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Barzó P, Szöts I, Tóth M, Csajbók ÉA, Molnár G, Tamás G. Electrophysiology and morphology of human cortical supragranular pyramidal cells in a wide age range. eLife 2025; 13:RP100390. [PMID: 40152903 PMCID: PMC11952751 DOI: 10.7554/elife.100390] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 03/29/2025] Open
Abstract
The basic excitatory neurons of the cerebral cortex, the pyramidal cells, are the most important signal integrators for the local circuit. They have quite characteristic morphological and electrophysiological properties that are known to be largely constant with age in the young and adult cortex. However, the brain undergoes several dynamic changes throughout life, such as in the phases of early development and cognitive decline in the aging brain. We set out to search for intrinsic cellular changes in supragranular pyramidal cells across a broad age range: from birth to 85 y of age and we found differences in several biophysical properties between defined age groups. During the first year of life, subthreshold and suprathreshold electrophysiological properties changed in a way that shows that pyramidal cells become less excitable with maturation, but also become temporarily more precise. According to our findings, the morphological features of the three-dimensional reconstructions from different life stages showed consistent morphological properties and systematic dendritic spine analysis of an infantile and an old pyramidal cell showed clear significant differences in the distribution of spine shapes. Overall, the changes that occur during development and aging may have lasting effects on the properties of pyramidal cells in the cerebral cortex. Understanding these changes is important to unravel the complex mechanisms underlying brain development, cognition, and age-related neurodegenerative diseases.
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Affiliation(s)
- Pál Barzó
- Department of Neurosurgery, University of SzegedSzegedHungary
| | - Ildikó Szöts
- HUN-REN-SZTE Research Group for Cortical Microcircuits, Department of Physiology, Anatomy and Neuroscience, University of SzegedSzegedHungary
| | - Martin Tóth
- HUN-REN-SZTE Research Group for Cortical Microcircuits, Department of Physiology, Anatomy and Neuroscience, University of SzegedSzegedHungary
| | - Éva Adrienn Csajbók
- HUN-REN-SZTE Research Group for Cortical Microcircuits, Department of Physiology, Anatomy and Neuroscience, University of SzegedSzegedHungary
| | - Gábor Molnár
- HUN-REN-SZTE Research Group for Cortical Microcircuits, Department of Physiology, Anatomy and Neuroscience, University of SzegedSzegedHungary
| | - Gábor Tamás
- HUN-REN-SZTE Research Group for Cortical Microcircuits, Department of Physiology, Anatomy and Neuroscience, University of SzegedSzegedHungary
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Barzó P, Szöts I, Tóth M, Csajbók ÉA, Molnár G, Tamás G. Electrophysiology and Morphology of Human Cortical Supragranular Pyramidal Cells in a Wide Age Range. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2025:2024.06.13.598792. [PMID: 38915496 PMCID: PMC11195274 DOI: 10.1101/2024.06.13.598792] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 06/26/2024]
Abstract
The basic excitatory neurons of the cerebral cortex, the pyramidal cells, are the most important signal integrators for the local circuit. They have quite characteristic morphological and electrophysiological properties that are known to be largely constant with age in the young and adult cortex. However, the brain undergoes several dynamic changes throughout life, such as in the phases of early development and cognitive decline in the aging brain. We set out to search for intrinsic cellular changes in supragranular pyramidal cells across a broad age range: from birth to 85 years of age and we found differences in several biophysical properties between defined age groups. During the first year of life, subthreshold and suprathreshold electrophysiological properties changed in a way that shows that pyramidal cells become less excitable with maturation, but also become temporarily more precise. According to our findings, the morphological features of the three-dimensional reconstructions from different life stages showed consistent morphological properties and systematic dendritic spine analysis of an infantile and an old pyramidal cell showed clear significant differences in the distribution of spine shapes. Overall, the changes that occur during development and aging may have lasting effects on the properties of pyramidal cells in the cerebral cortex. Understanding these changes is important to unravel the complex mechanisms underlying brain development, cognition and age-related neurodegenerative diseases.
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Affiliation(s)
- Pál Barzó
- Department of Neurosurgery, University of Szeged, Szeged, Hungary
| | - Ildikó Szöts
- HUN-REN-SZTE Research Group for Cortical Microcircuits, Department of Physiology, Anatomy and Neuroscience, University of Szeged, Szeged, Hungary
| | - Martin Tóth
- HUN-REN-SZTE Research Group for Cortical Microcircuits, Department of Physiology, Anatomy and Neuroscience, University of Szeged, Szeged, Hungary
| | - Éva Adrienn Csajbók
- HUN-REN-SZTE Research Group for Cortical Microcircuits, Department of Physiology, Anatomy and Neuroscience, University of Szeged, Szeged, Hungary
| | - Gábor Molnár
- HUN-REN-SZTE Research Group for Cortical Microcircuits, Department of Physiology, Anatomy and Neuroscience, University of Szeged, Szeged, Hungary
| | - Gábor Tamás
- HUN-REN-SZTE Research Group for Cortical Microcircuits, Department of Physiology, Anatomy and Neuroscience, University of Szeged, Szeged, Hungary
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Li J, Bauer R, Rentzeperis I, van Leeuwen C. Adaptive rewiring: a general principle for neural network development. FRONTIERS IN NETWORK PHYSIOLOGY 2024; 4:1410092. [PMID: 39534101 PMCID: PMC11554485 DOI: 10.3389/fnetp.2024.1410092] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 03/31/2024] [Accepted: 10/15/2024] [Indexed: 11/16/2024]
Abstract
The nervous system, especially the human brain, is characterized by its highly complex network topology. The neurodevelopment of some of its features has been described in terms of dynamic optimization rules. We discuss the principle of adaptive rewiring, i.e., the dynamic reorganization of a network according to the intensity of internal signal communication as measured by synchronization or diffusion, and its recent generalization for applications in directed networks. These have extended the principle of adaptive rewiring from highly oversimplified networks to more neurally plausible ones. Adaptive rewiring captures all the key features of the complex brain topology: it transforms initially random or regular networks into networks with a modular small-world structure and a rich-club core. This effect is specific in the sense that it can be tailored to computational needs, robust in the sense that it does not depend on a critical regime, and flexible in the sense that parametric variation generates a range of variant network configurations. Extreme variant networks can be associated at macroscopic level with disorders such as schizophrenia, autism, and dyslexia, and suggest a relationship between dyslexia and creativity. Adaptive rewiring cooperates with network growth and interacts constructively with spatial organization principles in the formation of topographically distinct modules and structures such as ganglia and chains. At the mesoscopic level, adaptive rewiring enables the development of functional architectures, such as convergent-divergent units, and sheds light on the early development of divergence and convergence in, for example, the visual system. Finally, we discuss future prospects for the principle of adaptive rewiring.
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Affiliation(s)
- Jia Li
- Brain and Cognition, KU Leuven, Leuven, Belgium
- Cognitive Science, RPTU Kaiserslautern, Kaiserslautern, Germany
| | - Roman Bauer
- NICE Research Group, Computer Science Research Centre, University of Surrey, Guildford, United Kingdom
| | - Ilias Rentzeperis
- Institute of Optics, Spanish National Research Council (CSIC), Madrid, Spain
| | - Cees van Leeuwen
- Brain and Cognition, KU Leuven, Leuven, Belgium
- Cognitive Science, RPTU Kaiserslautern, Kaiserslautern, Germany
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Wu MW, Kourdougli N, Portera-Cailliau C. Network state transitions during cortical development. Nat Rev Neurosci 2024; 25:535-552. [PMID: 38783147 PMCID: PMC11825063 DOI: 10.1038/s41583-024-00824-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 05/01/2024] [Indexed: 05/25/2024]
Abstract
Mammalian cortical networks are active before synaptogenesis begins in earnest, before neuronal migration is complete, and well before an animal opens its eyes and begins to actively explore its surroundings. This early activity undergoes several transformations during development. The most important of these is a transition from episodic synchronous network events, which are necessary for patterning the neocortex into functionally related modules, to desynchronized activity that is computationally more powerful and efficient. Network desynchronization is perhaps the most dramatic and abrupt developmental event in an otherwise slow and gradual process of brain maturation. In this Review, we summarize what is known about the phenomenology of developmental synchronous activity in the rodent neocortex and speculate on the mechanisms that drive its eventual desynchronization. We argue that desynchronization of network activity is a fundamental step through which the cortex transitions from passive, bottom-up detection of sensory stimuli to active sensory processing with top-down modulation.
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Affiliation(s)
- Michelle W Wu
- Department of Neurology, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, CA, USA
- Neuroscience Interdepartmental Graduate Program, University of California Los Angeles, Los Angeles, CA, USA
- UCLA-Caltech Medical Scientist Training Program, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, CA, USA
| | - Nazim Kourdougli
- Department of Neurology, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, CA, USA
| | - Carlos Portera-Cailliau
- Department of Neurology, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, CA, USA.
- Department of Neurobiology, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, CA, USA.
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Paterno R, Vu T, Hsieh C, Baraban SC. Host brain environmental influences on transplanted medial ganglionic eminence progenitors. Sci Rep 2024; 14:3610. [PMID: 38351191 PMCID: PMC10864292 DOI: 10.1038/s41598-024-52478-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/06/2023] [Accepted: 01/19/2024] [Indexed: 02/16/2024] Open
Abstract
Interneuron progenitor transplantation can ameliorate disease symptoms in a variety of neurological disorders. The strategy is based on transplantation of embryonic medial ganglionic eminence (MGE) progenitors. Elucidating how host brain environment influences the integration of interneuron progenitors is critical for optimizing this strategy across different disease states. Here, we systematically evaluated the influence of age and brain region on survival, migration, and differentiation of transplant-derived cells. We find that early postnatal MGE transplantation yields superior survival and more extensive migratory capabilities compared to transplantation during the juvenile or adult stages. MGE progenitors migrate more widely in the cortex compared to the hippocampus. Maturation to interneuron subtypes is regulated by age and brain region. MGE progenitors transplanted into the dentate gyrus sub-region of the early postnatal hippocampus can differentiate into astrocytes. Our results suggest that the host brain environment critically regulates survival, spatial distribution, and maturation of MGE-derived interneurons following transplantation. These findings inform and enable optimal conditions for interneuron transplant therapies.
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Affiliation(s)
- Rosalia Paterno
- Department of Neurological Surgery and Weill Institute of Neuroscience, University of California, 513 Parnassus Ave, Health Science East, E840, San Francisco, CA, 94143, USA.
| | - Thy Vu
- Department of Neurological Surgery and Weill Institute of Neuroscience, University of California, 513 Parnassus Ave, Health Science East, E840, San Francisco, CA, 94143, USA
| | - Caroline Hsieh
- Department of Neurological Surgery and Weill Institute of Neuroscience, University of California, 513 Parnassus Ave, Health Science East, E840, San Francisco, CA, 94143, USA
| | - Scott C Baraban
- Department of Neurological Surgery and Weill Institute of Neuroscience, University of California, 513 Parnassus Ave, Health Science East, E840, San Francisco, CA, 94143, USA
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Enck JR, Olson EC. Calcium Signaling during Cortical Apical Dendrite Initiation: A Role for Cajal-Retzius Neurons. Int J Mol Sci 2023; 24:12965. [PMID: 37629145 PMCID: PMC10455361 DOI: 10.3390/ijms241612965] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/12/2023] [Revised: 08/15/2023] [Accepted: 08/17/2023] [Indexed: 08/27/2023] Open
Abstract
The apical dendrite of a cortical projection neuron (CPN) is generated from the leading process of the migrating neuron as the neuron completes migration. This transformation occurs in the cortical marginal zone (MZ), a layer that contains the Cajal-Retzius neurons and their axonal projections. Cajal-Retzius neurons (CRNs) are well known for their critical role in secreting Reelin, a glycoprotein that controls dendritogenesis and cell positioning in many regions of the developing brain. In this study, we examine the possibility that CRNs in the MZ may provide additional signals to arriving CPNs, that may promote the maturation of CPNs and thus shape the development of the cortex. We use whole embryonic hemisphere explants and multiphoton microscopy to confirm that CRNs display intracellular calcium transients of <1-min duration and high amplitude during early corticogenesis. In contrast, developing CPNs do not show high-amplitude calcium transients, but instead show a steady increase in intracellular calcium that begins at the time of dendritic initiation, when the leading process of the migrating CPN is encountering the MZ. The possible existence of CRN to CPN communication was revealed by the application of veratridine, a sodium channel activator, which has been shown to preferentially stimulate more mature cells in the MZ at an early developmental time. Surprisingly, veratridine application also triggers large calcium transients in CPNs, which can be partially blocked by a cocktail of antagonists that block glutamate and glycine receptor activation. These findings outline a model in which CRN spontaneous activity triggers the release of glutamate and glycine, neurotransmitters that can trigger intracellular calcium elevations in CPNs. These elevations begin as CPNs initiate dendritogenesis and continue as waves in the post-migratory cells. Moreover, we show that the pharmacological blockade of glutamatergic signaling disrupts migration, while forced expression of a bacterial voltage-gated calcium channel (CavMr) in the migrating neurons promotes dendritic growth and migration arrest. The identification of CRN to CPN signaling during early development provides insight into the observation that many autism-linked genes encode synaptic proteins that, paradoxically, are expressed in the developing cortex well before the appearance of synapses and the establishment of functional circuits.
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Affiliation(s)
| | - Eric C. Olson
- Department of Neuroscience and Physiology, State University of New York Upstate Medical University, 505 Irving Ave., Syracuse, NY 13210, USA;
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Cao JW, Liu LY, Yu YC. Gap junctions regulate the development of neural circuits in the neocortex. Curr Opin Neurobiol 2023; 81:102735. [PMID: 37263136 DOI: 10.1016/j.conb.2023.102735] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/22/2023] [Revised: 04/12/2023] [Accepted: 05/07/2023] [Indexed: 06/03/2023]
Abstract
Gap junctions between cells are ubiquitously expressed in the developing brain. They are involved in major steps of neocortical development, including neurogenesis, cell migration, synaptogenesis, and neural circuit formation, and have been implicated in cortical column formation. Dysfunctional gap junctions can contribute to or even cause a variety of brain diseases. Although the role of gap junctions in neocortical development is better known, a comprehensive understanding of their functions is far from complete. Here we explore several critical open questions surrounding gap junctions and their involvement in neural circuit development. Addressing them will greatly impact our understanding of the fundamental mechanisms of neocortical structure and function as well as the etiology of brain disease.
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Affiliation(s)
- Jun-Wei Cao
- School of Basic Medical Sciences, Xiangnan University, Chenzhou, Hunan 423000, China
| | - Lin-Yun Liu
- Jing'an District Central Hospital of Shanghai, State Key Laboratory of Medical Neurobiology, MOE Frontiers Center for Brain Science, Institutes of Brain Science, Shanghai 200032, China
| | - Yong-Chun Yu
- Jing'an District Central Hospital of Shanghai, State Key Laboratory of Medical Neurobiology, MOE Frontiers Center for Brain Science, Institutes of Brain Science, Shanghai 200032, China.
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Abstract
The nervous system regulates tissue stem and precursor populations throughout life. Parallel to roles in development, the nervous system is emerging as a critical regulator of cancer, from oncogenesis to malignant growth and metastatic spread. Various preclinical models in a range of malignancies have demonstrated that nervous system activity can control cancer initiation and powerfully influence cancer progression and metastasis. Just as the nervous system can regulate cancer progression, cancer also remodels and hijacks nervous system structure and function. Interactions between the nervous system and cancer occur both in the local tumour microenvironment and systemically. Neurons and glial cells communicate directly with malignant cells in the tumour microenvironment through paracrine factors and, in some cases, through neuron-to-cancer cell synapses. Additionally, indirect interactions occur at a distance through circulating signals and through influences on immune cell trafficking and function. Such cross-talk among the nervous system, immune system and cancer-both systemically and in the local tumour microenvironment-regulates pro-tumour inflammation and anti-cancer immunity. Elucidating the neuroscience of cancer, which calls for interdisciplinary collaboration among the fields of neuroscience, developmental biology, immunology and cancer biology, may advance effective therapies for many of the most difficult to treat malignancies.
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Affiliation(s)
- Rebecca Mancusi
- Department of Neurology and Neurological Sciences, Stanford University, Stanford, CA, USA
| | - Michelle Monje
- Department of Neurology and Neurological Sciences, Stanford University, Stanford, CA, USA.
- Howard Hughes Medical Institute, Stanford University, Stanford, CA, USA.
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Rashid M, Olson EC. Delayed cortical development in mice with a neural specific deletion of β1 integrin. Front Neurosci 2023; 17:1158419. [PMID: 37250402 PMCID: PMC10213249 DOI: 10.3389/fnins.2023.1158419] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/03/2023] [Accepted: 04/24/2023] [Indexed: 05/31/2023] Open
Abstract
The adhesion systems employed by migrating cortical neurons are not well understood. Genetic deletion studies of focal adhesion kinase (FAK) and paxillin in mice suggested that these classical focal adhesion molecules control the morphology and speed of cortical neuron migration, but whether β1 integrins also regulate migration morphology and speed is not known. We hypothesized that a β1 integrin adhesion complex is required for proper neuronal migration and for proper cortical development. To test this, we have specifically deleted β1 integrin from postmitotic migrating and differentiating neurons by crossing conditional β1 integrin floxed mice into the NEX-Cre transgenic line. Similar to our prior findings with conditional paxillin deficiency, we found that both homozygous and heterozygous deletion of β1 integrin causes transient mispositioning of cortical neurons in the developing cortex when analyzed pre- and perinatally. Paxillin and β1 integrin colocalize in the migrating neurons and deletion of paxillin in the migrating neuron causes an overall reduction of the β1 integrin immunofluorescence signal and reduction in the number of activated β1 integrin puncta in the migrating neurons. These findings suggest that these molecules may form a functional complex in migrating neurons. Similarly, there was an overall reduced number of paxillin+ puncta in the β1 integrin deficient neurons, despite the normal distribution of FAK and Cx26, a connexin required for cortical migration. The double knockout of paxillin and β1 integrin produces a cortical malpositioning phenotype similar to the paxillin or β1 integrin single knockouts, as would be expected if paxillin and β1 integrin function on a common pathway. Importantly, an isolation-induced pup vocalization test showed that β1 integrin mutants produced a significantly smaller number of calls compared to their littermate controls when analyzed at postnatal day 4 (P4) and revealed a several days trend in reduced vocalization development compared to controls. The current study establishes a role for β1 integrin in cortical development and suggests that β1 integrin deficiency leads to migration and neurodevelopmental delays.
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Affiliation(s)
- Mamunur Rashid
- Department of Neuroscience and Physiology, State University of New York Upstate Medical University, Syracuse, NY, United States
- Department of Neurology, Columbia University Irving Medical Center, New York, NY, United States
| | - Eric C. Olson
- Department of Neuroscience and Physiology, State University of New York Upstate Medical University, Syracuse, NY, United States
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Powell SK, O'Shea C, Townsley K, Prytkova I, Dobrindt K, Elahi R, Iskhakova M, Lambert T, Valada A, Liao W, Ho SM, Slesinger PA, Huckins LM, Akbarian S, Brennand KJ. Induction of dopaminergic neurons for neuronal subtype-specific modeling of psychiatric disease risk. Mol Psychiatry 2023; 28:1970-1982. [PMID: 34493831 PMCID: PMC8898985 DOI: 10.1038/s41380-021-01273-0] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/03/2021] [Revised: 06/22/2021] [Accepted: 08/19/2021] [Indexed: 11/08/2022]
Abstract
Dopaminergic neurons are critical to movement, mood, addiction, and stress. Current techniques for generating dopaminergic neurons from human induced pluripotent stem cells (hiPSCs) yield heterogenous cell populations with variable purity and inconsistent reproducibility between donors, hiPSC clones, and experiments. Here, we report the rapid (5 weeks) and efficient (~90%) induction of induced dopaminergic neurons (iDANs) through transient overexpression of lineage-promoting transcription factors combined with stringent selection across five donors. We observe maturation-dependent increase in dopamine synthesis and electrophysiological properties consistent with midbrain dopaminergic neuron identity, such as slow-rising after- hyperpolarization potentials, an action potential duration of ~3 ms, tonic sub-threshold oscillatory activity, and spontaneous burst firing at a frequency of ~1.0-1.75 Hz. Transcriptome analysis reveals robust expression of genes involved in fetal midbrain dopaminergic neuron identity. Specifically expressed genes in iDANs, as well as those from isogenic induced GABAergic and glutamatergic neurons, were enriched in loci conferring heritability for cannabis use disorder, schizophrenia, and bipolar disorder; however, each neuronal subtype demonstrated subtype-specific heritability enrichments in biologically relevant pathways, and iDANs alone were uniquely enriched in autism spectrum disorder risk loci. Therefore, iDANs provide a critical tool for modeling midbrain dopaminergic neuron development and dysfunction in psychiatric disease.
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Affiliation(s)
- Samuel K Powell
- Pamela Sklar Division of Psychiatric Genomics, Department of Genetics and Genomics, Icahn Institute of Genomics and Multiscale Biology, Icahn School of Medicine at Mount Sinai, New York, NY, USA
- Nash Family Department of Neuroscience, Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA
- Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York, NY, USA
- Black Family Stem Cell Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA
- Graduate School of Biomedical Science, Icahn School of Medicine at Mount Sinai, New York, NY, USA
- Division of Molecular Psychiatry, Department of Psychiatry, Yale University, New Haven, CT, USA
| | - Callan O'Shea
- Pamela Sklar Division of Psychiatric Genomics, Department of Genetics and Genomics, Icahn Institute of Genomics and Multiscale Biology, Icahn School of Medicine at Mount Sinai, New York, NY, USA
- Nash Family Department of Neuroscience, Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA
- Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York, NY, USA
- Black Family Stem Cell Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA
- Division of Molecular Psychiatry, Department of Psychiatry, Yale University, New Haven, CT, USA
| | - Kayla Townsley
- Pamela Sklar Division of Psychiatric Genomics, Department of Genetics and Genomics, Icahn Institute of Genomics and Multiscale Biology, Icahn School of Medicine at Mount Sinai, New York, NY, USA
- Nash Family Department of Neuroscience, Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA
- Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York, NY, USA
- Black Family Stem Cell Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA
- Graduate School of Biomedical Science, Icahn School of Medicine at Mount Sinai, New York, NY, USA
| | - Iya Prytkova
- Pamela Sklar Division of Psychiatric Genomics, Department of Genetics and Genomics, Icahn Institute of Genomics and Multiscale Biology, Icahn School of Medicine at Mount Sinai, New York, NY, USA
- Nash Family Department of Neuroscience, Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA
- Graduate School of Biomedical Science, Icahn School of Medicine at Mount Sinai, New York, NY, USA
| | - Kristina Dobrindt
- Pamela Sklar Division of Psychiatric Genomics, Department of Genetics and Genomics, Icahn Institute of Genomics and Multiscale Biology, Icahn School of Medicine at Mount Sinai, New York, NY, USA
- Nash Family Department of Neuroscience, Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA
- Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York, NY, USA
- Black Family Stem Cell Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA
- Division of Molecular Psychiatry, Department of Psychiatry, Yale University, New Haven, CT, USA
| | - Rahat Elahi
- Pamela Sklar Division of Psychiatric Genomics, Department of Genetics and Genomics, Icahn Institute of Genomics and Multiscale Biology, Icahn School of Medicine at Mount Sinai, New York, NY, USA
- Nash Family Department of Neuroscience, Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA
- Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York, NY, USA
- Black Family Stem Cell Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA
| | - Marina Iskhakova
- Pamela Sklar Division of Psychiatric Genomics, Department of Genetics and Genomics, Icahn Institute of Genomics and Multiscale Biology, Icahn School of Medicine at Mount Sinai, New York, NY, USA
- Nash Family Department of Neuroscience, Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA
- Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York, NY, USA
| | - Tova Lambert
- Pamela Sklar Division of Psychiatric Genomics, Department of Genetics and Genomics, Icahn Institute of Genomics and Multiscale Biology, Icahn School of Medicine at Mount Sinai, New York, NY, USA
- Nash Family Department of Neuroscience, Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA
- Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York, NY, USA
| | - Aditi Valada
- Pamela Sklar Division of Psychiatric Genomics, Department of Genetics and Genomics, Icahn Institute of Genomics and Multiscale Biology, Icahn School of Medicine at Mount Sinai, New York, NY, USA
- Nash Family Department of Neuroscience, Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA
- Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York, NY, USA
| | - Will Liao
- New York Genome Center, New York, NY, USA
| | - Seok-Man Ho
- Pamela Sklar Division of Psychiatric Genomics, Department of Genetics and Genomics, Icahn Institute of Genomics and Multiscale Biology, Icahn School of Medicine at Mount Sinai, New York, NY, USA
- Nash Family Department of Neuroscience, Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA
- Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York, NY, USA
- Black Family Stem Cell Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA
| | - Paul A Slesinger
- Nash Family Department of Neuroscience, Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA
| | - Laura M Huckins
- Pamela Sklar Division of Psychiatric Genomics, Department of Genetics and Genomics, Icahn Institute of Genomics and Multiscale Biology, Icahn School of Medicine at Mount Sinai, New York, NY, USA
- Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York, NY, USA
| | - Schahram Akbarian
- Pamela Sklar Division of Psychiatric Genomics, Department of Genetics and Genomics, Icahn Institute of Genomics and Multiscale Biology, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
- Nash Family Department of Neuroscience, Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
- Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
| | - Kristen J Brennand
- Pamela Sklar Division of Psychiatric Genomics, Department of Genetics and Genomics, Icahn Institute of Genomics and Multiscale Biology, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
- Nash Family Department of Neuroscience, Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
- Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
- Black Family Stem Cell Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
- Division of Molecular Psychiatry, Department of Psychiatry, Yale University, New Haven, CT, USA.
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11
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Winkler F, Venkatesh HS, Amit M, Batchelor T, Demir IE, Deneen B, Gutmann DH, Hervey-Jumper S, Kuner T, Mabbott D, Platten M, Rolls A, Sloan EK, Wang TC, Wick W, Venkataramani V, Monje M. Cancer neuroscience: State of the field, emerging directions. Cell 2023; 186:1689-1707. [PMID: 37059069 PMCID: PMC10107403 DOI: 10.1016/j.cell.2023.02.002] [Citation(s) in RCA: 181] [Impact Index Per Article: 90.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/30/2022] [Revised: 02/01/2023] [Accepted: 02/01/2023] [Indexed: 04/16/2023]
Abstract
The nervous system governs both ontogeny and oncology. Regulating organogenesis during development, maintaining homeostasis, and promoting plasticity throughout life, the nervous system plays parallel roles in the regulation of cancers. Foundational discoveries have elucidated direct paracrine and electrochemical communication between neurons and cancer cells, as well as indirect interactions through neural effects on the immune system and stromal cells in the tumor microenvironment in a wide range of malignancies. Nervous system-cancer interactions can regulate oncogenesis, growth, invasion and metastatic spread, treatment resistance, stimulation of tumor-promoting inflammation, and impairment of anti-cancer immunity. Progress in cancer neuroscience may create an important new pillar of cancer therapy.
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Affiliation(s)
- Frank Winkler
- Neurology Clinic and National Center for Tumor Diseases, University Hospital Heidelberg and Clinical Cooperation Unit Neurooncology, German Cancer Consortium (DKTK), German Cancer Research Center (DKFZ), Heidelberg, Germany.
| | - Humsa S Venkatesh
- Department of Neurology, Brigham and Women's Hospital, Boston, MA, USA
| | - Moran Amit
- Department of Head and Neck Surgery, MD Anderson Cancer Center and The University of Texas Graduate School of Biomedical Sciences, Houston, TX, USA
| | - Tracy Batchelor
- Department of Neurology, Brigham and Women's Hospital, Boston, MA, USA
| | - Ihsan Ekin Demir
- Department of Surgery, Technical University of Munich, Munich, Germany
| | - Benjamin Deneen
- Center for Stem Cells and Regenerative Medicine, Baylor College of Medicine, Houston, TX, USA
| | - David H Gutmann
- Department of Neurology, Washington University, St Louis, MO, USA
| | - Shawn Hervey-Jumper
- Department of Neurosurgery, University of California, San Francisco, San Francisco, CA, USA
| | - Thomas Kuner
- Department of Functional Neuroanatomy, University of Heidelberg, Heidelberg, Germany
| | - Donald Mabbott
- Department of Psychology, University of Toronto and Neuroscience & Mental Health Program, Research Institute, The Hospital for Sick Children, Toronto, Canada
| | - Michael Platten
- Department of Neurology, Medical Faculty Mannheim, University of Heidelberg, Heidelberg, Germany
| | - Asya Rolls
- Department of Immunology, Rappaport Faculty of Medicine, Technion - Israel Institute of Technology, Haifa, Israel
| | - Erica K Sloan
- Monash Institute of Pharmaceutical Sciences, Drug Discovery Biology Theme, Monash University, Parkville, VIC, Australia
| | - Timothy C Wang
- Department of Medicine, Division of Digestive and Gastrointestinal Diseases, Columbia University, New York, NY, USA
| | - Wolfgang Wick
- Neurology Clinic and National Center for Tumor Diseases, University Hospital Heidelberg and Clinical Cooperation Unit Neurooncology, German Cancer Consortium (DKTK), German Cancer Research Center (DKFZ), Heidelberg, Germany
| | - Varun Venkataramani
- Neurology Clinic and National Center for Tumor Diseases, University Hospital Heidelberg and Clinical Cooperation Unit Neurooncology, German Cancer Consortium (DKTK), German Cancer Research Center (DKFZ), Heidelberg, Germany; Department of Functional Neuroanatomy, University of Heidelberg, Heidelberg, Germany.
| | - Michelle Monje
- Department of Neurology and Neurological Sciences, Stanford University, Stanford, CA, USA; Howard Hughes Medical Institute, Stanford University, Stanford, CA, USA.
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12
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Gamma oscillations provide insights into cortical circuit development. Pflugers Arch 2023; 475:561-568. [PMID: 36864347 PMCID: PMC10105678 DOI: 10.1007/s00424-023-02801-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/24/2023] [Revised: 02/20/2023] [Accepted: 02/22/2023] [Indexed: 03/04/2023]
Abstract
Rhythmic coordination in gamma oscillations provides temporal structure to neuronal activity. Gamma oscillations are commonly observed in the mammalian cerebral cortex, are altered early on in several neuropsychiatric disorders, and provide insights into the development of underlying cortical networks. However, a lack of knowledge on the developmental trajectory of gamma oscillations prevented the combination of findings from the immature and the adult brain. This review is intended to provide an overview on the development of cortical gamma oscillations, the maturation of the underlying network, and the implications for cortical function and dysfunction. The majority of information is drawn from work in rodents with particular emphasis on the prefrontal cortex, the developmental trajectory of gamma oscillations, and potential implications for neuropsychiatric disorders. Current evidence supports the idea that fast oscillations during development are indeed an immature form of adult gamma oscillations and can help us understand the pathology of neuropsychiatric disorders.
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13
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5-HT-dependent synaptic plasticity of the prefrontal cortex in postnatal development. Sci Rep 2022; 12:21015. [PMID: 36470912 PMCID: PMC9723183 DOI: 10.1038/s41598-022-23767-9] [Citation(s) in RCA: 15] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/08/2022] [Accepted: 11/04/2022] [Indexed: 12/12/2022] Open
Abstract
Important functions of the prefrontal cortex (PFC) are established during early life, when neurons exhibit enhanced synaptic plasticity and synaptogenesis. This developmental stage drives the organization of cortical connectivity, responsible for establishing behavioral patterns. Serotonin (5-HT) emerges among the most significant factors that modulate brain activity during postnatal development. In the PFC, activated 5-HT receptors modify neuronal excitability and interact with intracellular signaling involved in synaptic modifications, thus suggesting that 5-HT might participate in early postnatal plasticity. To test this hypothesis, we employed intracellular electrophysiological recordings of PFC layer 5 neurons to study the modulatory effects of 5-HT on plasticity induced by theta-burst stimulation (TBS) in two postnatal periods of rats. Our results indicate that 5-HT is essential for TBS to result in synaptic changes during the third postnatal week, but not later. TBS coupled with 5-HT2A or 5-HT1A and 5-HT7 receptors stimulation leads to long-term depression (LTD). On the other hand, TBS and synergic activation of 5-HT1A, 5-HT2A, and 5-HT7 receptors lead to long-term potentiation (LTP). Finally, we also show that 5-HT dependent synaptic plasticity of the PFC is impaired in animals that are exposed to early-life chronic stress.
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14
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Bigiani A, Tirindelli R, Bigiani L, Mapelli J. Changes of the biophysical properties of voltage-gated Na + currents during maturation of the sodium-taste cells in rat fungiform papillae. J Physiol 2022; 600:5119-5144. [PMID: 36250254 DOI: 10.1113/jp283636] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/22/2022] [Accepted: 10/13/2022] [Indexed: 01/05/2023] Open
Abstract
Taste cells are a heterogeneous population of sensory receptors that undergo continuous turnover. Different chemo-sensitive cell lines rely on action potentials to release the neurotransmitter onto nerve endings. The electrical excitability is due to the presence of a tetrodotoxin-sensitive, voltage-gated sodium current (INa ) similar to that found in neurons. Since the biophysical properties of neuronal INa change during development, we wondered whether the same also occurred in taste cells. Here, we used the patch-clamp recording technique to study INa in salt-sensing cells (sodium cells) of rat fungiform papillae. We identified these cells by exploiting the known blocking effect of amiloride on ENaC, the sodium (salt) receptor. Based on the amplitude of INa , which is known to increase during development, we subdivided sodium cells into two groups: cells with small sodium current (SSC cells; INa < 1 nA) and cells with large sodium current (LSC cells; INa > 1 nA). We found that: the voltage dependence of activation and inactivation significantly differed between these subsets; a slowly inactivating sodium current was more prominent in LSC cells; membrane capacitance in SSC cells was larger than in LSC cells. mRNA expression analysis of the α-subunits of voltage-gated sodium channels in fungiform taste buds supported the functional data. Lucifer Yellow labelling of recorded cells revealed that our electrophysiological criterion for distinguishing two broad groups of taste cells was in good agreement with morphological observations for cell maturity. Thus, all these findings are consistent with developmental changes in the voltage-dependent properties of sodium-taste cells. KEY POINTS: Taste cells are sensory receptors that undergo continuous turnover while they detect food chemicals and communicate with afferent nerve fibres. The voltage-gated sodium current (INa ) is a key ion current for generating action potentials in fully differentiated and chemo-sensitive taste cells, which use electrical signalling to release neurotransmitters. Here we show that, during the maturation of rat taste cells involved in salt detection (sodium cells), the biophysical properties of INa , such as voltage dependence of activation and inactivation, change significantly. Our results help reveal how taste cells gain electrical excitability during turnover, a property critical to their operation as chemical detectors that relay sensory information to nerve fibres.
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Affiliation(s)
- Albertino Bigiani
- Dipartimento di Scienze Biomediche, Metaboliche e Neuroscienze, Università di Modena e Reggio Emilia, Modena, Italy
| | - Roberto Tirindelli
- Dipartimento di Medicina e Chirurgia, SMart Laboratory, Università di Parma, Parma, Italy
| | | | - Jonathan Mapelli
- Dipartimento di Scienze Biomediche, Metaboliche e Neuroscienze, Università di Modena e Reggio Emilia, Modena, Italy
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15
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Braz BY, Wennagel D, Ratié L, de Souza DAR, Deloulme JC, Barbier EL, Buisson A, Lanté F, Humbert S. Treating early postnatal circuit defect delays Huntington's disease onset and pathology in mice. Science 2022; 377:eabq5011. [PMID: 36137051 DOI: 10.1126/science.abq5011] [Citation(s) in RCA: 42] [Impact Index Per Article: 14.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/13/2023]
Abstract
Recent evidence has shown that even mild mutations in the Huntingtin gene that are associated with late-onset Huntington's disease (HD) disrupt various aspects of human neurodevelopment. To determine whether these seemingly subtle early defects affect adult neural function, we investigated neural circuit physiology in newborn HD mice. During the first postnatal week, HD mice have less cortical layer 2/3 excitatory synaptic activity than wild-type mice, express fewer glutamatergic receptors, and show sensorimotor deficits. The circuit self-normalizes in the second postnatal week but the mice nonetheless develop HD. Pharmacologically enhancing glutamatergic transmission during the neonatal period, however, rescues these deficits and preserves sensorimotor function, cognition, and spine and synapse density as well as brain region volume in HD adult mice.
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Affiliation(s)
- Barbara Yael Braz
- Univ. Grenoble Alpes, Inserm, U1216, Grenoble Institut Neurosciences, 38000 Grenoble, France
| | - Doris Wennagel
- Univ. Grenoble Alpes, Inserm, U1216, Grenoble Institut Neurosciences, 38000 Grenoble, France
| | - Leslie Ratié
- Univ. Grenoble Alpes, Inserm, U1216, Grenoble Institut Neurosciences, 38000 Grenoble, France
| | | | | | - Emmanuel L Barbier
- Univ. Grenoble Alpes, Inserm, U1216, Grenoble Institut Neurosciences, 38000 Grenoble, France
| | - Alain Buisson
- Univ. Grenoble Alpes, Inserm, U1216, Grenoble Institut Neurosciences, 38000 Grenoble, France
| | - Fabien Lanté
- Univ. Grenoble Alpes, Inserm, U1216, Grenoble Institut Neurosciences, 38000 Grenoble, France
| | - Sandrine Humbert
- Univ. Grenoble Alpes, Inserm, U1216, Grenoble Institut Neurosciences, 38000 Grenoble, France.,Institut du Cerveau-Paris Brain Institute, Sorbonne Université, Inserm, CNRS, Hôpital Pitié-Salpêtrière, Paris, France
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16
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Tomasello U, Klingler E, Niquille M, Mule N, Santinha AJ, de Vevey L, Prados J, Platt RJ, Borrell V, Jabaudon D, Dayer A. miR-137 and miR-122, two outer subventricular zone non-coding RNAs, regulate basal progenitor expansion and neuronal differentiation. Cell Rep 2022; 38:110381. [PMID: 35172154 PMCID: PMC8864305 DOI: 10.1016/j.celrep.2022.110381] [Citation(s) in RCA: 16] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/05/2021] [Revised: 04/22/2021] [Accepted: 01/24/2022] [Indexed: 12/29/2022] Open
Abstract
Cortical expansion in primate brains relies on enlargement of germinal zones during a prolonged developmental period. Although most mammals have two cortical germinal zones, the ventricular zone (VZ) and subventricular zone (SVZ), gyrencephalic species display an additional germinal zone, the outer subventricular zone (oSVZ), which increases the number and diversity of neurons generated during corticogenesis. How the oSVZ emerged during evolution is poorly understood, but recent studies suggest a role for non-coding RNAs, which allow tight genetic program regulation during development. Here, using in vivo functional genetics, single-cell RNA sequencing, live imaging, and electrophysiology to assess progenitor and neuronal properties in mice, we identify two oSVZ-expressed microRNAs (miRNAs), miR-137 and miR-122, which regulate key cellular features of cortical expansion. miR-137 promotes basal progenitor self-replication and superficial layer neuron fate, whereas miR-122 decreases the pace of neuronal differentiation. These findings support a cell-type-specific role of miRNA-mediated gene expression in cortical expansion.
oSVZ-expressed microRNAs 137 and 122 promote superficial layer identity of neurons miR-137 promotes basal progenitor proliferation and layer 2/3 neuron generation miR-122 slows down neuronal differentiation pace
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Affiliation(s)
- Ugo Tomasello
- Department of Basic Neurosciences, University of Geneva, 1205 Geneva, Switzerland; Instituto de Neurociencias, Consejo Superior de Investigaciones Científicas and Universidad Miguel Hernández, Sant Joan d'Alacant, 03550 Alacant, Spain
| | - Esther Klingler
- Department of Basic Neurosciences, University of Geneva, 1205 Geneva, Switzerland
| | - Mathieu Niquille
- Department of Basic Neurosciences, University of Geneva, 1205 Geneva, Switzerland; Department of Psychiatry, Geneva University Hospital, 1205 Geneva, Switzerland
| | - Nandkishor Mule
- Department of Basic Neurosciences, University of Geneva, 1205 Geneva, Switzerland
| | - Antonio J Santinha
- Department of Biosystems Science and Engineering, ETH Zurich, 4058 Basel, Switzerland
| | - Laura de Vevey
- Department of Basic Neurosciences, University of Geneva, 1205 Geneva, Switzerland
| | - Julien Prados
- Department of Psychiatry, Geneva University Hospital, 1205 Geneva, Switzerland
| | - Randall J Platt
- Department of Biosystems Science and Engineering, ETH Zurich, 4058 Basel, Switzerland
| | - Victor Borrell
- Instituto de Neurociencias, Consejo Superior de Investigaciones Científicas and Universidad Miguel Hernández, Sant Joan d'Alacant, 03550 Alacant, Spain
| | - Denis Jabaudon
- Department of Basic Neurosciences, University of Geneva, 1205 Geneva, Switzerland; Clinic of Neurology, Geneva University Hospital, 1205 Geneva, Switzerland.
| | - Alexandre Dayer
- Department of Basic Neurosciences, University of Geneva, 1205 Geneva, Switzerland; Department of Psychiatry, Geneva University Hospital, 1205 Geneva, Switzerland
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17
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Bando Y, Ishibashi M, Yamagishi S, Fukuda A, Sato K. Orchestration of Ion Channels and Transporters in Neocortical Development and Neurological Disorders. Front Neurosci 2022; 16:827284. [PMID: 35237124 PMCID: PMC8884360 DOI: 10.3389/fnins.2022.827284] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/01/2021] [Accepted: 01/24/2022] [Indexed: 12/17/2022] Open
Abstract
Electrical activity plays crucial roles in neural circuit formation and remodeling. During neocortical development, neurons are generated in the ventricular zone, migrate to their correct position, elongate dendrites and axons, and form synapses. In this review, we summarize the functions of ion channels and transporters in neocortical development. Next, we discuss links between neurological disorders caused by dysfunction of ion channels (channelopathies) and neocortical development. Finally, we introduce emerging optical techniques with potential applications in physiological studies of neocortical development and the pathophysiology of channelopathies.
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Affiliation(s)
- Yuki Bando
- Department of Organ and Tissue Anatomy, Hamamatsu University School of Medicine, Hamamatsu, Japan
- *Correspondence: Yuki Bando,
| | - Masaru Ishibashi
- Department of Neurophysiology, Hamamatsu University School of Medicine, Hamamatsu, Japan
| | - Satoru Yamagishi
- Department of Organ and Tissue Anatomy, Hamamatsu University School of Medicine, Hamamatsu, Japan
| | - Atsuo Fukuda
- Department of Neurophysiology, Hamamatsu University School of Medicine, Hamamatsu, Japan
| | - Kohji Sato
- Department of Organ and Tissue Anatomy, Hamamatsu University School of Medicine, Hamamatsu, Japan
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18
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Perez-García P, Pardillo-Díaz R, Geribaldi-Doldán N, Gómez-Oliva R, Domínguez-García S, Castro C, Nunez-Abades P, Carrascal L. Refinement of Active and Passive Membrane Properties of Layer V Pyramidal Neurons in Rat Primary Motor Cortex During Postnatal Development. Front Mol Neurosci 2021; 14:754393. [PMID: 34924951 PMCID: PMC8671142 DOI: 10.3389/fnmol.2021.754393] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/06/2021] [Accepted: 10/19/2021] [Indexed: 11/13/2022] Open
Abstract
Achieving the distinctive complex behaviors of adult mammals requires the development of a great variety of specialized neural circuits. Although the development of these circuits begins during the embryonic stage, they remain immature at birth, requiring a postnatal maturation process to achieve these complex tasks. Understanding how the neuronal membrane properties and circuits change during development is the first step to understand their transition into efficient ones. Thus, using whole cell patch clamp recordings, we have studied the changes in the electrophysiological properties of layer V pyramidal neurons of the rat primary motor cortex during postnatal development. Among all the parameters studied, only the voltage threshold was established at birth and, although some of the changes occurred mainly during the second postnatal week, other properties such as membrane potential, capacitance, duration of the post-hyperpolarization phase or the maximum firing rate were not defined until the beginning of adulthood. Those modifications lead to a decrease in neuronal excitability and to an increase in the working range in young adult neurons, allowing more sensitive and accurate responses. This maturation process, that involves an increase in neuronal size and changes in ionic conductances, seems to be influenced by the neuronal type and by the task that neurons perform as inferred from the comparison with other pyramidal and motor neuron populations.
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Affiliation(s)
- Patricia Perez-García
- Department of Physiology, School of Pharmacy, University of Seville, Seville, Spain.,Division of Physiology, School of Medicine, University of Cádiz, Cádiz, Spain
| | - Ricardo Pardillo-Díaz
- Division of Physiology, School of Medicine, University of Cádiz, Cádiz, Spain.,Biomedical Research and Innovation Institute of Cádiz (INiBICA), Cádiz, Spain
| | - Noelia Geribaldi-Doldán
- Biomedical Research and Innovation Institute of Cádiz (INiBICA), Cádiz, Spain.,Department of Human Anatomy and Embriology, University of Cádiz, Cádiz, Spain
| | - Ricardo Gómez-Oliva
- Division of Physiology, School of Medicine, University of Cádiz, Cádiz, Spain.,Biomedical Research and Innovation Institute of Cádiz (INiBICA), Cádiz, Spain
| | - Samuel Domínguez-García
- Division of Physiology, School of Medicine, University of Cádiz, Cádiz, Spain.,Biomedical Research and Innovation Institute of Cádiz (INiBICA), Cádiz, Spain
| | - Carmen Castro
- Division of Physiology, School of Medicine, University of Cádiz, Cádiz, Spain.,Biomedical Research and Innovation Institute of Cádiz (INiBICA), Cádiz, Spain
| | - Pedro Nunez-Abades
- Department of Physiology, School of Pharmacy, University of Seville, Seville, Spain.,Biomedical Research and Innovation Institute of Cádiz (INiBICA), Cádiz, Spain
| | - Livia Carrascal
- Department of Physiology, School of Pharmacy, University of Seville, Seville, Spain.,Biomedical Research and Innovation Institute of Cádiz (INiBICA), Cádiz, Spain
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19
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Developmental HCN channelopathy results in decreased neural progenitor proliferation and microcephaly in mice. Proc Natl Acad Sci U S A 2021; 118:2009393118. [PMID: 34429357 DOI: 10.1073/pnas.2009393118] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/30/2023] Open
Abstract
The development of the cerebral cortex relies on the controlled division of neural stem and progenitor cells. The requirement for precise spatiotemporal control of proliferation and cell fate places a high demand on the cell division machinery, and defective cell division can cause microcephaly and other brain malformations. Cell-extrinsic and -intrinsic factors govern the capacity of cortical progenitors to produce large numbers of neurons and glia within a short developmental time window. In particular, ion channels shape the intrinsic biophysical properties of precursor cells and neurons and control their membrane potential throughout the cell cycle. We found that hyperpolarization-activated cyclic nucleotide-gated cation (HCN) channel subunits are expressed in mouse, rat, and human neural progenitors. Loss of HCN channel function in rat neural stem cells impaired their proliferation by affecting the cell-cycle progression, causing G1 accumulation and dysregulation of genes associated with human microcephaly. Transgene-mediated, dominant-negative loss of HCN channel function in the embryonic mouse telencephalon resulted in pronounced microcephaly. Together, our findings suggest a role for HCN channel subunits as a part of a general mechanism influencing cortical development in mammals.
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20
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Bragg-Gonzalo L, De León Reyes NS, Nieto M. Genetic and activity dependent-mechanisms wiring the cortex: Two sides of the same coin. Semin Cell Dev Biol 2021; 118:24-34. [PMID: 34030948 DOI: 10.1016/j.semcdb.2021.05.011] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/26/2021] [Revised: 04/27/2021] [Accepted: 05/08/2021] [Indexed: 01/17/2023]
Abstract
The cerebral cortex is responsible for the higher-order functions of the brain such as planning, cognition, or social behaviour. It provides us with the capacity to interact with and transform our world. The substrates of cortical functions are complex neural circuits that arise during development from the dynamic remodelling and progressive specialization of immature undefined networks. Here, we review the genetic and activity-dependent mechanisms of cortical wiring focussing on the importance of their interaction. Cortical circuits emerge from an initial set of neuronal types that engage in sequential forms of embryonic and postnatal activity. Such activities further complement the cells' genetic programs, increasing neuronal diversity and modifying the electrical properties while promoting selective connectivity. After a temporal window of enhanced plasticity, the main features of mature circuits are established. Failures in these processes can lead to neurodevelopmental disorders whose treatment remains elusive. However, a deeper dissection of cortical wiring will pave the way for innovative therapies.
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Affiliation(s)
- L Bragg-Gonzalo
- Department of Cellular and Molecular Biology, Centro Nacional de Biotecnología, Consejo Superior de Investigaciones Científicas, (CNB-CSIC) Campus de Cantoblanco, Darwin 3, 28049 Madrid, Spain
| | - N S De León Reyes
- Department of Cellular and Molecular Biology, Centro Nacional de Biotecnología, Consejo Superior de Investigaciones Científicas, (CNB-CSIC) Campus de Cantoblanco, Darwin 3, 28049 Madrid, Spain; Instituto de Neurociencias de Alicante, CSIC-UMH, 03550 San Juan de Alicante, Spain
| | - M Nieto
- Department of Cellular and Molecular Biology, Centro Nacional de Biotecnología, Consejo Superior de Investigaciones Científicas, (CNB-CSIC) Campus de Cantoblanco, Darwin 3, 28049 Madrid, Spain.
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21
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Boeri J, Meunier C, Le Corronc H, Branchereau P, Timofeeva Y, Lejeune FX, Mouffle C, Arulkandarajah H, Mangin JM, Legendre P, Czarnecki A. Two opposite voltage-dependent currents control the unusual early development pattern of embryonic Renshaw cell electrical activity. eLife 2021; 10:62639. [PMID: 33899737 PMCID: PMC8139835 DOI: 10.7554/elife.62639] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/31/2020] [Accepted: 04/24/2021] [Indexed: 11/25/2022] Open
Abstract
Renshaw cells (V1R) are excitable as soon as they reach their final location next to the spinal motoneurons and are functionally heterogeneous. Using multiple experimental approaches, in combination with biophysical modeling and dynamical systems theory, we analyzed, for the first time, the mechanisms underlying the electrophysiological properties of V1R during early embryonic development of the mouse spinal cord locomotor networks (E11.5–E16.5). We found that these interneurons are subdivided into several functional clusters from E11.5 and then display an unexpected transitory involution process during which they lose their ability to sustain tonic firing. We demonstrated that the essential factor controlling the diversity of the discharge pattern of embryonic V1R is the ratio of a persistent sodium conductance to a delayed rectifier potassium conductance. Taken together, our results reveal how a simple mechanism, based on the synergy of two voltage-dependent conductances that are ubiquitous in neurons, can produce functional diversity in embryonic V1R and control their early developmental trajectory.
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Affiliation(s)
- Juliette Boeri
- INSERM, UMR_S 1130, CNRS, UMR 8246, Neuroscience Paris Seine, Institute of Biology Paris Seine, Sorbonne Univ, Paris, France
| | - Claude Meunier
- Centre de Neurosciences Intégratives et Cognition, CNRS UMR 8002, Institut Neurosciences et Cognition, Université de Paris, Paris, France
| | - Hervé Le Corronc
- INSERM, UMR_S 1130, CNRS, UMR 8246, Neuroscience Paris Seine, Institute of Biology Paris Seine, Sorbonne Univ, Paris, France.,Univ Angers, Angers, France
| | | | - Yulia Timofeeva
- Department of Computer Science and Centre for Complexity Science, University of Warwick, Coventry, United Kingdom.,Department of Clinical and Experimental Epilepsy, UCL Queen Square Institute of Neurology, University College London, London, United Kingdom
| | - François-Xavier Lejeune
- Institut du Cerveau et de la Moelle Epinière, Centre de Recherche CHU Pitié-Salpétrière, INSERM, U975, CNRS, UMR 7225, Sorbonne Univ, Paris, France
| | - Christine Mouffle
- INSERM, UMR_S 1130, CNRS, UMR 8246, Neuroscience Paris Seine, Institute of Biology Paris Seine, Sorbonne Univ, Paris, France
| | - Hervé Arulkandarajah
- INSERM, UMR_S 1130, CNRS, UMR 8246, Neuroscience Paris Seine, Institute of Biology Paris Seine, Sorbonne Univ, Paris, France
| | - Jean Marie Mangin
- INSERM, UMR_S 1130, CNRS, UMR 8246, Neuroscience Paris Seine, Institute of Biology Paris Seine, Sorbonne Univ, Paris, France
| | - Pascal Legendre
- INSERM, UMR_S 1130, CNRS, UMR 8246, Neuroscience Paris Seine, Institute of Biology Paris Seine, Sorbonne Univ, Paris, France
| | - Antonny Czarnecki
- INSERM, UMR_S 1130, CNRS, UMR 8246, Neuroscience Paris Seine, Institute of Biology Paris Seine, Sorbonne Univ, Paris, France.,Univ. Bordeaux, CNRS, EPHE, INCIA, Bordeaux, France
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22
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Pires J, Nelissen R, Mansvelder HD, Meredith RM. Spontaneous synchronous network activity in the neonatal development of mPFC in mice. Dev Neurobiol 2021; 81:207-225. [PMID: 33453138 PMCID: PMC8048581 DOI: 10.1002/dneu.22811] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/15/2020] [Revised: 12/31/2020] [Accepted: 01/03/2021] [Indexed: 12/28/2022]
Abstract
Spontaneous Synchronous Network Activity (SSA) is a hallmark of neurodevelopment found in numerous central nervous system structures, including neocortex. SSA occurs during restricted developmental time‐windows, commonly referred to as critical periods in sensory neocortex. Although part of the neocortex, the critical period for SSA in the medial prefrontal cortex (mPFC) and the underlying mechanisms for generation and propagation are unknown. Using Ca2+ imaging and whole‐cell patch‐clamp in an acute mPFC slice mouse model, the development of spontaneous activity and SSA was investigated at cellular and network levels during the two first postnatal weeks. The data revealed that developing mPFC neuronal networks are spontaneously active and exhibit SSA in the first two postnatal weeks, with peak synchronous activity at postnatal days (P)8–9. Networks remain active but are desynchronized by the end of this 2‐week period. SSA was driven by excitatory ionotropic glutamatergic transmission with a small contribution of excitatory GABAergic transmission at early time points. The neurohormone oxytocin desynchronized SSA in the first postnatal week only without affecting concurrent spontaneous activity. By the end of the second postnatal week, inhibiting GABAA receptors restored SSA. These findings point to the emergence of GABAA receptor‐mediated inhibition as a major factor in the termination of SSA in mouse mPFC.
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Affiliation(s)
- Johny Pires
- Department of Integrative Neurophysiology, Center for Neurogenomics & Cognitive Research, Faculty of Science, Neuroscience Campus Amsterdam, VU University Amsterdam, Amsterdam, the Netherlands
| | - Rosalie Nelissen
- Department of Integrative Neurophysiology, Center for Neurogenomics & Cognitive Research, Faculty of Science, Neuroscience Campus Amsterdam, VU University Amsterdam, Amsterdam, the Netherlands
| | - Huibert D Mansvelder
- Department of Integrative Neurophysiology, Center for Neurogenomics & Cognitive Research, Faculty of Science, Neuroscience Campus Amsterdam, VU University Amsterdam, Amsterdam, the Netherlands
| | - Rhiannon M Meredith
- Department of Integrative Neurophysiology, Center for Neurogenomics & Cognitive Research, Faculty of Science, Neuroscience Campus Amsterdam, VU University Amsterdam, Amsterdam, the Netherlands
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23
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Medvedeva VP, Pierani A. How Do Electric Fields Coordinate Neuronal Migration and Maturation in the Developing Cortex? Front Cell Dev Biol 2020; 8:580657. [PMID: 33102486 PMCID: PMC7546860 DOI: 10.3389/fcell.2020.580657] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/06/2020] [Accepted: 09/04/2020] [Indexed: 12/13/2022] Open
Abstract
During development the vast majority of cells that will later compose the mature cerebral cortex undergo extensive migration to reach their final position. In addition to intrinsically distinct migratory behaviors, cells encounter and respond to vastly different microenvironments. These range from axonal tracts to cell-dense matrices, electrically active regions and extracellular matrix components, which may all change overtime. Furthermore, migrating neurons themselves not only adapt to their microenvironment but also modify the local niche through cell-cell contacts, secreted factors and ions. In the radial dimension, the developing cortex is roughly divided into dense progenitor and cortical plate territories, and a less crowded intermediate zone. The cortical plate is bordered by the subplate and the marginal zone, which are populated by neurons with high electrical activity and characterized by sophisticated neuritic ramifications. Neuronal migration is influenced by these boundaries resulting in dramatic changes in migratory behaviors as well as morphology and electrical activity. Modifications in the levels of any of these parameters can lead to alterations and even arrest of migration. Recent work indicates that morphology and electrical activity of migrating neuron are interconnected and the aim of this review is to explore the extent of this connection. We will discuss on one hand how the response of migrating neurons is altered upon modification of their intrinsic electrical properties and whether, on the other hand, the electrical properties of the cellular environment can modify the morphology and electrical activity of migrating cortical neurons.
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Affiliation(s)
- Vera P Medvedeva
- Imagine Institute of Genetic Diseases, Université de Paris, Paris, France.,Institute of Psychiatry and Neuroscience of Paris, INSERM U1266, Université de Paris, Paris, France
| | - Alessandra Pierani
- Imagine Institute of Genetic Diseases, Université de Paris, Paris, France.,Institute of Psychiatry and Neuroscience of Paris, INSERM U1266, Université de Paris, Paris, France
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24
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Hunsberger MS, Mynlieff M. BK potassium currents contribute differently to action potential waveform and firing rate as rat hippocampal neurons mature in the first postnatal week. J Neurophysiol 2020; 124:703-714. [DOI: 10.1152/jn.00711.2019] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/17/2022] Open
Abstract
This work describes the early developmental trends of large-conductance calcium-activated potassium (BK) channel activity. Early developmental trends in expression of BK channels, both total expression and relative isoform expression, have been previously reported, but little work describes the effect of these changes in expression patterns on excitability. Here, we show that early changes in BK channel expression patterns lead to changes in the role of BK channels in determining the action potential waveform and neuronal excitability.
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Affiliation(s)
| | - Michelle Mynlieff
- Department of Biological Sciences, Marquette University, Milwaukee, Wisconsin
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25
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The early overgrowth theory of autism spectrum disorder: Insight into convergent mechanisms from valproic acid exposure and translational models. PROGRESS IN MOLECULAR BIOLOGY AND TRANSLATIONAL SCIENCE 2020. [PMID: 32711813 DOI: 10.1016/bs.pmbts.2020.04.014] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 03/02/2024]
Abstract
The development of new approaches for the clinical management of autism spectrum disorder (ASD) can only be realized through a better understanding of the neurobiological changes associated with ASD. One strategy for gaining deeper insight into the neurobiological mechanisms associated with ASD is to identify converging pathogenic processes associated with human idiopathic clinicopathology that are conserved in translational models of ASD. In this chapter, we first present the early overgrowth theory of ASD. Second, we introduce valproic acid (VPA), one of the most robust and well-known environmental risk factors associated with ASD, and we summarize the rapidly growing body of animal research literature using VPA as an ASD translational model. Lastly, we will detail the mechanisms of action of VPA and its impact on functional neural systems, as well as discuss future research directions that could have a lasting impact on the field.
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26
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Evans MG, Al-Shakli A, Chari DM. Electrophysiological properties of neurons grown on soft polymer scaffolds reveal the potential to develop neuromimetic culture environments. Integr Biol (Camb) 2019; 11:395-403. [PMID: 31922538 DOI: 10.1093/intbio/zyz033] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/17/2019] [Revised: 09/28/2019] [Accepted: 10/02/2019] [Indexed: 11/12/2022]
Abstract
Tissue engineering methodologies for various physiological systems are seeing a significant trend towards 3D cell culture in or on 'soft' polymeric hydrogel materials, widely considered to provide a more biomimetic environment for cell growth versus 'hard' materials such as glass or plastic. Progress has been slower with 3D neural cell culture with current studies overwhelmingly reliant on hard substrates. Accordingly, our knowledge of the alterations in electrochemical properties of neurons propagated in soft materials is relatively limited. In this study, primary cortical neurons and glial cells were seeded onto the surface of collagen hydrogels and grown in vitro for 7-8 days. At this time, neurons had formed a complex neurite web interspersed with astrocytes. Neuronal patch clamp recordings revealed voltage-gated Na+ and K+ currents in voltage clamp and action potentials in current clamp. When measured at voltages close to maximum activation, both currents were >1 nA in mean amplitude. When compared to primary cortical neurons cultured on glass coverslips, but otherwise under similar conditions (Evans et al., 2017), the Na+ current from hydrogel neurons was found to be significantly larger although there were no differences in the K+ current amplitude, membrane potential, input resistance or cell capacitance. We speculate that the larger size of the neuronal voltage-dependent Na+ current in the hydrogels is related to the better biomimetic properties of the soft material, being close to values reported for neurons recorded in brain slices. The results highlight the potential benefits offered by neuronal culture on soft and biomimetic polymeric materials for neural tissue engineering studies.
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Affiliation(s)
| | - Arwa Al-Shakli
- School of Medicine, Keele University, Staffordshire ST5 5BG, UK
| | - Divya M Chari
- School of Medicine, Keele University, Staffordshire ST5 5BG, UK
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27
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Slow-Wave Activity in the S1HL Cortex Is Contributed by Different Layer-Specific Field Potential Sources during Development. J Neurosci 2019; 39:8900-8915. [PMID: 31548234 PMCID: PMC6832678 DOI: 10.1523/jneurosci.1212-19.2019] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/24/2019] [Revised: 08/06/2019] [Accepted: 08/27/2019] [Indexed: 01/12/2023] Open
Abstract
Spontaneous correlated activity in cortical columns is critical for postnatal circuit refinement. We used spatial discrimination techniques to explore the late maturation of synaptic pathways through the laminar distribution of the field potential (FP) generators underlying spontaneous and evoked activities of the S1HL cortex in juvenile (P14-P16) and adult anesthetized rats. Juveniles exhibit an intermittent FP pattern resembling Up/Down states in adults, but with much reduced power and different laminar distribution. Whereas FPs in active periods are dominated by a layer VI generator in juveniles, in adults a developing multipart generator takes over, displaying current sinks in middle layers (III-V). The blockade of excitatory transmission in upper and middle layers of adults recovered the juvenile-like FP profiles. In addition to the layer VI generator, a gamma-specific generator in supragranular layers was the same in both age groups. While searching for dynamical coupling among generators in juveniles we found significant cross-correlation in ∼one-half of the tested pairs, whereas excessive coherence hindered their efficient separation in adults. Also, potentials evoked by tactile and electrical stimuli showed different short-latency dipoles between the two age groups, and the juveniles lacked the characteristic long latency UP state currents in middle layers. In addition, the mean firing rate of neurons was lower in juveniles. Thus, cortical FPs originate from different intra-columnar segments as they become active postnatally. We suggest that although some cortical segments are active early postnatally, a functional sensory-motor control relies on a delayed maturation and network integration of synaptic connections in middle layers.SIGNIFICANCE STATEMENT Early postnatal activity in the rodent cortex is mostly endogenous, whereas it becomes driven by peripheral input at later stages. The precise schedule for the maturation of synaptic pathways is largely unknown. We explored this in the somatosensory hindlimb cortex at an age when animals begin to use their limbs by uncovering the laminar distribution of the field potential generators underlying the dominant delta waves in juveniles and adults. Our results suggest that field potentials are mostly generated by a pathway in deep layers, whereas other pathways mature later in middle layers and take over in adults. We suggest that a functional sensory-motor control relies on a delayed maturation and network integration of synaptic connections in middle layers.
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28
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Lucas JA, Schmidt TM. Cellular properties of intrinsically photosensitive retinal ganglion cells during postnatal development. Neural Dev 2019; 14:8. [PMID: 31470901 PMCID: PMC6716945 DOI: 10.1186/s13064-019-0132-2] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/18/2019] [Accepted: 08/12/2019] [Indexed: 01/25/2023] Open
Abstract
BACKGROUND Melanopsin-expressing, intrinsically photosensitive retinal ganglion cells (ipRGCs) respond directly to light and have been shown to mediate a broad variety of visual behaviors in adult animals. ipRGCs are also the first light sensitive cells in the developing retina, and have been implicated in a number of retinal developmental processes such as pruning of retinal vasculature and refinement of retinofugal projections. However, little is currently known about the properties of the six ipRGC subtypes during development, and how these cells act to influence retinal development. We therefore sought to characterize the structure, physiology, and birthdate of the most abundant ipRGC subtypes, M1, M2, and M4, at discrete postnatal developmental timepoints. METHODS We utilized whole cell patch clamp to measure the electrophysiological and morphological properties of ipRGC subtypes through postnatal development. We also used EdU labeling to determine the embryonic timepoints at which ipRGC subtypes terminally differentiate. RESULTS Our data show that ipRGC subtypes are distinguishable from each other early in postnatal development. Additionally, we find that while ipRGC subtypes terminally differentiate at similar embryonic stages, the subtypes reach adult-like morphology and physiology at different developmental timepoints. CONCLUSIONS This work provides a broad assessment of ipRGC morphological and physiological properties during the postnatal stages at which they are most influential in modulating retinal development, and lays the groundwork for further understanding of the specific role of each ipRGC subtype in influencing retinal and visual system development.
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Affiliation(s)
- Jasmine A. Lucas
- Department of Neurobiology, Northwestern University, Evanston, IL USA
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29
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Carrasco M, Stafstrom CE. How Early Can a Seizure Happen? Pathophysiological Considerations of Extremely Premature Infant Brain Development. Dev Neurosci 2019; 40:417-436. [PMID: 30947192 DOI: 10.1159/000497471] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/12/2018] [Accepted: 02/04/2019] [Indexed: 11/19/2022] Open
Abstract
Seizures in neonates represent a neurologic emergency requiring prompt recognition, determination of etiology, and treatment. Yet, the definition and identification of neonatal seizures remain challenging and controversial, in part due to the unique physiology of brain development at this life stage. These issues are compounded when considering seizures in premature infants, in whom the complexities of brain development may engender different clinical and electrographic seizure features at different points in neuronal maturation. In extremely premature infants (< 28 weeks gestational age), seizure pathophysiology has not been explored in detail. This review discusses the physiological and structural development of the brain in this developmental window, focusing on factors that may lead to seizures and their consequences at this early time point. We hypothesize that the clinical and electrographic phenomenology of seizures in extremely preterm infants reflects the specific pathophysiology of brain development in that age window.
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Affiliation(s)
- Melisa Carrasco
- Division of Pediatric Neurology, Department of Neurology, The Johns Hopkins University School of Medicine, Baltimore, Maryland, USA
| | - Carl E Stafstrom
- Division of Pediatric Neurology, Department of Neurology, The Johns Hopkins University School of Medicine, Baltimore, Maryland, USA,
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30
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Alzu’bi A, Homman-Ludiye J, Bourne JA, Clowry GJ. Thalamocortical Afferents Innervate the Cortical Subplate much Earlier in Development in Primate than in Rodent. Cereb Cortex 2019; 29:1706-1718. [PMID: 30668846 PMCID: PMC6418397 DOI: 10.1093/cercor/bhy327] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/18/2018] [Revised: 10/16/2018] [Accepted: 11/29/2018] [Indexed: 12/21/2022] Open
Abstract
The current model, based on rodent data, proposes that thalamocortical afferents (TCA) innervate the subplate towards the end of cortical neurogenesis. This implies that the laminar identity of cortical neurons is specified by intrinsic instructions rather than information of thalamic origin. In order to determine whether this mechanism is conserved in the primates, we examined the growth of thalamocortical (TCA) and corticofugal afferents in early human and monkey fetal development. In the human, TCA, identified by secretagogin, calbindin, and ROBO1 immunoreactivity, were observed in the internal capsule of the ventral telencephalon as early as 7-7.5 PCW, crossing the pallial/subpallial boundary (PSB) by 8 PCW before the calretinin immunoreactive corticofugal fibers do. Furthermore, TCA were observed to be passing through the intermediate zone and innervating the presubplate of the dorsolateral cortex, and already by 10-12 PCW TCAs were occupying much of the cortex. Observations at equivalent stages in the marmoset confirmed that this pattern is conserved across primates. Therefore, our results demonstrate that in primates, TCAs innervate the cortical presubplate at earlier stages than previously demonstrated by acetylcholinesterase histochemistry, suggesting that pioneer thalamic afferents may contribute to early cortical circuitry that can participate in defining cortical neuron phenotypes.
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Affiliation(s)
- Ayman Alzu’bi
- Institute of Neuroscience, Newcastle University, Framlington Place, Newcastle upon Tyne, UK
- Institute of Genetic Medicine, Newcastle University, Newcastle upon Tyne, UK
- Department of Basic Medical Sciences, Faculty of Medicine, Yarmouk University, Irbid, Jordan
| | - Jihane Homman-Ludiye
- Australian Regenerative Medicine Institute, Monash University, Clayton, Victoria, Australia
| | - James A Bourne
- Australian Regenerative Medicine Institute, Monash University, Clayton, Victoria, Australia
| | - Gavin J Clowry
- Institute of Neuroscience, Newcastle University, Framlington Place, Newcastle upon Tyne, UK
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31
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Kroon T, van Hugte E, van Linge L, Mansvelder HD, Meredith RM. Early postnatal development of pyramidal neurons across layers of the mouse medial prefrontal cortex. Sci Rep 2019; 9:5037. [PMID: 30911152 PMCID: PMC6433913 DOI: 10.1038/s41598-019-41661-9] [Citation(s) in RCA: 89] [Impact Index Per Article: 14.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/20/2018] [Accepted: 03/12/2019] [Indexed: 12/24/2022] Open
Abstract
Mammalian neocortex is a highly layered structure. Each layer is populated by distinct subtypes of principal cells that are born at different times during development. While the differences between principal cells across layers have been extensively studied, it is not known how the developmental profiles of neurons in different layers compare. Here, we provide a detailed morphological and functional characterisation of pyramidal neurons in mouse mPFC during the first postnatal month, corresponding to known critical periods for synapse and neuron formation in mouse sensory neocortex. Our data demonstrate similar maturation profiles of dendritic morphology and intrinsic properties of pyramidal neurons in both deep and superficial layers. In contrast, the balance of synaptic excitation and inhibition differs in a layer-specific pattern from one to four postnatal weeks of age. Our characterisation of the early development and maturation of pyramidal neurons in mouse mPFC not only demonstrates a comparable time course of postnatal maturation to that in other neocortical circuits, but also implies that consideration of layer- and time-specific changes in pyramidal neurons may be relevant for studies in mouse models of neuropsychiatric and neurodevelopmental disorders.
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Affiliation(s)
- Tim Kroon
- Department of Integrative Neurophysiology, Center for Neurogenomics & Cognitive Research, Vrije Universiteit Amsterdam, De Boelelaan 1085, 1081 HV, Amsterdam, The Netherlands.
- MRC Centre for Developmental Neurobiology, Institute of Psychiatry, Psychology & Neuroscience, King's College London, New Hunt's House, Guy's Campus, London, SE1 1UL, UK.
| | - Eline van Hugte
- Department of Integrative Neurophysiology, Center for Neurogenomics & Cognitive Research, Vrije Universiteit Amsterdam, De Boelelaan 1085, 1081 HV, Amsterdam, The Netherlands
- Department Cognitive Neurosciences, Department of Human Genetics, Donders Institute for Brain, Cognition and Behaviour, Radboud University Medical Centre, Geert Grooteplein 10 Noord, 6500 HB, Nijmegen, The Netherlands
| | - Lola van Linge
- Department of Integrative Neurophysiology, Center for Neurogenomics & Cognitive Research, Vrije Universiteit Amsterdam, De Boelelaan 1085, 1081 HV, Amsterdam, The Netherlands
- Department of Functional Genomics, Center for Neurogenomics & Cognitive Research, Vrije Universiteit Amsterdam, De Boelelaan 1085, 1081 HV, Amsterdam, The Netherlands
| | - Huibert D Mansvelder
- Department of Integrative Neurophysiology, Center for Neurogenomics & Cognitive Research, Vrije Universiteit Amsterdam, De Boelelaan 1085, 1081 HV, Amsterdam, The Netherlands
| | - Rhiannon M Meredith
- Department of Integrative Neurophysiology, Center for Neurogenomics & Cognitive Research, Vrije Universiteit Amsterdam, De Boelelaan 1085, 1081 HV, Amsterdam, The Netherlands
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32
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Wang D, Enck J, Howell BW, Olson EC. Ethanol Exposure Transiently Elevates but Persistently Inhibits Tyrosine Kinase Activity and Impairs the Growth of the Nascent Apical Dendrite. Mol Neurobiol 2019; 56:5749-5762. [PMID: 30674037 DOI: 10.1007/s12035-019-1473-x] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/04/2018] [Accepted: 01/10/2019] [Indexed: 12/11/2022]
Abstract
Dendritogenesis can be impaired by exposure to alcohol, and aspects of this impairment share phenotypic similarities to dendritic defects observed after blockade of the Reelin-Dab1 tyrosine kinase signaling pathway. In this study, we find that 10 min of alcohol exposure (400 mg/dL ethanol) by itself causes an unexpected increase in tyrosine phosphorylation of many proteins including Src and Dab1 that are essential downstream effectors of Reelin signaling. This increase in phosphotyrosine is dose-dependent and blockable by selective inhibitors of Src Family Kinases (SFKs). However, the response is transient, and phosphotyrosine levels return to baseline after 30 min of continuous ethanol exposure, both in vitro and in vivo. During this latter period, Src is inactivated and Reelin application cannot stimulate Dab1 phosphorylation. This suggests that ethanol initially activates but then silences the Reelin-Dab1 signaling pathway by brief activation and then sustained inactivation of SFKs. Time-lapse analyses of dendritic growth dynamics show an overall decrease in growth and branching compared to controls after ethanol-exposure that is similar to that observed with Reelin-deficiency. However, unlike Reelin-signaling disruptions, the dendritic filopodial speeds are decreased after ethanol exposure, and this decrease is associated with sustained dephosphorylation and activation of cofilin, an F-actin severing protein. These findings suggest that persistent Src inactivation coupled to cofilin activation may contribute to the dendritic disruptions observed with fetal alcohol exposure.
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Affiliation(s)
- Dandan Wang
- Department of Neuroscience and Physiology, SUNY Upstate Medical University, 505 Irving Ave, Syracuse, NY, 13210, USA.,Developmental Exposure to Alcohol Research Center (DEARC), Binghamton University, Binghamton, NY, 13902, USA
| | - Joshua Enck
- Department of Neuroscience and Physiology, SUNY Upstate Medical University, 505 Irving Ave, Syracuse, NY, 13210, USA.,Developmental Exposure to Alcohol Research Center (DEARC), Binghamton University, Binghamton, NY, 13902, USA
| | - Brian W Howell
- Department of Neuroscience and Physiology, SUNY Upstate Medical University, 505 Irving Ave, Syracuse, NY, 13210, USA
| | - Eric C Olson
- Department of Neuroscience and Physiology, SUNY Upstate Medical University, 505 Irving Ave, Syracuse, NY, 13210, USA. .,Developmental Exposure to Alcohol Research Center (DEARC), Binghamton University, Binghamton, NY, 13902, USA.
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33
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Harbom LJ, Rudisill TL, Michel N, Litwa KA, Beenhakker MP, McConnell MJ. The effect of rho kinase inhibition on morphological and electrophysiological maturity in iPSC-derived neurons. Cell Tissue Res 2018; 375:641-654. [PMID: 30406823 DOI: 10.1007/s00441-018-2942-7] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/07/2018] [Accepted: 10/05/2018] [Indexed: 02/07/2023]
Abstract
Induced pluripotent stem cell (iPSC)-derived neurons permit the study of neurogenesis and neurological disease in a human setting. However, the electrophysiological properties of iPSC-derived neurons are consistent with those observed in immature cortical neurons, including a high membrane resistance depolarized resting membrane potential and immature firing properties, limiting their use in modeling neuronal activity in adult cells. Based on the proven association between inhibiting rho kinase (ROCK) and increased neurite complexity, we seek to determine if short-term ROCK inhibition during the first 1-2 weeks of differentiation would increase morphological complexity and electrophysiological maturity after several weeks of differentiation. While inhibiting ROCK resulted in increased neurite formation after 24 h, this effect did not persist at 3 and 6 weeks of age. Additionally, there was no effect of ROCK inhibition on electrophysiological properties at 2-3, 6, or 12 weeks of age, despite an increase in evoked and spontaneous firing and a more hyperpolarized resting membrane potential over time. These results indicate that while there is a clear effect of time on electrophysiological maturity, ROCK inhibition did not accelerate maturity.
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Affiliation(s)
- Lise J Harbom
- Department of Pharmacology, University of Virginia School of Medicine, Charlottesville, VA, 22903, USA
- Department of Biochemistry and Molecular Genetics and Neuroscience, Centers for Brain Immunology and Glia, Public Health Genomics, and Children's Health Research, University of Virginia School of Medicine, Charlottesville, VA, 22903, USA
- Neuroscience Graduate Program, University of Virginia School of Medicine, Charlottesville, VA, USA
| | - Taylor L Rudisill
- Department of Anatomy and Cell Biology, Brody School of Medicine, East Carolina University, Greenville, NC, 27834, USA
| | - Nadine Michel
- Department of Biochemistry and Molecular Genetics and Neuroscience, Centers for Brain Immunology and Glia, Public Health Genomics, and Children's Health Research, University of Virginia School of Medicine, Charlottesville, VA, 22903, USA
- Neuroscience Graduate Program, University of Virginia School of Medicine, Charlottesville, VA, USA
| | - Karen A Litwa
- Department of Anatomy and Cell Biology, Brody School of Medicine, East Carolina University, Greenville, NC, 27834, USA
| | - Mark P Beenhakker
- Department of Pharmacology, University of Virginia School of Medicine, Charlottesville, VA, 22903, USA.
| | - Michael J McConnell
- Department of Biochemistry and Molecular Genetics and Neuroscience, Centers for Brain Immunology and Glia, Public Health Genomics, and Children's Health Research, University of Virginia School of Medicine, Charlottesville, VA, 22903, USA.
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34
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Berry BJ, Smith AST, Long CJ, Martin CC, Hickman JJ. Physiological Aβ Concentrations Produce a More Biomimetic Representation of the Alzheimer's Disease Phenotype in iPSC Derived Human Neurons. ACS Chem Neurosci 2018; 9:1693-1701. [PMID: 29746089 DOI: 10.1021/acschemneuro.8b00067] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/17/2023] Open
Abstract
Alzheimer's disease (AD) is characterized by slow, progressive neurodegeneration leading to severe neurological impairment, but current drug development efforts are limited by the lack of robust, human-based disease models. Amyloid-β (Aβ) is known to play an integral role in AD progression as it has been shown to interfere with neurological function. However, studies into AD pathology commonly apply Aβ to neurons for short durations at nonphysiological concentrations to induce an exaggerated dysfunctional phenotype. Such methods are unlikely to elucidate early stage disease dysfunction, when treatment is still possible, since damage to neurons by these high concentrations is extensive. In this study, we investigated chronic, pathologically relevant Aβ oligomer concentrations to induce an electrophysiological phenotype that is more representative of early AD progression compared to an acute high-dose application in human cortical neurons. The high, acute oligomer dose resulted in severe neuronal toxicity as well as upregulation of tau and phosphorylated tau. Chronic, low-dose treatment produced significant functional impairment without increased cell death or accumulation of tau protein. This in vitro phenotype more closely mirrors the status of early stage neural decline in AD pathology and could provide a valuable tool to further understanding of early stage AD pathophysiology and for screening potential therapeutic compounds.
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Affiliation(s)
- Bonnie J. Berry
- NanoScience Technology Center, University of Central Florida, 12424 Research Parkway, Suite 400, Orlando, Florida 32826 United States
| | - Alec S. T. Smith
- NanoScience Technology Center, University of Central Florida, 12424 Research Parkway, Suite 400, Orlando, Florida 32826 United States
| | - Christopher J. Long
- NanoScience Technology Center, University of Central Florida, 12424 Research Parkway, Suite 400, Orlando, Florida 32826 United States
| | - Candace C. Martin
- NanoScience Technology Center, University of Central Florida, 12424 Research Parkway, Suite 400, Orlando, Florida 32826 United States
| | - James J. Hickman
- NanoScience Technology Center, University of Central Florida, 12424 Research Parkway, Suite 400, Orlando, Florida 32826 United States
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35
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Cortical and spinal conditioned media modify the inward ion currents and excitability and promote differentiation of human striatal primordium. J Chem Neuroanat 2018; 90:87-97. [DOI: 10.1016/j.jchemneu.2017.12.005] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/02/2017] [Revised: 12/19/2017] [Accepted: 12/19/2017] [Indexed: 11/18/2022]
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36
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Anastasiades PG, Marques‐Smith A, Butt SJB. Studies of cortical connectivity using optical circuit mapping methods. J Physiol 2018; 596:145-162. [PMID: 29110301 PMCID: PMC5767689 DOI: 10.1113/jp273463] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/21/2017] [Accepted: 10/11/2017] [Indexed: 11/08/2022] Open
Abstract
An important consideration when probing the function of any neuron is to uncover the source of synaptic input onto the cell, its intrinsic physiology and efferent targets. Over the years, electrophysiological approaches have generated considerable insight into these properties in a variety of cortical neuronal subtypes and circuits. However, as researchers explore neuronal function in greater detail, they are increasingly turning to optical techniques to bridge the gap between local network interactions and behaviour. The application of optical methods has increased dramatically over the past decade, spurred on by the optogenetic revolution. In this review, we provide an account of recent innovations, providing researchers with a primer detailing circuit mapping strategies in the cerebral cortex. We will focus on technical aspects of performing neurotransmitter uncaging and channelrhodopsin-assisted circuit mapping, with the aim of identifying common pitfalls that can negatively influence the collection of reliable data.
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Gawlak M, Szulczyk B, Berłowski A, Grzelka K, Stachurska A, Pełka J, Czarzasta K, Małecki M, Kurowski P, Nurowska E, Szulczyk P. Age-dependent expression of Nav1.9 channels in medial prefrontal cortex pyramidal neurons in rats. Dev Neurobiol 2017; 77:1371-1384. [PMID: 28913981 DOI: 10.1002/dneu.22537] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/31/2017] [Revised: 09/08/2017] [Accepted: 09/10/2017] [Indexed: 12/19/2022]
Abstract
Developmental changes that occur in the prefrontal cortex during adolescence alter behavior. These behavioral alterations likely stem from changes in prefrontal cortex neuronal activity, which may depend on the properties and expression of ion channels. Nav1.9 sodium channels conduct a Na+ current that is TTX resistant with a low threshold and noninactivating over time. The purpose of this study was to assess the presence of Nav1.9 channels in medial prefrontal cortex (mPFC) layer II and V pyramidal neurons in young (20-day old), late adolescent (60-day old), and adult (6- to 7-month old) rats. First, we demonstrated that layer II and V mPFC pyramidal neurons in slices obtained from young rats exhibited a TTX-resistant, low-threshold, noninactivating, and voltage-dependent Na+ current. The mRNA expression of the SCN11a gene (which encodes the Nav1.9 channel) in mPFC tissue was significantly higher in young rats than in late adolescent and adult rats. Nav1.9 protein was immunofluorescently labeled in mPFC cells in slices and analyzed via confocal microscopy. Nav1.9 immunolabeling was present in layer II and V mPFC pyramidal neurons and was more prominent in the neurons of young rats than in the neurons of late adolescent and adult rats. We conclude that Nav1.9 channels are expressed in layer II and V mPFC pyramidal neurons and that Nav1.9 protein expression in the mPFC pyramidal neurons of late adolescent and adult rats is lower than that in the neurons of young rats. © 2017 Wiley Periodicals, Inc. Develop Neurobiol 77: 1371-1384, 2017.
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Affiliation(s)
- Maciej Gawlak
- Laboratory of Physiology and Pathophysiology, Centre for Preclinical Research and Technology, The Medical University of Warsaw, Warsaw, Poland
| | - Bartłomiej Szulczyk
- Department of Drug Technology and Pharmaceutical Biotechnology, The Medical University of Warsaw, Warsaw, Poland
| | - Adam Berłowski
- Department of Physiology and Pathophysiology, The Medical University of Warsaw, Warsaw, Poland
| | - Katarzyna Grzelka
- Laboratory of Physiology and Pathophysiology, Centre for Preclinical Research and Technology, The Medical University of Warsaw, Warsaw, Poland
| | - Anna Stachurska
- Department of Molecular Biology, The Medical University of Warsaw, Warsaw, Poland
| | - Justyna Pełka
- Department of Physiology and Pathophysiology, The Medical University of Warsaw, Warsaw, Poland
| | - Katarzyna Czarzasta
- Laboratory of Experimental and Clinical Physiology, Centre for Preclinical Research, Medical University of Warsaw, Warsaw, Poland
| | - Maciej Małecki
- Department of Molecular Biology, The Medical University of Warsaw, Warsaw, Poland
| | - Przemysław Kurowski
- Laboratory of Physiology and Pathophysiology, Centre for Preclinical Research and Technology, The Medical University of Warsaw, Warsaw, Poland
| | - Ewa Nurowska
- Laboratory of Physiology and Pathophysiology, Centre for Preclinical Research and Technology, The Medical University of Warsaw, Warsaw, Poland
| | - Paweł Szulczyk
- Laboratory of Physiology and Pathophysiology, Centre for Preclinical Research and Technology, The Medical University of Warsaw, Warsaw, Poland
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Kumar A, Dudhal S, Sundari T A, Sunkara M, Usman H, Varshney A, Mukhopadhyay A. Dopaminergic-primed fetal liver mesenchymal stromal-like cells can reverse parkinsonian symptoms in 6-hydroxydopamine-lesioned mice. Cytotherapy 2016; 18:307-19. [PMID: 26857226 DOI: 10.1016/j.jcyt.2015.11.007] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/05/2015] [Accepted: 10/12/2015] [Indexed: 02/07/2023]
Abstract
BACKGROUND AIMS Cell replacement therapy is considered a promising alternative in the treatment of degenerative diseases, and in this context, mesenchymal stromal cells (MSCs) have been proposed for transplantation in Parkinson disease (PD). Thus far, the results of animal studies are found to be inconsistent and inconclusive regarding the therapeutic ability of the cells. This study investigated the efficacy of fetal liver (FL)-MSC-derived dopaminergic (DA) neuronal primed cells for correction of parkinsonian symptoms in mice. METHODS FL-MSCs were differentiated for 21 days in the presence of a combination of neurotropic factors. The extent of cellular reprogramming was analyzed by quantitative polymerase chain reaction for DA-specific neuronal gene expressions and protein expressions by immuno-cytochemistry. The functionality of the cells was determined by electrophysiology and dopamine release assays. Ten-day-primed neuron-like cells or unprimed MSCs were transplanted into the 6-hydroxydopamine (6-OHDA)-lesioned striatum using a stereotaxic device. Dopamine-secreting properties and behavioral studies were used to assess improvement of parkinsonian symptoms. RESULTS The differentiated cells expressed DA-specific genes and proteins, while exhibiting a high level of voltage-gated potassium current. Furthermore, neuronal primed cells differentiated into tyrosine hydroxylase immunoreactive and dopamine-secreting functional neuron-like cells. Symptomatic correction of PD in the recipient mice within 2 months of transplantation was also observed. DISCUSSION FL-MSC-derived primed neuron-like cells integrated into the striatum of PD mice, improving parkinsonian symptoms. This study demonstrates an effective cell-based therapy for PD.
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Affiliation(s)
- Amit Kumar
- Stem Cell Biology Laboratory, National Institute of Immunology, Aruna Asaf Ali Marg, New Delhi, India
| | - Swati Dudhal
- Stem Cell Biology Laboratory, National Institute of Immunology, Aruna Asaf Ali Marg, New Delhi, India
| | - Abinaya Sundari T
- Stem Cell Biology Laboratory, National Institute of Immunology, Aruna Asaf Ali Marg, New Delhi, India
| | | | - Hyder Usman
- Daiichi Sankyo India Pharma Pvt Ltd, Village Sarhaul, Gurgaon, India
| | - Anurag Varshney
- Daiichi Sankyo India Pharma Pvt Ltd, Village Sarhaul, Gurgaon, India
| | - Asok Mukhopadhyay
- Stem Cell Biology Laboratory, National Institute of Immunology, Aruna Asaf Ali Marg, New Delhi, India.
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Yavorska I, Wehr M. Somatostatin-Expressing Inhibitory Interneurons in Cortical Circuits. Front Neural Circuits 2016; 10:76. [PMID: 27746722 PMCID: PMC5040712 DOI: 10.3389/fncir.2016.00076] [Citation(s) in RCA: 111] [Impact Index Per Article: 12.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/11/2016] [Accepted: 09/12/2016] [Indexed: 12/30/2022] Open
Abstract
Cortical inhibitory neurons exhibit remarkable diversity in their morphology, connectivity, and synaptic properties. Here, we review the function of somatostatin-expressing (SOM) inhibitory interneurons, focusing largely on sensory cortex. SOM neurons also comprise a number of subpopulations that can be distinguished by their morphology, input and output connectivity, laminar location, firing properties, and expression of molecular markers. Several of these classes of SOM neurons show unique dynamics and characteristics, such as facilitating synapses, specific axonal projections, intralaminar input, and top-down modulation, which suggest possible computational roles. SOM cells can be differentially modulated by behavioral state depending on their class, sensory system, and behavioral paradigm. The functional effects of such modulation have been studied with optogenetic manipulation of SOM cells, which produces effects on learning and memory, task performance, and the integration of cortical activity. Different classes of SOM cells participate in distinct disinhibitory circuits with different inhibitory partners and in different cortical layers. Through these disinhibitory circuits, SOM cells help encode the behavioral relevance of sensory stimuli by regulating the activity of cortical neurons based on subcortical and intracortical modulatory input. Associative learning leads to long-term changes in the strength of connectivity of SOM cells with other neurons, often influencing the strength of inhibitory input they receive. Thus despite their heterogeneity and variability across cortical areas, current evidence shows that SOM neurons perform unique neural computations, forming not only distinct molecular but also functional subclasses of cortical inhibitory interneurons.
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Affiliation(s)
| | - Michael Wehr
- Institute of Neuroscience and Department of Psychology, University of OregonEugene, OR, USA
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M Hao M. Development of Neural Activity in the Enteric Nervous System: Similarities and Differences to Other Parts of the Nervous System. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2016; 891:43-51. [PMID: 27379633 DOI: 10.1007/978-3-319-27592-5_5] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 02/25/2023]
Abstract
All the neurons and glia of the enteric nervous system (ENS) arise from neural crest-derived cells that migrate into the gastrointestinal (GI) tract during development (Yntema and Hammond 1954; Le Douarin and Teillet 1973). Most of the ENS originates from vagal neural crest cells (NCCs), which arise from the caudal hindbrain region of the neural tube, adjacent to somites 1-7. In the developing mouse, vagal NCCs migrate into the developing oesophagus and stomach at embryonic day (E)9.5, enter the small intestine at E10.5, and colonise the developing GI tract in a rostral-to-caudal wave, reaching the anal end of the colon at E14.5 (Serbedzija et al. 1991; Kapur et al. 1992; Anderson et al. 2006). Recent evidence indicates that there is also trans-mesenteric migration of vagal NCCs, where some NCCs leave the small intestine and migrate directly across the mesentery into the colon (Nishiyama et al. 2012). Sacral NCCs also contribute to a small population of neurons and glia in the colon (Burns and Le Douarin 1998; Wang et al. 2011).
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Affiliation(s)
- Marlene M Hao
- Laboratory for Enteric Neuroscience, TARGID, University of Leuven, Herestraat 49, O&N1, Box 701, Leuven, 3000, Belgium.
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Squecco R, Idrizaj E, Morelli A, Gallina P, Vannelli GB, Francini F. An electrophysiological study on the effects of BDNF and FGF2 on voltage dependent Ca(2+) currents in developing human striatal primordium. Mol Cell Neurosci 2016; 75:50-62. [PMID: 27370937 DOI: 10.1016/j.mcn.2016.06.008] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/31/2016] [Revised: 05/24/2016] [Accepted: 06/27/2016] [Indexed: 01/06/2023] Open
Abstract
Over the past decades, studies in both Huntington's disease animal models and pilot clinical trials have demonstrated that replacement of degenerated striatum and repair of circuitries by grafting fetal striatal primordium is feasible, safe and may counteract disease progression. However, a better comprehension of striatal ontogenesis is required to assess the fetal graft regenerative potential. During neuronal development, neurotrophins exert pleiotropic actions in regulating cell fate and synaptic plasticity. In this regard, brain-derived neurotrophic factor (BDNF) and fibroblast growth factor 2 (FGF2) are crucially implicated in the control of fate choice of striatal progenitor cells. In this study, we intended to refine the functional features of human striatal precursor (HSP) cells isolated from ganglionic eminence of 9-12week old human fetuses, by studying with electrophysiological methods the effect of BDNF and FGF2 on the membrane biophysical properties and the voltage-dependent Ca(2+) currents. These features are particularly relevant to evaluate neuronal cell functioning and can be considered reliable markers of the developmental phenotype of human striatal primordium. Our results have demonstrated that BDNF and FGF2 induced membrane hyperpolarization, increased the membrane capacitance and reduced the resting total and specific conductance values, suggesting a more efficient control of resting ionic fluxes. Moreover, the treatment with both neurotrophins enhanced N-type Ca(2+) current amplitude and reduced L- and T-type ones. Overall, our data indicate that BDNF and FGF2 may help HSP cells to attain a more functionally mature phenotype.
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Affiliation(s)
- Roberta Squecco
- Department of Experimental and Clinical Medicine, Section of Physiological Sciences, University of Florence, viale Morgagni 63, 50134 Florence, Italy.
| | - Eglantina Idrizaj
- Department of Experimental and Clinical Medicine, Section of Physiological Sciences, University of Florence, viale Morgagni 63, 50134 Florence, Italy
| | - Annamaria Morelli
- Department of Experimental and Clinical Medicine, Section of Anatomy and Histology, University of Florence, Largo Brambilla 3, 50134 Florence, Italy
| | - Pasquale Gallina
- Department of Surgery and Translational Medicine, University of Florence, Largo Palagi 1, 50139 Florence, Italy
| | - Gabriella B Vannelli
- Department of Experimental and Clinical Medicine, Section of Anatomy and Histology, University of Florence, Largo Brambilla 3, 50134 Florence, Italy
| | - Fabio Francini
- Department of Experimental and Clinical Medicine, Section of Physiological Sciences, University of Florence, viale Morgagni 63, 50134 Florence, Italy
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Chomiak T, Hung J, Nguyen MD, Hu B. Somato-dendritic decoupling as a novel mechanism for protracted cortical maturation. BMC Biol 2016; 14:48. [PMID: 27328836 PMCID: PMC4916537 DOI: 10.1186/s12915-016-0270-5] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/26/2016] [Accepted: 06/06/2016] [Indexed: 12/20/2022] Open
Abstract
BACKGROUND Both human and animal data indicate that disruption of the endogenously slow maturation of temporal association cortical (TeA) networks is associated with abnormal higher order cognitive development. However, the neuronal mechanisms underlying the endogenous maturation delay of the TeA are poorly understood. RESULTS Here we report a novel form of developmental plasticity that is present in the TeA. It was found that deep layer TeA neurons, but not hippocampal or primary visual neurons, exist in a protracted 'embryonic-like' state through a mechanism involving reduced somato-dendritic communication and a non-excitable somatic membrane. This mechanism of neural inactivity is present in intact tissue and shows a remarkable transition into an active somato-dendritically coupled state. The quantity of decoupled cells diminishes in a protracted and age-dependent manner, continuing into adolescence. CONCLUSIONS Based on our data, we propose a model of neural plasticity through which protracted compartmentalization and decoupling in somato-dendritic signalling plays a key role in controlling how excitable neurons are incorporated into recurrent cortical networks independent of neurogenesis.
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Affiliation(s)
- Taylor Chomiak
- Division of Translational Neuroscience, Department of Clinical Neurosciences, Hotchkiss Brain Institute, Cumming School of Medicine, University of Calgary, 3330 Hospital Drive NW, Calgary, Alberta, T2N 4N1, Canada.
| | - Johanna Hung
- Division of Translational Neuroscience, Department of Clinical Neurosciences, Hotchkiss Brain Institute, Cumming School of Medicine, University of Calgary, 3330 Hospital Drive NW, Calgary, Alberta, T2N 4N1, Canada
| | - Minh Dang Nguyen
- Division of Translational Neuroscience, Department of Clinical Neurosciences, Hotchkiss Brain Institute, Cumming School of Medicine, University of Calgary, 3330 Hospital Drive NW, Calgary, Alberta, T2N 4N1, Canada
| | - Bin Hu
- Division of Translational Neuroscience, Department of Clinical Neurosciences, Hotchkiss Brain Institute, Cumming School of Medicine, University of Calgary, 3330 Hospital Drive NW, Calgary, Alberta, T2N 4N1, Canada.
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Hernan AE, Holmes GL. Antiepileptic drug treatment strategies in neonatal epilepsy. PROGRESS IN BRAIN RESEARCH 2016; 226:179-93. [PMID: 27323943 DOI: 10.1016/bs.pbr.2016.03.011] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Abstract
The highest risk of seizures across the lifespan is in the neonatal period. The enhanced excitability of the immature brain compared to the mature brain is related to the sequential development and expression of essential neurotransmitter signaling pathways. During the neonatal period there is an overabundance of excitatory receptors, and γ-amino-butyric acid (GABA) is potentially depolarizing, as opposed to hyperpolarizing in the older brain. While this enhanced excitability is required for regulation of activity-dependent synapse formation and refining of synaptic connections that are necessary for normal brain development, enhanced excitability predisposes the immature brain to seizures. In addition to being common, neonatal seizures are very difficult to treat; antiepileptic drugs used in older children and adults are less efficacious, and possibly detrimental to brain development. In an effort to target the unique features of neurotransmission in the neonate, bumetanide, an NKCC1 inhibitor which reduces intraneuronal Cl(-) and induces a significant shift of EGABA toward more hyperpolarized values in vitro, has been used to treat neonatal seizures. As the understanding of the pathophysiology of genetic forms of neonatal epilepsy has evolved there have been a few successful attempts to pharmacologically target the mutated protein. This approach, while promising, is challenging due to the findings that the genetic syndromes presenting in infancy demonstrate genetic heterogeneity in regard to both the mutated gene and its function.
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Affiliation(s)
- A E Hernan
- University of Vermont College of Medicine, Burlington, VT, United States
| | - G L Holmes
- University of Vermont College of Medicine, Burlington, VT, United States.
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Easton CR, Dickey CW, Moen SP, Neuzil KE, Barger Z, Anderson TM, Moody WJ, Hevner RF. Distinct calcium signals in developing cortical interneurons persist despite disorganization of cortex by Tbr1 KO. Dev Neurobiol 2015; 76:705-20. [PMID: 26473411 DOI: 10.1002/dneu.22354] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/05/2015] [Revised: 10/08/2015] [Accepted: 10/12/2015] [Indexed: 11/05/2022]
Abstract
Cortical development involves the structuring of network features by genetically programmed molecular signaling pathways. Additionally, spontaneous ion channel activity refines neuronal connections. We examine Ca(2+) fluctuations in the first postnatal week of normal mouse neocortex and that expressing knockout of the transcription factor T-brain-1 (Tbr1): a signaling molecule in cortical patterning and differentiation of excitatory neurons. In cortex, glutamatergic neurons express Tbr1 just before the onset of population electrical activity that is accompanied by intracellular Ca(2+) increases. It is known that glutamatergic cells are disordered with Tbr1 KO such that normal laying of the cortex, with newer born cells residing in superficial layers, does not occur. However, the fate of cortical interneurons is not well studied, nor is the ability of Tbr1 deficient cortex to express normal physiological activity. Using fluorescent proteins targeted to interneurons, we find that cortical interneurons are also disordered in the Tbr1 knockout. Using Ca(2+) imaging we find that population activity in mutant cortex occurs at normal frequencies with similar sensitivity to GABAA receptor blockade as in nonmutant cortex. Finally, using multichannel fluorescence imaging of Ca(2+) indicator dye and interneurons labeled with red fluorescent protein, we identify an additional Ca(2+) signal in interneurons distinct from population activity and with different pharmacological sensitivities. Our results show the population activity described here is a robust property of the developing network that continues in the absence of an important signaling molecule, Tbr1, and that cortical interneurons generate distinct forms of activity that may serve different developmental functions. © 2015 Wiley Periodicals, Inc. Develop Neurobiol 76: 705-720, 2016.
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Affiliation(s)
- C R Easton
- Department of Biology, University of Washington, Seattle, Washington, 98195.,Center for Integrative Brain Research, Seattle Children's Research Institute, Seattle, Washington, 98101
| | - C W Dickey
- Department of Biology, University of Washington, Seattle, Washington, 98195
| | - S P Moen
- Department of Biology, University of Washington, Seattle, Washington, 98195
| | - K E Neuzil
- Department of Biology, University of Washington, Seattle, Washington, 98195
| | - Z Barger
- Department of Biology, University of Washington, Seattle, Washington, 98195
| | - T M Anderson
- Department of Biology, University of Washington, Seattle, Washington, 98195
| | - W J Moody
- Department of Biology, University of Washington, Seattle, Washington, 98195
| | - R F Hevner
- Department of Biology, University of Washington, Seattle, Washington, 98195.,Department of Neurological Surgery, University of Washington, Seattle, Washington, 98195.,Center for Integrative Brain Research, Seattle Children's Research Institute, Seattle, Washington, 98101
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Iovino M, Agathou S, González-Rueda A, Del Castillo Velasco-Herrera M, Borroni B, Alberici A, Lynch T, O'Dowd S, Geti I, Gaffney D, Vallier L, Paulsen O, Káradóttir RT, Spillantini MG. Early maturation and distinct tau pathology in induced pluripotent stem cell-derived neurons from patients with MAPT mutations. Brain 2015; 138:3345-59. [PMID: 26220942 PMCID: PMC4620511 DOI: 10.1093/brain/awv222] [Citation(s) in RCA: 113] [Impact Index Per Article: 11.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/21/2015] [Revised: 07/02/2015] [Accepted: 07/08/2015] [Indexed: 02/02/2023] Open
Abstract
Tauopathies, such as Alzheimer's disease, some cases of frontotemporal dementia, corticobasal degeneration and progressive supranuclear palsy, are characterized by aggregates of the microtubule-associated protein tau, which are linked to neuronal death and disease development and can be caused by mutations in the MAPT gene. Six tau isoforms are present in the adult human brain and they differ by the presence of 3(3R) or 4(4R) C-terminal repeats. Only the shortest 3R isoform is present in foetal brain. MAPT mutations found in human disease affect tau binding to microtubules or the 3R:4R isoform ratio by altering exon 10 splicing. We have differentiated neurons from induced pluripotent stem cells derived from fibroblasts of controls and patients with N279K and P301L MAPT mutations. Induced pluripotent stem cell-derived neurons recapitulate developmental tau expression, showing the adult brain tau isoforms after several months in culture. Both N279K and P301L neurons exhibit earlier electrophysiological maturation and altered mitochondrial transport compared to controls. Specifically, the N279K neurons show abnormally premature developmental 4R tau expression, including changes in the 3R:4R isoform ratio and AT100-hyperphosphorylated tau aggregates, while P301L neurons are characterized by contorted processes with varicosity-like structures, some containing both alpha-synuclein and 4R tau. The previously unreported faster maturation of MAPT mutant human neurons, the developmental expression of 4R tau and the morphological alterations may contribute to disease development.
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Affiliation(s)
- Mariangela Iovino
- 1 Department of Clinical Neurosciences, Clifford Allbutt Building, University of Cambridge, Cambridge, UK
| | - Sylvia Agathou
- 2 Wellcome-Trust Medical Research Council Stem Cell Institute and Department of Veterinary Medicine, University of Cambridge, Cambridge, UK
| | - Ana González-Rueda
- 3 Department of Physiology, Development and Neuroscience, Physiological Laboratory, University of Cambridge, Cambridge, UK
| | | | - Barbara Borroni
- 5 Department of Neurological Sciences, University of Brescia, Brescia, Italy
| | - Antonella Alberici
- 5 Department of Neurological Sciences, University of Brescia, Brescia, Italy
| | - Timothy Lynch
- 6 Dublin Neurological Institute, Mater Misericordiae University Hospital and Conway Institute of Biomolecular and Biomedical Research, University College Dublin, Dublin Ireland
| | - Sean O'Dowd
- 6 Dublin Neurological Institute, Mater Misericordiae University Hospital and Conway Institute of Biomolecular and Biomedical Research, University College Dublin, Dublin Ireland
| | - Imbisaat Geti
- 7 Wellcome Trust-Medical Research Council Stem Cell Institute, Anne McLaren Laboratory, Department of Surgery, University of Cambridge, Cambridge UK
| | - Daniel Gaffney
- 4 Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, Cambridge, UK
| | - Ludovic Vallier
- 4 Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, Cambridge, UK 7 Wellcome Trust-Medical Research Council Stem Cell Institute, Anne McLaren Laboratory, Department of Surgery, University of Cambridge, Cambridge UK
| | - Ole Paulsen
- 3 Department of Physiology, Development and Neuroscience, Physiological Laboratory, University of Cambridge, Cambridge, UK
| | - Ragnhildur Thóra Káradóttir
- 2 Wellcome-Trust Medical Research Council Stem Cell Institute and Department of Veterinary Medicine, University of Cambridge, Cambridge, UK
| | - Maria Grazia Spillantini
- 1 Department of Clinical Neurosciences, Clifford Allbutt Building, University of Cambridge, Cambridge, UK
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Berry BJ, Akanda N, Smith AST, Long CJ, Schnepper MT, Guo X, Hickman JJ. Morphological and functional characterization of human induced pluripotent stem cell-derived neurons (iCell Neurons) in defined culture systems. Biotechnol Prog 2015; 31:1613-22. [PMID: 26317319 DOI: 10.1002/btpr.2160] [Citation(s) in RCA: 21] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/08/2015] [Revised: 08/20/2015] [Indexed: 01/09/2023]
Abstract
Pre-clinical testing of drug candidates in animal models is expensive, time-consuming, and often fails to predict drug effects in humans. Industry and academia alike are working to build human-based in vitro test beds and advanced high throughput screening systems to improve the translation of preclinical results to human drug trials. Human neurons derived from induced pluripotent stems cells (hiPSCs) are readily available for use within these test-beds and high throughput screens, but there remains a need to robustly evaluate cellular behavior prior to their incorporation in such systems. This study reports on the characterization of one source of commercially available hiPSC-derived neurons, iCell(®) Neurons, for their long-term viability and functional performance to assess their suitability for integration within advanced in vitro platforms. The purity, morphology, survival, identity, and functional maturation of the cells utilizing different culture substrates and medium combinations were evaluated over 28 days in vitro (DIV). Patch-clamp electrophysiological data demonstrated increased capacity for repetitive firing of action potentials across all culture conditions. Significant differences in cellular maturity, morphology, and functional performance were observed in the different conditions, highlighting the importance of evaluating different surface types and growth medium compositions for application in specific in vitro protocols.
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Affiliation(s)
- Bonnie J Berry
- NanoScience Technology Center, University of Central Florida, 12424 Research Parkway, Suite 400, Orlando, FL, 32826
| | - Nesar Akanda
- NanoScience Technology Center, University of Central Florida, 12424 Research Parkway, Suite 400, Orlando, FL, 32826
| | - Alec S T Smith
- NanoScience Technology Center, University of Central Florida, 12424 Research Parkway, Suite 400, Orlando, FL, 32826
| | - Christopher J Long
- NanoScience Technology Center, University of Central Florida, 12424 Research Parkway, Suite 400, Orlando, FL, 32826
| | - Mark T Schnepper
- NanoScience Technology Center, University of Central Florida, 12424 Research Parkway, Suite 400, Orlando, FL, 32826
| | - Xiufang Guo
- NanoScience Technology Center, University of Central Florida, 12424 Research Parkway, Suite 400, Orlando, FL, 32826
| | - James J Hickman
- NanoScience Technology Center, University of Central Florida, 12424 Research Parkway, Suite 400, Orlando, FL, 32826
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Bradford AB, McNutt PM. Importance of being Nernst: Synaptic activity and functional relevance in stem cell-derived neurons. World J Stem Cells 2015; 7:899-921. [PMID: 26240679 PMCID: PMC4515435 DOI: 10.4252/wjsc.v7.i6.899] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/19/2014] [Revised: 02/28/2015] [Accepted: 05/11/2015] [Indexed: 02/06/2023] Open
Abstract
Functional synaptogenesis and network emergence are signature endpoints of neurogenesis. These behaviors provide higher-order confirmation that biochemical and cellular processes necessary for neurotransmitter release, post-synaptic detection and network propagation of neuronal activity have been properly expressed and coordinated among cells. The development of synaptic neurotransmission can therefore be considered a defining property of neurons. Although dissociated primary neuron cultures readily form functioning synapses and network behaviors in vitro, continuously cultured neurogenic cell lines have historically failed to meet these criteria. Therefore, in vitro-derived neuron models that develop synaptic transmission are critically needed for a wide array of studies, including molecular neuroscience, developmental neurogenesis, disease research and neurotoxicology. Over the last decade, neurons derived from various stem cell lines have shown varying ability to develop into functionally mature neurons. In this review, we will discuss the neurogenic potential of various stem cells populations, addressing strengths and weaknesses of each, with particular attention to the emergence of functional behaviors. We will propose methods to functionally characterize new stem cell-derived neuron (SCN) platforms to improve their reliability as physiological relevant models. Finally, we will review how synaptically active SCNs can be applied to accelerate research in a variety of areas. Ultimately, emphasizing the critical importance of synaptic activity and network responses as a marker of neuronal maturation is anticipated to result in in vitro findings that better translate to efficacious clinical treatments.
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Brizuela M, Blizzard CA, Chuckowree JA, Dawkins E, Gasperini RJ, Young KM, Dickson TC. The microtubule-stabilizing drug Epothilone D increases axonal sprouting following transection injury in vitro. Mol Cell Neurosci 2015; 66:129-40. [PMID: 25684676 DOI: 10.1016/j.mcn.2015.02.006] [Citation(s) in RCA: 31] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/30/2014] [Revised: 02/03/2015] [Accepted: 02/06/2015] [Indexed: 11/26/2022] Open
Abstract
Neuronal cytoskeletal alterations, in particular the loss and misalignment of microtubules, are considered a hallmark feature of the degeneration that occurs after traumatic brain injury (TBI). Therefore, microtubule-stabilizing drugs are attractive potential therapeutics for use following TBI. The best-known drug in this category is Paclitaxel, a widely used anti-cancer drug that has produced promising outcomes when employed in the treatment of various animal models of nervous system trauma. However, Paclitaxel is not ideal for the treatment of patients with TBI due to its limited blood-brain barrier (BBB) permeability. Herein we have characterized the effect of the brain penetrant microtubule-stabilizing agent Epothilone D (Epo D) on post-injury axonal sprouting in an in vitro model of CNS trauma. Epo D was found to modulate axonal sprout number in a dose dependent manner, increasing the number of axonal sprouts generated post-injury. Elevated sprouting was observed when analyzing the total population of injured neurons, as well as in selective analysis of Thy1-YFP-labeled excitatory neurons. However, we found no effect of Epo D on axonal sprout length or outgrowth speed. These findings indicate that Epo D specifically affects injury-induced axonal sprout generation, but not net growth. Our investigation demonstrates that primary cultures of cortical neurons are tolerant of Epo D exposure, and that Epo D significantly increases their regenerative response following structural injury. Therefore Epo D may be a potent therapeutic for enhancing regeneration following CNS injury. This article is part of a Special Issue entitled 'Traumatic Brain Injury'.
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Affiliation(s)
- Mariana Brizuela
- Menzies Institute for Medical Research Tasmania, University of Tasmania, Hobart, Tasmania 7000, Australia
| | - Catherine A Blizzard
- Menzies Institute for Medical Research Tasmania, University of Tasmania, Hobart, Tasmania 7000, Australia
| | - Jyoti A Chuckowree
- Menzies Institute for Medical Research Tasmania, University of Tasmania, Hobart, Tasmania 7000, Australia
| | - Edgar Dawkins
- Menzies Institute for Medical Research Tasmania, University of Tasmania, Hobart, Tasmania 7000, Australia
| | - Robert J Gasperini
- Menzies Institute for Medical Research Tasmania, University of Tasmania, Hobart, Tasmania 7000, Australia
| | - Kaylene M Young
- Menzies Institute for Medical Research Tasmania, University of Tasmania, Hobart, Tasmania 7000, Australia
| | - Tracey C Dickson
- Menzies Institute for Medical Research Tasmania, University of Tasmania, Hobart, Tasmania 7000, Australia.
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Dufour MA, Woodhouse A, Amendola J, Goaillard JM. Non-linear developmental trajectory of electrical phenotype in rat substantia nigra pars compacta dopaminergic neurons. eLife 2014; 3:e04059. [PMID: 25329344 PMCID: PMC4241557 DOI: 10.7554/elife.04059] [Citation(s) in RCA: 31] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/17/2014] [Accepted: 10/19/2014] [Indexed: 12/12/2022] Open
Abstract
Neurons have complex electrophysiological properties, however, it is often difficult to determine which properties are the most relevant to neuronal function. By combining current-clamp measurements of electrophysiological properties with multi-variate analysis (hierarchical clustering, principal component analysis), we were able to characterize the postnatal development of substantia nigra dopaminergic neurons' electrical phenotype in an unbiased manner, such that subtle changes in phenotype could be analyzed. We show that the intrinsic electrical phenotype of these neurons follows a non-linear trajectory reaching maturity by postnatal day 14, with two developmental transitions occurring between postnatal days 3-5 and 9-11. This approach also predicted which parameters play a critical role in phenotypic variation, enabling us to determine (using pharmacology, dynamic-clamp) that changes in the leak, sodium and calcium-activated potassium currents are central to these two developmental transitions. This analysis enables an unbiased definition of neuronal type/phenotype that is applicable to a range of research questions.
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Affiliation(s)
- Martial A Dufour
- Inserm UMR 1072, Faculté de Médecine Secteur Nord, Université de la Méditerranée, Marseille, France
- Aix-Marseille Université, Marseille, France
| | - Adele Woodhouse
- Inserm UMR 1072, Faculté de Médecine Secteur Nord, Université de la Méditerranée, Marseille, France
- Aix-Marseille Université, Marseille, France
| | - Julien Amendola
- Inserm UMR 1072, Faculté de Médecine Secteur Nord, Université de la Méditerranée, Marseille, France
- Aix-Marseille Université, Marseille, France
| | - Jean-Marc Goaillard
- Inserm UMR 1072, Faculté de Médecine Secteur Nord, Université de la Méditerranée, Marseille, France
- Aix-Marseille Université, Marseille, France
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Bando Y, Irie K, Shimomura T, Umeshima H, Kushida Y, Kengaku M, Fujiyoshi Y, Hirano T, Tagawa Y. Control of Spontaneous Ca2+ Transients Is Critical for Neuronal Maturation in the Developing Neocortex. Cereb Cortex 2014; 26:106-117. [PMID: 25112282 DOI: 10.1093/cercor/bhu180] [Citation(s) in RCA: 60] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/13/2022] Open
Abstract
Neural activity plays roles in the later stages of development of cortical excitatory neurons, including dendritic and axonal arborization, remodeling, and synaptogenesis. However, its role in earlier stages, such as migration and dendritogenesis, is less clear. Here we investigated roles of neural activity in the maturation of cortical neurons, using calcium imaging and expression of prokaryotic voltage-gated sodium channel, NaChBac. Calcium imaging experiments showed that postmigratory neurons in layer II/III exhibited more frequent spontaneous calcium transients than migrating neurons. To test whether such an increase of neural activity may promote neuronal maturation, we elevated the activity of migrating neurons by NaChBac expression. Elevation of neural activity impeded migration, and induced premature branching of the leading process before neurons arrived at layer II/III. Many NaChBac-expressing neurons in deep cortical layers were not attached to radial glial fibers, suggesting that these neurons had stopped migration. Morphological and immunohistochemical analyses suggested that branched leading processes of NaChBac-expressing neurons differentiated into dendrites. Our results suggest that developmental control of spontaneous calcium transients is critical for maturation of cortical excitatory neurons in vivo: keeping cellular excitability low is important for migration, and increasing spontaneous neural activity may stop migration and promote dendrite formation.
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Affiliation(s)
- Yuki Bando
- Department of Biophysics, Kyoto University Graduate School of Science, Kyoto 606-8502, Japan.,CREST, Japan Science and Technology Agency, Kawaguchi, Saitama 332-0012, Japan
| | - Katsumasa Irie
- Department of Biophysics, Kyoto University Graduate School of Science, Kyoto 606-8502, Japan.,Cellular and Structural Physiology Institute, Nagoya University, Nagoya, Aichi 464-8601, Japan
| | - Takushi Shimomura
- Department of Biophysics, Kyoto University Graduate School of Science, Kyoto 606-8502, Japan.,Cellular and Structural Physiology Institute, Nagoya University, Nagoya, Aichi 464-8601, Japan
| | - Hiroki Umeshima
- Institute for Integrated Cell-Material Sciences (WPI-iCeMS), Kyoto University, Kyoto 606-8501, Japan
| | - Yuki Kushida
- Department of Biophysics, Kyoto University Graduate School of Science, Kyoto 606-8502, Japan
| | - Mineko Kengaku
- Institute for Integrated Cell-Material Sciences (WPI-iCeMS), Kyoto University, Kyoto 606-8501, Japan
| | - Yoshinori Fujiyoshi
- Department of Biophysics, Kyoto University Graduate School of Science, Kyoto 606-8502, Japan.,Cellular and Structural Physiology Institute, Nagoya University, Nagoya, Aichi 464-8601, Japan
| | - Tomoo Hirano
- Department of Biophysics, Kyoto University Graduate School of Science, Kyoto 606-8502, Japan
| | - Yoshiaki Tagawa
- Department of Biophysics, Kyoto University Graduate School of Science, Kyoto 606-8502, Japan.,CREST, Japan Science and Technology Agency, Kawaguchi, Saitama 332-0012, Japan
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