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Neuron Apr 2019The mechanisms underlying the pathophysiology and treatment of depression and stress-related disorders remain unclear, but studies in depressed patients and rodent... (Review)
Review
The mechanisms underlying the pathophysiology and treatment of depression and stress-related disorders remain unclear, but studies in depressed patients and rodent models are beginning to yield promising insights. These studies demonstrate that depression and chronic stress exposure cause atrophy of neurons in cortical and limbic brain regions implicated in depression, and brain imaging studies demonstrate altered connectivity and network function in the brains of depressed patients. Studies of the neurobiological basis of the these alterations have focused on both the principle, excitatory glutamate neurons, as well as inhibitory GABA interneurons. They demonstrate structural, functional, and neurochemical deficits in both major neuronal types that could lead to degradation of signal integrity in cortical and hippocampal regions. The molecular mechanisms underlying these changes have not been identified but are thought to be related to stress induced excitotoxic effects in combination with elevated adrenal glucocorticoids and inflammatory cytokines as well as other environmental factors. Transcriptomic studies are beginning to demonstrate important sex differences and, together with genomic studies, are starting to reveal mechanistic domains of overlap and uniqueness with regards to risk and pathophysiological mechanisms with schizophrenia and bipolar disorder. These studies also implicate GABA and glutamate dysfunction as well as immunologic mechanisms. While current antidepressants have significant time lag and efficacy limitations, new rapid-acting agents that target the glutamate and GABA systems address these issues and offer superior therapeutic interventions for this widespread and debilitating disorder.
Topics: Animals; Antidepressive Agents; Brain; Cerebral Cortex; Depressive Disorder; Glutamic Acid; Hippocampus; Humans; Interneurons; Ketamine; Neurons; Sex Factors; Synaptic Transmission; gamma-Aminobutyric Acid
PubMed: 30946828
DOI: 10.1016/j.neuron.2019.03.013 -
Genome Biology Mar 2018Despite the many approaches to study differential splicing from RNA-seq, many challenges remain unsolved, including computing capacity and sequencing depth requirements....
Despite the many approaches to study differential splicing from RNA-seq, many challenges remain unsolved, including computing capacity and sequencing depth requirements. Here we present SUPPA2, a new method that addresses these challenges, and enables streamlined analysis across multiple conditions taking into account biological variability. Using experimental and simulated data, we show that SUPPA2 achieves higher accuracy compared to other methods, especially at low sequencing depth and short read length. We use SUPPA2 to identify novel Transformer2-regulated exons, novel microexons induced during differentiation of bipolar neurons, and novel intron retention events during erythroblast differentiation.
Topics: Alternative Splicing; Cell Line; Erythroblasts; Exons; Humans; Neurons; Sequence Analysis, RNA; Software
PubMed: 29571299
DOI: 10.1186/s13059-018-1417-1 -
Cell Aug 2016Patterns of gene expression can be used to characterize and classify neuronal types. It is challenging, however, to generate taxonomies that fulfill the essential...
Patterns of gene expression can be used to characterize and classify neuronal types. It is challenging, however, to generate taxonomies that fulfill the essential criteria of being comprehensive, harmonizing with conventional classification schemes, and lacking superfluous subdivisions of genuine types. To address these challenges, we used massively parallel single-cell RNA profiling and optimized computational methods on a heterogeneous class of neurons, mouse retinal bipolar cells (BCs). From a population of ∼25,000 BCs, we derived a molecular classification that identified 15 types, including all types observed previously and two novel types, one of which has a non-canonical morphology and position. We validated the classification scheme and identified dozens of novel markers using methods that match molecular expression to cell morphology. This work provides a systematic methodology for achieving comprehensive molecular classification of neurons, identifies novel neuronal types, and uncovers transcriptional differences that distinguish types within a class.
Topics: Amacrine Cells; Animals; Cluster Analysis; Female; Genetic Markers; Male; Mice; Mice, Inbred Strains; Mice, Transgenic; Retinal Bipolar Cells; Sequence Analysis, RNA; Single-Cell Analysis; Transcription, Genetic; Transcriptome
PubMed: 27565351
DOI: 10.1016/j.cell.2016.07.054 -
Nature Nov 2015Bipolar disorder is a complex neuropsychiatric disorder that is characterized by intermittent episodes of mania and depression; without treatment, 15% of patients commit...
Bipolar disorder is a complex neuropsychiatric disorder that is characterized by intermittent episodes of mania and depression; without treatment, 15% of patients commit suicide. Hence, it has been ranked by the World Health Organization as a top disorder of morbidity and lost productivity. Previous neuropathological studies have revealed a series of alterations in the brains of patients with bipolar disorder or animal models, such as reduced glial cell number in the prefrontal cortex of patients, upregulated activities of the protein kinase A and C pathways and changes in neurotransmission. However, the roles and causation of these changes in bipolar disorder have been too complex to exactly determine the pathology of the disease. Furthermore, although some patients show remarkable improvement with lithium treatment for yet unknown reasons, others are refractory to lithium treatment. Therefore, developing an accurate and powerful biological model for bipolar disorder has been a challenge. The introduction of induced pluripotent stem-cell (iPSC) technology has provided a new approach. Here we have developed an iPSC model for human bipolar disorder and investigated the cellular phenotypes of hippocampal dentate gyrus-like neurons derived from iPSCs of patients with bipolar disorder. Guided by RNA sequencing expression profiling, we have detected mitochondrial abnormalities in young neurons from patients with bipolar disorder by using mitochondrial assays; in addition, using both patch-clamp recording and somatic Ca(2+) imaging, we have observed hyperactive action-potential firing. This hyperexcitability phenotype of young neurons in bipolar disorder was selectively reversed by lithium treatment only in neurons derived from patients who also responded to lithium treatment. Therefore, hyperexcitability is one early endophenotype of bipolar disorder, and our model of iPSCs in this disease might be useful in developing new therapies and drugs aimed at its clinical treatment.
Topics: Action Potentials; Antipsychotic Agents; Bipolar Disorder; Calcium Signaling; Dentate Gyrus; Endophenotypes; Humans; Induced Pluripotent Stem Cells; Lithium Compounds; Male; Mitochondria; Neurons; Patch-Clamp Techniques
PubMed: 26524527
DOI: 10.1038/nature15526 -
Nature Communications Oct 2019Genome-wide association studies (GWAS) have identified genetic variants associated with age-related macular degeneration (AMD), one of the leading causes of blindness in...
Genome-wide association studies (GWAS) have identified genetic variants associated with age-related macular degeneration (AMD), one of the leading causes of blindness in the elderly. However, it has been challenging to identify the cell types associated with AMD given the genetic complexity of the disease. Here we perform massively parallel single-cell RNA sequencing (scRNA-seq) of human retinas using two independent platforms, and report the first single-cell transcriptomic atlas of the human retina. Using a multi-resolution network-based analysis, we identify all major retinal cell types, and their corresponding gene expression signatures. Heterogeneity is observed within macroglia, suggesting that human retinal glia are more diverse than previously thought. Finally, GWAS-based enrichment analysis identifies glia, vascular cells, and cone photoreceptors to be associated with the risk of AMD. These data provide a detailed analysis of the human retina, and show how scRNA-seq can provide insight into cell types involved in complex, inflammatory genetic diseases.
Topics: Amacrine Cells; Astrocytes; Blood Vessels; Ependymoglial Cells; Gene Expression; Gene Expression Profiling; Genetic Predisposition to Disease; High-Throughput Nucleotide Sequencing; Humans; Macular Degeneration; Microglia; Neuroglia; Retina; Retinal Bipolar Cells; Retinal Cone Photoreceptor Cells; Retinal Ganglion Cells; Retinal Horizontal Cells; Retinal Neurons; Retinal Rod Photoreceptor Cells; Retinal Vessels; Sequence Analysis, RNA; Single-Cell Analysis
PubMed: 31653841
DOI: 10.1038/s41467-019-12780-8 -
Proceedings of the National Academy of... May 2023Temporal identity factors are sufficient to reprogram developmental competence of neural progenitors and shift cell fate output, but whether they can also reprogram the...
Temporal identity factors are sufficient to reprogram developmental competence of neural progenitors and shift cell fate output, but whether they can also reprogram the identity of terminally differentiated cells is unknown. To address this question, we designed a conditional gene expression system that allows rapid screening of potential reprogramming factors in mouse retinal glial cells combined with genetic lineage tracing. Using this assay, we found that coexpression of the early temporal identity transcription factors Ikzf1 and Ikzf4 is sufficient to directly convert Müller glial (MG) cells into cells that translocate to the outer nuclear layer (ONL), where photoreceptor cells normally reside. We name these "induced ONL (iONL)" cells. Using genetic lineage tracing, histological, immunohistochemical, and single-cell transcriptome and multiome analyses, we show that expression of Ikzf1/4 in MG in vivo, without retinal injury, mostly generates iONL cells that share molecular characteristics with bipolar cells, although a fraction of them stain for Rxrg, a cone photoreceptor marker. Furthermore, we show that coexpression of Ikzf1 and Ikzf4 can reprogram mouse embryonic fibroblasts to induced neurons in culture by rapidly remodeling chromatin and activating a neuronal gene expression program. This work uncovers general neuronal reprogramming properties for temporal identity factors in terminally differentiated cells.
Topics: Animals; Mice; Fibroblasts; Retina; Retinal Cone Photoreceptor Cells; Transcription Factors; Cell Differentiation; Cellular Reprogramming
PubMed: 37126716
DOI: 10.1073/pnas.2122168120 -
Neuron Jun 2019Precise temporal control of gene expression in neuronal progenitors is necessary for correct regulation of neurogenesis and cell fate specification. However, the...
Precise temporal control of gene expression in neuronal progenitors is necessary for correct regulation of neurogenesis and cell fate specification. However, the cellular heterogeneity of the developing CNS has posed a major obstacle to identifying the gene regulatory networks that control these processes. To address this, we used single-cell RNA sequencing to profile ten developmental stages encompassing the full course of retinal neurogenesis. This allowed us to comprehensively characterize changes in gene expression that occur during initiation of neurogenesis, changes in developmental competence, and specification and differentiation of each major retinal cell type. We identify the NFI transcription factors (Nfia, Nfib, and Nfix) as selectively expressed in late retinal progenitor cells and show that they control bipolar interneuron and Müller glia cell fate specification and promote proliferative quiescence.
Topics: Animals; Cell Proliferation; Ependymoglial Cells; Gene Expression Regulation, Developmental; Interneurons; Mice; Mitosis; NFI Transcription Factors; Neural Stem Cells; Neurogenesis; RNA-Seq; Retina; Retinal Neurons; Single-Cell Analysis
PubMed: 31128945
DOI: 10.1016/j.neuron.2019.04.010 -
Neuropsychopharmacology : Official... Jan 2021Parvalbumin-expressing interneurons (PV-INs) are highly vulnerable to stressors and have been implicated in many neuro-psychiatric diseases such as schizophrenia,... (Review)
Review
Parvalbumin-expressing interneurons (PV-INs) are highly vulnerable to stressors and have been implicated in many neuro-psychiatric diseases such as schizophrenia, Alzheimer's disease, autism spectrum disorder, and bipolar disorder. We examined the literature about the current knowledge of the physiological properties of PV-INs and gathered results from diverse research areas to provide insight into their vulnerability to stressors. Among the factors that confer heightened vulnerability are the substantial energy requirements, a strong excitatory drive, and a unique developmental trajectory. Understanding these stressors and elaborating on their impact on PV-IN health is a step toward developing therapies to protect these neurons in various disease states and to retain critical brain functions.
Topics: Alzheimer Disease; Autism Spectrum Disorder; Humans; Interneurons; Neurons; Parvalbumins
PubMed: 32722660
DOI: 10.1038/s41386-020-0778-9 -
Pflugers Archiv : European Journal of... Jul 2020αδ proteins are membrane-anchored extracellular glycoproteins which are abundantly expressed in the brain and the peripheral nervous system. They serve as regulatory... (Review)
Review
αδ proteins are membrane-anchored extracellular glycoproteins which are abundantly expressed in the brain and the peripheral nervous system. They serve as regulatory subunits of voltage-gated calcium channels and, particularly in nerve cells, regulate presynaptic and postsynaptic functions independently from their role as channel subunits. αδ proteins are the targets of the widely prescribed anti-epileptic and anti-allodynic drugs gabapentin and pregabalin, particularly for the treatment of neuropathic pain conditions. Recently, the human genes (CACNA2D1-4) encoding for the four known αδ proteins (isoforms αδ-1 to αδ-4) have been linked to a large variety of neurological and neuropsychiatric disorders including epilepsy, autism spectrum disorders, bipolar disorders, schizophrenia, and depressive disorders. Here, we provide an overview of the hitherto identified disease associations of all known αδ genes, hypothesize on the pathophysiological mechanisms considering their known physiological roles, and discuss the most immanent future research questions. Elucidating their specific physiological and pathophysiological mechanisms may open the way for developing entirely novel therapeutic paradigms for treating brain disorders.
Topics: Animals; Brain Diseases; Calcium Channels; Epilepsy; Humans; Membrane Glycoproteins; Neurons; Protein Isoforms
PubMed: 32607809
DOI: 10.1007/s00424-020-02420-2 -
Developmental Biology Aug 2021Synapses in the outer retina are the first information relay points in vision. Here, photoreceptors form synapses onto two types of interneurons, bipolar cells and... (Review)
Review
Synapses in the outer retina are the first information relay points in vision. Here, photoreceptors form synapses onto two types of interneurons, bipolar cells and horizontal cells. Because outer retina synapses are particularly large and highly ordered, they have been a useful system for the discovery of mechanisms underlying synapse specificity and maintenance. Understanding these processes is critical to efforts aimed at restoring visual function through repairing or replacing neurons and promoting their connectivity. We review outer retina neuron synapse architecture, neural migration modes, and the cellular and molecular pathways that play key roles in the development and maintenance of these connections. We further discuss how these mechanisms may impact connectivity in the retina.
Topics: Animals; Humans; Interneurons; Photoreceptor Cells; Retina; Retinal Cone Photoreceptor Cells; Retinal Horizontal Cells; Synapses; Vision, Ocular
PubMed: 33848537
DOI: 10.1016/j.ydbio.2021.04.001