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1.
J Neurosci ; 37(31): 7347-7361, 2017 08 02.
Article in English | MEDLINE | ID: mdl-28663201

ABSTRACT

Angelman syndrome (AS) is a debilitating neurodevelopmental disorder caused by loss of function of the maternally inherited UBE3A allele. It is currently unclear how the consequences of this genetic insult unfold to impair neurodevelopment. We reasoned that by elucidating the basis of microcephaly in AS, a highly penetrant syndromic feature with early postnatal onset, we would gain new insights into the mechanisms by which maternal UBE3A loss derails neurotypical brain growth and function. Detailed anatomical analysis of both male and female maternal Ube3a-null mice reveals that microcephaly in the AS mouse model is primarily driven by deficits in the growth of white matter tracts, which by adulthood are characterized by densely packed axons of disproportionately small caliber. Our results implicate impaired axon growth in the pathogenesis of AS and identify noninvasive structural neuroimaging as a potentially valuable tool for gauging therapeutic efficacy in the disorder.SIGNIFICANCE STATEMENT People who maternally inherit a deletion or nonfunctional copy of the UBE3A gene develop Angelman syndrome (AS), a severe neurodevelopmental disorder. To better understand how loss of maternal UBE3A function derails brain development, we analyzed brain structure in a maternal Ube3a knock-out mouse model of AS. We report that the volume of white matter (WM) is disproportionately reduced in AS mice, indicating that deficits in WM development are a major factor underlying impaired brain growth and microcephaly in the disorder. Notably, we find that axons within the WM pathways of AS model mice are abnormally small in caliber. This defect is associated with slowed nerve conduction, which could contribute to behavioral deficits in AS, including motor dysfunction.


Subject(s)
Angelman Syndrome/pathology , Axons/pathology , Microcephaly/pathology , Nerve Fibers/pathology , Ubiquitin-Protein Ligases/genetics , White Matter/pathology , Angelman Syndrome/physiopathology , Animals , Female , Male , Mice , Mice, Inbred C57BL , Mice, Knockout , Microcephaly/physiopathology , White Matter/physiopathology
2.
Neuron ; 78(1): 138-51, 2013 Apr 10.
Article in English | MEDLINE | ID: mdl-23523592

ABSTRACT

Calcitonin gene-related peptide (CGRP) is a classic molecular marker of peptidergic primary somatosensory neurons. Despite years of research, it is unknown whether these neurons are required to sense pain or other sensory stimuli. Here, we found that genetic ablation of CGRPα-expressing sensory neurons reduced sensitivity to noxious heat, capsaicin, and itch (histamine and chloroquine) and impaired thermoregulation but did not impair mechanosensation or ß-alanine itch-stimuli associated with nonpeptidergic sensory neurons. Unexpectedly, ablation enhanced behavioral responses to cold stimuli and cold mimetics without altering peripheral nerve responses to cooling. Mechanistically, ablation reduced tonic and evoked activity in postsynaptic spinal neurons associated with TRPV1/heat, while profoundly increasing tonic and evoked activity in spinal neurons associated with TRPM8/cold. Our data reveal that CGRPα sensory neurons encode heat and itch and tonically cross-inhibit cold-responsive spinal neurons. Disruption of this crosstalk unmasks cold hypersensitivity, with mechanistic implications for neuropathic pain and temperature perception.


Subject(s)
Calcitonin Gene-Related Peptide/metabolism , Cold Temperature , Hot Temperature , Pruritus/pathology , Sensory Receptor Cells/physiology , Sural Nerve/physiology , Animals , Calcitonin Gene-Related Peptide/genetics , Capsaicin/pharmacology , Diphtheria Toxin/pharmacology , Excitatory Postsynaptic Potentials/drug effects , Excitatory Postsynaptic Potentials/genetics , Female , Ganglia, Spinal/cytology , Gene Expression Regulation/drug effects , Gene Expression Regulation/genetics , Green Fluorescent Proteins/genetics , Green Fluorescent Proteins/metabolism , Histamine/adverse effects , In Vitro Techniques , Lectins/metabolism , Male , Mice , Mice, Transgenic , Neurofilament Proteins/metabolism , Pruritus/chemically induced , Pyrimidinones/pharmacology , Reaction Time/drug effects , Reaction Time/genetics , Receptors, Calcitonin Gene-Related Peptide/metabolism , Sensory Receptor Cells/drug effects , Sensory Receptor Cells/metabolism , Sensory Thresholds/physiology , Skin/innervation , Sural Nerve/drug effects , TRPM Cation Channels/metabolism , TRPV Cation Channels/metabolism , Time Factors , Ubiquitin Thiolesterase/metabolism
3.
Neuron ; 69(2): 244-57, 2011 Jan 27.
Article in English | MEDLINE | ID: mdl-21262464

ABSTRACT

Accumulation of voltage-gated sodium (Na(v)) channels at nodes of Ranvier is paramount for action potential propagation along myelinated fibers, yet the mechanisms governing nodal development, organization, and stabilization remain unresolved. Here, we report that genetic ablation of the neuron-specific isoform of Neurofascin (Nfasc(NF¹86)) in vivo results in nodal disorganization, including loss of Na(v) channel and ankyrin-G (AnkG) enrichment at nodes in the peripheral nervous system (PNS) and central nervous system (CNS). Interestingly, the presence of paranodal domains failed to rescue nodal organization in the PNS and the CNS. Most importantly, using ultrastructural analysis, we demonstrate that the paranodal domains invade the nodal space in Nfasc(NF¹86) mutant axons and occlude node formation. Our results suggest that Nfasc(NF¹86)-dependent assembly of the nodal complex acts as a molecular boundary to restrict the movement of flanking paranodal domains into the nodal area, thereby facilitating the stereotypic axonal domain organization and saltatory conduction along myelinated axons.


Subject(s)
Cell Adhesion Molecules/metabolism , Nerve Fibers, Myelinated/physiology , Nerve Fibers, Myelinated/ultrastructure , Nerve Growth Factors/metabolism , Ranvier's Nodes/physiology , Ranvier's Nodes/ultrastructure , Sodium Channels/metabolism , Animals , Cell Adhesion Molecules/genetics , Central Nervous System/anatomy & histology , Central Nervous System/pathology , Central Nervous System/physiology , Mice , Mice, Knockout , Nerve Fibers, Myelinated/pathology , Nerve Growth Factors/genetics , Neural Conduction/physiology , Peripheral Nervous System/anatomy & histology , Peripheral Nervous System/pathology , Peripheral Nervous System/physiology , Protein Isoforms/genetics , Protein Isoforms/metabolism , Ranvier's Nodes/pathology
4.
J Neurosci Methods ; 194(2): 235-41, 2011 Jan 15.
Article in English | MEDLINE | ID: mdl-20970454

ABSTRACT

A skin-nerve preparation is useful for study of heat transduction mechanisms of A- and C-high threshold primary afferents (nociceptors), but the small dimension and liquid environment of the skin organ bath do not readily accommodate conventional noxious heat delivery systems. For these reasons, a 980 nm (near-infrared) diode laser was tested for activation and differentiation of cutaneous afferents. Current to the laser driver was varied. Exposure time and area, angle of approach, and stand-off distance from the bath solution surface were held constant. Seventy-eight fibers were classified by: conduction velocity, mechanical threshold, and responsiveness to laser radiation. A subset of the sampled fibers was also tested for sensitivity to convective heat. Most C (30/43) and a few A (6/25) nociceptors responded to laser irradiation. All low mechanical threshold primary afferents (10/10) were unresponsive to laser irradiation. Laser-sensitive fibers responded to convective heat, whereas laser-insensitive fibers did not. Laser-induced responses were consistent with literature reports of responses to traditional heat stimulation. Laser stimulation proved to be a rapid, unobtrusive method for reproducible heat stimulation of primary afferents of the mouse skin-nerve preparation. It is effective for defining subpopulations of primary afferent fibers and holds promise as a tool for gauging modification of C-fiber activity.


Subject(s)
Action Potentials/physiology , Lasers, Semiconductor , Lasers/adverse effects , Nerve Fibers/physiology , Nociceptors/physiology , Skin/innervation , Age Factors , Animals , Biophysics , Female , In Vitro Techniques , Mice , Mice, Inbred C57BL , Physical Stimulation/methods , Sensory Thresholds/physiology , Stress, Mechanical , Temperament , Visceral Afferents/physiology
5.
J Neurosci ; 30(14): 4868-76, 2010 Apr 07.
Article in English | MEDLINE | ID: mdl-20371806

ABSTRACT

The formation of paranodal axo-glial junctions is critical for the rapid and efficient propagation of nerve impulses. Genetic ablation of genes encoding the critical paranodal proteins Caspr, contactin (Cont), and the myelinating glia-specific isoform of Neurofascin (Nfasc(NF155)) results in the disruption of the paranodal axo-glial junctions, loss of ion channel segregation, and impaired nerve conduction, but the mechanisms regulating their interactions remain elusive. Here, we report that loss of immunoglobulin (Ig) domains 5 and 6 in Nfasc(NF155) in mice phenocopies complete ablation of Nfasc(NF155). The mutant mice lack paranodal septate junctions, resulting in the diffusion of Caspr and Cont from the paranodes, and redistribution of the juxtaparanodal potassium channels toward the nodes. Although critical for Nfasc(NF155) function, we find that Ig5-6 are dispensable for nodal Nfasc(NF186) function. Moreover, in vitro binding assays using Ig5-6 deletion constructs reveal their importance for the association of Nfasc(NF155) with Cont. These findings provide the first molecular evidence demonstrating domain-specific requirements controlling the association of the paranodal tripartite complex in vivo. Our studies further emphasize that in vivo structure/function analysis is necessary to define the unique protein-protein interactions that differentially regulate the functions of Neurofascins during axonal domain organization.


Subject(s)
Cell Adhesion Molecules/deficiency , Cell Adhesion Molecules/physiology , Gene Deletion , Immunoglobulins/deficiency , Nerve Fibers, Myelinated/metabolism , Nerve Growth Factors/deficiency , Nerve Growth Factors/physiology , Animals , Axons/metabolism , Axons/pathology , CHO Cells , Cell Adhesion Molecules/chemistry , Cricetinae , Cricetulus , Humans , Immunoglobulins/genetics , Mice , Mice, Knockout , Mice, Transgenic , Nerve Fibers, Myelinated/pathology , Nerve Growth Factors/chemistry , Protein Interaction Mapping , Protein Isoforms/chemistry , Protein Isoforms/deficiency , Protein Isoforms/physiology , Protein Stability , Protein Structure, Tertiary/genetics , Rats
6.
J Neurosci Res ; 87(8): 1773-93, 2009 Jun.
Article in English | MEDLINE | ID: mdl-19185024

ABSTRACT

The evolutionary demand for rapid nerve impulse conduction led to the process of myelination-dependent organization of axons into distinct molecular domains. These domains include the node of Ranvier flanked by highly specialized paranodal domains where myelin loops and axolemma orchestrate the axoglial septate junctions. These junctions are formed by interactions between a glial isoform of neurofascin (Nfasc(NF155)) and axonal Caspr and Cont. Here we report the generation of myelinating glia-specific Nfasc(NF155) null mouse mutants. These mice exhibit severe ataxia, motor paresis, and death before the third postnatal week. In the absence of glial Nfasc(NF155), paranodal axoglial junctions fail to form, axonal domains fail to segregate, and myelinated axons undergo degeneration. Electrophysiological measurements of peripheral nerves from Nfasc(NF155) mutants revealed dramatic reductions in nerve conduction velocities. By using inducible PLP-CreER recombinase to ablate Nfasc(NF155) in adult myelinating glia, we demonstrate that paranodal axoglial junctions disorganize gradually as the levels of Nfasc(NF155) protein at the paranodes begin to drop. This coincides with the loss of the paranodal region and concomitant disorganization of the axonal domains. Our results provide the first direct evidence that the maintenance of axonal domains requires the fence function of the paranodal axoglial junctions. Together, our studies establish a central role for paranodal axoglial junctions in both the organization and the maintenance of axonal domains in myelinated axons.


Subject(s)
Axons/pathology , Cell Adhesion Molecules/genetics , Demyelinating Diseases/pathology , Myelin Sheath/pathology , Nerve Fibers, Myelinated/pathology , Nerve Growth Factors/genetics , Neuroglia/pathology , Animals , Axons/metabolism , Cell Adhesion Molecules/metabolism , Demyelinating Diseases/genetics , Demyelinating Diseases/physiopathology , Disease Models, Animal , Mice , Mice, Knockout , Mice, Mutant Strains , Mice, Transgenic , Movement Disorders/genetics , Movement Disorders/pathology , Movement Disorders/physiopathology , Myelin Proteolipid Protein/genetics , Myelin Proteolipid Protein/metabolism , Myelin Sheath/metabolism , Nerve Fibers, Myelinated/metabolism , Nerve Growth Factors/metabolism , Neural Conduction/genetics , Neuroglia/metabolism , Peripheral Nerves/metabolism , Peripheral Nerves/pathology , Peripheral Nerves/physiopathology , Ranvier's Nodes/metabolism , Ranvier's Nodes/pathology , Recombinant Fusion Proteins/genetics , Recombinant Fusion Proteins/metabolism , Wallerian Degeneration/genetics , Wallerian Degeneration/pathology , Wallerian Degeneration/physiopathology
7.
AORN J ; 77(1): 104-6, 109-14, 116-7; quiz 118-20, 2003 Jan.
Article in English | MEDLINE | ID: mdl-12575627

ABSTRACT

The purpose of this article is to help nurses prevent adverse drug reactions (ADRs) in the perioperative, endoscopic, and special procedure areas. Up to 30% of hospitalized patients experience an ADR. Taking comprehensive medication histories, maintaining constant vigilance, and recognizing inherently dangerous patient/medication combinations are essential in preventing ADRs. The mechanisms of medication toxicity and identifying potentially preventable adverse reactions are discussed. Practical nursing guidelines and tips that patients can use to prevent ADRs from occurring are delineated. Not every ADR can be prevented, but informed nurses can implement measures to reduce their occurrence.


Subject(s)
Drug Hypersensitivity/prevention & control , Drug-Related Side Effects and Adverse Reactions , Perioperative Nursing/methods , Drug Hypersensitivity/etiology , Drug Hypersensitivity/physiopathology , Humans , Medical History Taking/standards , Medical Records , Patient Education as Topic
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