Richard Blazeski

Columbia University, New York, New York, United States

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Publications (8)100.95 Total impact

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    ABSTRACT: Thalamus is a potent driver of cortical activity even though cortical synapses onto excitatory layer 4 neurons outnumber thalamic synapses 10 to 1. Previous in vitro studies have proposed that thalamocortical (TC) synapses are stronger than corticocortical (CC) synapses. Here, we investigated possible anatomical and physiological differences between these inputs in the rat in vivo. We developed a high-throughput light microscopy method, validated by electron microscopy, to completely map the locations of synapses across an entire dendritic tree. This demonstrated that TC synapses are slightly more proximal to the soma than CC synapses, but detailed compartmental modeling predicted that dendritic filtering does not appreciably favor one synaptic class over another. Measurements of synaptic strength in intact animals confirmed that both TC and CC synapses are weak and approximately equivalent. We conclude that thalamic effectiveness does not rely on enhanced TC strength, but rather on coincident activation of converging inputs.
    The Journal of Neuroscience : The Official Journal of the Society for Neuroscience 05/2014; 34(20):6746-58. DOI:10.1523/JNEUROSCI.0305-14.2014 · 6.75 Impact Factor
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    ABSTRACT: Dendrites achieve characteristic spacing patterns during development to ensure appropriate coverage of territories. Mechanisms of dendrite positioning via repulsive dendrite-dendrite interactions are beginning to be elucidated, but the control, and importance, of dendrite positioning relative to their substrate is poorly understood. We found that dendritic branches of Drosophila dendritic arborization sensory neurons can be positioned either at the basal surface of epidermal cells, or enclosed within epidermal invaginations. We show that integrins control dendrite positioning on or within the epidermis in a cell autonomous manner by promoting dendritic retention on the basal surface. Loss of integrin function in neurons resulted in excessive self-crossing and dendrite maintenance defects, the former indicating a role for substrate interactions in self-avoidance. In contrast to a contact-mediated mechanism, we find that integrins prevent crossings that are noncontacting between dendrites in different three-dimensional positions, revealing a requirement for combined dendrite-dendrite and dendrite-substrate interactions in self-avoidance.
    Neuron 01/2012; 73(1):79-91. DOI:10.1016/j.neuron.2011.10.033 · 15.77 Impact Factor
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    ABSTRACT: Carefully designed animal models of genetic risk factors are likely to aid our understanding of the pathogenesis of schizophrenia. Here, we study a mouse strain with a truncating lesion in the endogenous Disc1 ortholog designed to model the effects of a schizophrenia-predisposing mutation and offer a detailed account of the consequences that this mutation has on the development and function of a hippocampal circuit. We uncover widespread and cumulative cytoarchitectural alterations in the dentate gyrus during neonatal and adult neurogenesis, which include errors in axonal targeting and are accompanied by changes in short-term plasticity at the mossy fiber/CA3 circuit. We also provide evidence that cAMP levels are elevated as a result of the Disc1 mutation, leading to altered axonal targeting and dendritic growth. The identified structural alterations are, for the most part, not consistent with the growth-promoting and premature maturation effects inferred from previous RNAi-based Disc1 knockdown. Our results provide support to the notion that modest disturbances of neuronal connectivity and accompanying deficits in short-term synaptic dynamics is a general feature of schizophrenia-predisposing mutations.
    Proceedings of the National Academy of Sciences 11/2011; 108(49):E1349-58. DOI:10.1073/pnas.1114113108 · 9.81 Impact Factor
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    ABSTRACT: The function of neuronal networks relies on selective assembly of synaptic connections during development. We examined how synaptic specificity emerges in the pontocerebellar projection. Analysis of axon-target interactions with correlated light-electron microscopy revealed that developing pontine mossy fibers elaborate extensive cell-cell contacts and synaptic connections with Purkinje cells, an inappropriate target. Subsequently, mossy fiber-Purkinje cell connections are eliminated resulting in granule cell-specific mossy fiber connectivity as observed in mature cerebellar circuits. Formation of mossy fiber-Purkinje cell contacts is negatively regulated by Purkinje cell-derived BMP4. BMP4 limits mossy fiber growth in vitro and Purkinje cell-specific ablation of BMP4 in mice results in exuberant mossy fiber-Purkinje cell interactions. These findings demonstrate that synaptic specificity in the pontocerebellar projection is achieved through a stepwise mechanism that entails transient innervation of Purkinje cells, followed by synapse elimination. Moreover, this work establishes BMP4 as a retrograde signal that regulates the axon-target interactions during development.
    PLoS Biology 02/2011; 9(2):e1001013. DOI:10.1371/journal.pbio.1001013 · 11.77 Impact Factor
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    ABSTRACT: Activity-dependent competition that operates on branch stability or formation plays a critical role in shaping the pattern and complexity of axonal terminal arbors. In the mammalian central nervous system (CNS), the effect of activity-dependent competition on axon arborization and on the assembly of sensory maps is well established. However, the molecular pathways that modulate axonal-branch stability or formation in competitive environments remain unknown. We establish an in vivo axonal-competition paradigm in the mouse olfactory system by employing a genetic strategy that permits suppression of neurosecretory activity in random subsets of olfactory sensory neurons (OSNs). Long-term follow up confirmed that this genetic manipulation triggers competition by revealing a bias toward selective stabilization of active arbors and local degeneration of synaptically silent ones. By using a battery of genetically modified mouse models, we demonstrate that a decrease either in the total levels or the levels of activity-dependent secreted BDNF (due to a val66met substitution), rescues silent arbors from withering. We show that this effect may be mediated, at least in part, by p75(NTR). We establish and experimentally validate a genetic in vivo axonal-competition paradigm in the mammalian CNS. By using this paradigm, we provide evidence for a specific effect of BDNF signaling on terminal-arbor pruning under competition in vivo. Our results have implications for the formation and refinement of the olfactory and other sensory maps, as well as for neuropsychiatric diseases and traits modulated by the BDNF val66met variant.
    Current Biology 07/2007; 17(11):911-21. DOI:10.1016/j.cub.2007.04.040 · 9.92 Impact Factor
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    ABSTRACT: The rapid motility of axonal filopodia and dendritic spines is prevalent throughout the developing CNS, although the function of this motility remains controversial. Using two-photon microscopy, we imaged hippocampal mossy fiber axons in slice cultures and discovered that filopodial extensions are highly motile. Axonal filopodial motility is actin based and is downregulated with development, although it remains in mature cultures. This motility is correlated with free extracellular space yet is inversely correlated with contact with postsynaptic targets, indicating a potential role in synaptogenesis. Filopodial motility is differentially regulated by kainate receptors: synaptic stimulation of kainate receptors enhances motility in younger slices, but it inhibits it in mature slices. We propose that neuronal activity controls filopodial motility in a developmentally regulated manner, in order to establish synaptic contacts in a two-step process. A two-step model of synaptogenesis can also explain the opposite effects of neuronal activity on the motility of dendritic protrusions.
    Neuron 07/2003; 38(5):773-84. DOI:10.1016/S0896-6273(03)00299-X · 15.98 Impact Factor
  • A Dunaevsky, R Blazeski, R Yuste, C Mason
    Nature Neuroscience 08/2001; 4(7):685-6. DOI:10.1038/89460 · 14.98 Impact Factor
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    ABSTRACT: Weaver is a spontaneous mutation in mice characterized by the postnatal loss of external granule cells in the cerebellum and dopaminergic neurons of the midbrain, especially in the substantia nigra. We have shown previously that natural cell death with the morphology of apoptosis occurs in the substantia nigra of normal rodents during postnatal development. We therefore sought to determine whether the loss of dopaminergic neurons in homozygous weaver mice occurs during the period of natural cell death in the substantia nigra and whether it has the morphology of apoptosis. We have found, using a silver stain technique, that although apoptotic cell death does occur early postnatally in homozygous weaver substantia nigra, it also does so with equal magnitude in wild-type and heterozygous weaver littermates. Unique to homozygous weavers is the occurrence of degenerating neurons in the nigra that are not apoptotic. These degenerating neurons are observed at postnatal day 7, and they are most abundant on postnatal days 24-25. The nonapoptotic nature of this cell death is confirmed by negative in situ end labeling of nuclear DNA fragmentation and by ultrastructural analysis. Ultrastructural studies reveal irregular chromatin aggregates in the nucleus, as well as marked cytoplasmic changes, including the formation of vacuoles and distinctive stacks of dilated cisternae of endoplasmic reticulum. We interpret these changes as indicative of either a variant morphology of programmed cell death or a pathological degenerative process mediated by an as yet unknown mechanism related to the recently described mutation in the GIRK2 potassium channel.
    The Journal of Neuroscience : The Official Journal of the Society for Neuroscience 11/1996; 16(19):6134-45. · 6.75 Impact Factor
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    ABSTRACT: A long-standing question is how fiber pathways in the mammalian CNS project to both sides of the brain. Static and real-time analyses of dye-labeled retinal axons (Godement et al., 1990, 1994) have demonstrated that at embryonic day 15-17 in the mouse, crossed and uncrossed axons from each eye diverge in a zone 100-200 microns proximal to the midline of the optic chiasm. In this study, we identify cellular specializations in this zone that might serve as cues for retinal axon divergence. Second, using growth cone morphology as an indicator of growth cone destination, we analyzed how crossed and uncrossed retinal growth cones related to these cellular components. Monoclonal antibody RC2, a marker for radial glia in embryonic mouse CNS, revealed a palisade of radial glia straddling the midline. At the midline, a thin raphe of cells that appear morphologically distinct from the radial glia express a free carbohydrate epitope, stage-specific embryonic antigen 1 (SSEA-1). Sections containing Dil-labeled axons and immunolabeled cells indicated that all axons enter the radial glial palisade. Uncrossed axons turn within the palisade, but never beyond the raphe of SSEA-1-positive cells. In addition, ultrastructural analysis indicated that all growth cones contact radial glia, with projections of the growth cone interdigitating with glial fibers. These results demonstrate that retinal axons diverge within a cellular specialization centered around the midline of the developing optic chiasm, consistent with the hypothesis that cues for divergence are located in this zone.
    The Journal of Neuroscience : The Official Journal of the Society for Neuroscience 06/1995; 15(5 Pt 2):3716-29. · 6.75 Impact Factor
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    ABSTRACT: For decades, time-lapse microscopy has been used to track dynamic events associated with biological phenomena. Time-lapse studies of the developing nervous system have been restricted to analysis of dissociated cell cultures or of a series of static images from living organisms. The advent of new fluorescent dyes and video imaging technology has produced novel views of the behavior of neurons in the context of the developing nervous tissue, such as migrations within and away from proliferative zones and navigation of axonal processes to synaptic targets. After fixation of the tissue preparation, time-lapse monitoring can be followed by other analytical techniques and forms of microscopy, e.g., immunocytochemistry or electron microscopy, producing information on the interactions of individual cells whose behavioral histories are known. The power of video time-lapse microscopy of living brain tissue lies in the firsthand documentation of developmental patterning, which in turn can serve as an experimental assay.
    The FASEB Journal 04/1995; 9(5):324-34. · 5.48 Impact Factor
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    ABSTRACT: To determine the role of cell-cell interactions in Purkinje cell survival and dendritic differentiation, perinatal mouse Purkinje cells were purified, and their development was analyzed in vitro. In isolation at low density, Purkinje cell survival was poor, improved by neuronal contacts, either with purified granule neurons or with Purkinje cells themselves. Moreover, coculture with specific cell populations led to widely different degrees of Purkinje cell differentiation. Purified Purkinje cells cultured alone or with an inappropriate afferent, the mossy fibers, did not progress beyond immature forms. With astroglia, Purkinje cells had thin smooth processes. Proper Purkinje cell differentiation was driven only by coculture with granule cells, resulting in dendrites with spines receiving synapses. These results suggest that Purkinje cell differentiation is regulated by local epigenetic factors, provided in large part by the granule neuron.
    Neuron 03/1994; 12(2):243-60. DOI:10.1016/0896-6273(94)90268-2 · 15.98 Impact Factor

Publication Stats

320 Citations
100.95 Total Impact Points

Institutions

  • 2001–2012
    • Columbia University
      • • Department of Pathology & Cell Biology
      • • Center for Neurobiology and Behavior
      New York, New York, United States
  • 2003
    • Brown University
      • Department of Neuroscience
      Providence, Rhode Island, United States