission, including cell-surface proteins (CSPs), neurotransmitter receptors and ion channels. In addition, we find a differential vulnerability to disease, with a marked enrichment of autism risk genes in the synaptic signature of L5 IT neurons compared to PT neurons. Our results align with human studies and suggest that the excitatory postsynaptic compartment of L5 IT neurons is notably susceptible in autism. Together, our analysis sheds light on the proteins that regulate synaptic organization and function of L5 neuron types and contribute to their susceptibility in disease. Our approach is versatile and can be broadly applied to other neuron types to create a protein-based, synaptic atlas of cortical circuits.
2024-11-04 | PXD052081 | Pride
Project description:Pyramidal neurons in the cortex are embedded in distinct information processing pathways. Cortical layer 5 (L5) intratelencephalic (IT) and pyramidal tract (PT) neurons receive different input and project to distinct brain regions. The synaptic molecular signatures that define synaptic connectivity and function of L5 IT and PT neurons are largely unknown. Here, we use an optimized proximity biotinylation workflow to characterize the excitatory postsynaptic proteomes of L5 IT and PT neurons in intact somatosensory circuits. We find that differential expression of neurotransmitter receptors, ion channels and cell-surface proteins (CSPs), most prominently of the leucine-rich repeat (LRR) family, specifies L5 IT and PT neuron input connectivity and function. Our analysis further uncovers differential vulnerability to neurodevelopmental disorders for L5 IT and PT neurons, with a marked enrichment of autism risk genes in the postsynaptic excitatory proteome of IT, but not of PT, neurons. Together, cell type- and input type-specific synaptic proteome profiling implies that many of the proteins specifying connectivity and function of two closely related cortical pyramidal cell types also underlie their differential vulnerability to neurodevelopmental disorders.
2024-11-04 | PXD046812 | Pride
Project description:Impairments in certain cognitive processes (e.g., working memory) are typically most pronounced in schizophrenia (SZ), intermediate in bipolar disorder (BP) and least in major depressive disorder (MDD). Given that working memory depends, in part, on neural circuitry that includes pyramidal neurons in layer 3 (L3) and layer 5 (L5) of the dorsolateral prefrontal cortex (DLPFC), we sought to determine if transcriptome alterations in these neurons were shared or distinctive for each diagnosis.
2017-04-04 | GSE87610 | GEO
Project description:The mammalian cerebral cortex comprises a complex neuronal network that maintains a delicate balance between excitatory neurons and inhibitory interneurons. Previous studies, including our own research, have shown that specific interneuron subtypes are closely associated with particular pyramidal neuron types, forming stereotyped local inhibitory microcircuits. However, the developmental processes that establish these precise networks are not well understood. Here we show that pyramidal neuron types are instrumental in maintaining the terminal differentiation and survival of specific associated interneuron subtypes. In a wild-type cortex, the relative abundance of different interneuron subtypes aligns precisely with the pyramidal neuron types with which they synaptically target. In Fezf2 mutant cortex, characterized by the absence of layer 5 pyramidal tract neurons and an expansion of layer 6 intratelencephalic neurons, we observed a corresponding decrease in associated layer 5b interneurons and an increase in layer 6 subtypes. Interestingly, these shifts in composition are achieved through mechanisms that are specific to different interneuron types. While SST interneurons adjust their abundance to the change in pyramidal neuron prevalence through the regulation of programmed cell death, parvalbumin cells alter their identity. These findings illustrate two key strategies by which the dynamic interplay between pyramidal neurons and interneurons allows local microcircuits to be sculpted precisely. These insights underscored the precise roles of extrinsic signals from pyramidal cells in the establishment of interneuron diversity and their subsequent integration into local cortical microcircuits.
2024-08-15 | GSE272706 | GEO
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
Project description:The medial prefrontal cortex (mPFC) is a key brain region involved in controlling working memory, executive function, and self-regulatory behaviours, and its malfunction is a hallmark of several neuropsychiatric disorders such as schizophrenia, depression, and post-traumatic stress disorder. One of the main risk factors for the development of mental illness is chronic stress (CS). Despite some evidence pointing to possible excitation-inhibition (E/I) imbalances caused by CS, the precise mechanism by which CS triggers mPFC dysfunction is not fully understood. Here, using neuroproteomics analysis and whole-cell patch-clamp recordings, we investigated the functional changes in E/I ratio and synaptic drive onto pyramidal neurons and parvalbumin interneurons (PV) in the prelimbic (PL) and infralimbic (IL) cortices, following exposure to 21 days of chronic unpredictable stress. We demonstrate that CS impacts PL- versus IL-pyramidal neurons differently, driving a common decrease in E/I ratio without affecting PV interneurons. Our work brings insightful information and corroborates the hypothesis of stress-induced hypofunction of the mPFC.
2024-10-17 | PXD047291 | Pride
Project description:Down syndrome (DS) is the most prevalent genetic abnormality, occurring in ~1/700 live births caused by triplication of human chromosome 21 (HSA21). DS individuals have a multitude of phenotypic changes in peripheral systems and most notably, are cognitively impaired, with deficits in learning, language and memory acquisition and consolidation. Further, individuals with DS develop Alzheimer’s disease (AD) pathology during early middle-age (mid-30’s), although the underlying mechanism(s) driving this pathology onset are not well understood. Contributing to cognitive impairment in DS, morphological deficits are present in cortical lamination and distribution, with Layer III (L3) and Layer V (L5) pyramidal neurons showing reduced proliferation and a disorganized laminar structure. As such, examining cortical L3 and L5 pyramidal neurons in DS individuals with AD pathology may elucidate alternate driver mechanisms of disease onset. We examined DS and age-matched control (CTR) brains from individuals without intellectual disabilities or dementia using postmortem frontal cortex (BA9) via single population low input RNA-sequencing. We specifically targeted L3 and L5 pyramidal neurons to understand circuitry-based alterations in DS/AD individuals to elucidate mechanistic drivers of disease pathology. We show convergent and divergent gene expression changes in L3 and L5 pyramidal neurons which may underlie cognitive deficits and degenerative pathology associated with aging in the DS brain. We pinpoint alterations in HSA21 gene expression as well as a multitude of convergent differentially expressed genes (DEGs) and relevant pathways via bioinformatic inquiry in the DS brains that underlie mechanisms of degeneration. Distinctly, convergent gene expression reveals a neurotoxic phenotype, with multiple canonical pathways of dysregulation and disease functions linked to the convergent DEGs, including downregulation of the CLEAR signaling pathway and significantly increased activation of the neuroinflammation signaling pathway. We identify several target genes including mitogen activated protein kinase 1 and 3 (MAPK1/3), calcium voltage-gated channel subunit alpha1 A (CACNA1A) and superoxide dismutase 1 (SOD1), which exhibit overlap in multiple pathways and disease functions and/or display dysfunctional protein-protein network interactions for further examination. Novel targets identified by our single population approach in L3 and L5 pyramidal neurons may be drivers of the disease mechanism and therefore may be therapeutic candidates for amelioration of degenerative pathology that targets memory and executive function circuits in DS/AD.
2024-08-07 | GSE251939 | GEO
Project description:We studied the transcriptomes of mouse CA1 inhibitory cells. Novel clustering methods identified all 23 previously described CA1 inhibitory types, while also suggesting 6 new inhibitory classes. Latent‐factor analysis revealed a common continuum of expression of many genes within and between classes, which we hypothesized correlates with a continuum from faster‐spiking cells that proximally target pyramidal cells, to slower active cells targeting pyramidal distal dendrites or interneurons.
2018-05-11 | GSE99888 | GEO