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The Journal of Neuroscience, February 11, 2009, 29(6)
This Week in The Journal
This Week in The Journal
Cellular/Molecular
FGF Signaling in Glia Is Required for Axon Maintenance
Miki Furusho, Jeff L. Dupree, Melissa Bryant, and Rashmi Bansal
(see pages 1608–1614)
Schwann cells form myelin sheaths around large PNS axons, form Remak bundles around groups of small-diameter axons, and promote neuronal survival and regeneration. Fibroblast growth factor (FGF) is important for nerve regeneration, and its receptors Fgfr1 and Fgfr2 are expressed in both neurons and Schwann cells. To examine the role of FGF signaling in normal axon–glia interactions, Furusho et al. knocked out Fgfr1 and Fgfr2 specifically in Schwann cells. Interestingly, loss of Fgfr did not produce obvious detrimental effects in the Schwann cells themselves, but instead resulted in distal degeneration of nociceptive C-fiber axons ensheathed by Remak bundles. Fgfr knock-out also increased paw-withdrawal latency in a hot-plate test, suggesting that it reduced thermal nociception mediated by C-fibers. In contrast, myelinated axons were not affected. The results suggest that although FGF signaling in Schwann cells is not required for their survival, it regulates their release of factors that maintain neuronal health.
Development/Plasticity/Repair
LIGHT Negatively Regulates Nodose Neurite Growth
Núria Gavaldà, Humberto Gutierrez, and Alun M. Davies
(see pages 1599–1607)
Tumor necrosis factor superfamily (TNFSF) cytokines and their receptors are expressed throughout the body. Although typically associated with inflammation and cell death, they have increasingly been linked to developmental processes. Using PCR to determine expression patterns of all TNFSF cytokines and their receptors in the nervous system, Gavaldà et al. identified LIGHT as a potential regulator of development of nodose ganglion neurons. LIGHT and its receptors—herpesvirus entry mediator (HVEM) and lymphotoxin-β receptor—were expressed in all cultured nodose neurons. Overexpressing LIGHT in neurons from perinatal mice significantly decreased neurite length and branching, whereas knocking out LIGHT or blocking HVEM function with antibodies increased neurite outgrowth. LIGHT overexpression also inhibited nuclear transcription factor
β, a downstream effector of the growth-promoting molecule brain-derived neurotrophic factor (BDNF). The authors hypothesize that LIGHT counteracts growth-promoting effects of target-derived BDNF to help match the growth of nodose axonal arbors to the size of their target.
Behavioral/Systems/Cognitive
Aging-Related Gene Expression Changes Begin in Midlife
Inga Kadish, Olivier Thibault, Eric M. Blalock, Kuey-Chu Chen, John C. Gant, Nada M. Porter, and Philip W. Landfield
(see pages 1805–1816)
As the brain ages, cognitive abilities decline and gene expression patterns change. Some changes in gene expression are likely to contribute to cognitive decline, whereas others are probably neuroprotective or incidental to cognitive decline. To determine which genes fall into which category, one must first know what genes show age-related changes in expression and when these changes occur. Kadish et al. have therefore used microarrays to comprehensively profile gene expression in rat hippocampus throughout adulthood (at 3, 6, 9, 12, and 23 months of age). Hundreds of genes were upregulated or downregulated over the adult lifespan, and the expression level of
20–30% of these genes was correlated with spatial memory performance. The largest upregulation of aging- and memory-related genes occurred during middle age (9–12 months), coinciding with the earliest signs of cognitive decline. Many of the upregulated genes were expressed in astrocytes and were involved in cholesterol trafficking, lipid metabolism, and glial activation.
Neurobiology of Disease
Increases in T-Type Calcium Current Cause Absence Seizures
Wayne L. Ernst, Yi Zhang, Jong W. Yoo, Sara J. Ernst, and Jeffrey L. Noebels
(see pages 1615–1625)
Absence seizures are characterized by brief lapses in consciousness that coincide with cortical spike-wave discharge patterns in electroencephalograms. Mutations in several genes—including the hyperpolarization-activated potassium channel HCN2, P/Q-type high-voltage-activated (HVA) calcium channels, and HVA-associated proteins—produce absence seizures in mice. In all these mutants, however, increases in T-type low-voltage-activated (LVA) calcium currents occur secondary to the primary mutation, suggesting LVA currents may contribute to the phenotype. Ernst et al. now show that increasing LVA currents by overexpressing a T-type calcium channel gene (in neurons that normally express them) caused frequent spike-wave discharges and associated behavioral arrest in mice. Interestingly, overexpression of T-type channels did not cause ataxia, unlike other mutations that produce absence epilepsy. The data demonstrate that primary mutations in T-type calcium channels can produce pure absence epilepsy, and support the hypothesis that secondary effects on LVA currents may cause seizure phenotypes in other animal models.
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Merged in situ hybridization images (courtesy of the Allen Brain Atlas) showing T-type calcium channel expression in wild-type (left) and transgenic (right) mice. EEG traces (top) show spike-wave discharges in transgenic mice. See the article by Ernst et al. for details.
Related articles in J. Neurosci.:
- Developmental Regulation of Sensory Neurite Growth by the Tumor Necrosis Factor Superfamily Member LIGHT
- Núria Gavaldà, Humberto Gutierrez, and Alun M. Davies
J. Neurosci. 2009 29: 1599-1607.[Abstract] [Full Text] - Disruption of Fibroblast Growth Factor Receptor Signaling in Nonmyelinating Schwann Cells Causes Sensory Axonal Neuropathy and Impairment of Thermal Pain Sensitivity
- Miki Furusho, Jeffrey L. Dupree, Melissa Bryant, and Rashmi Bansal
J. Neurosci. 2009 29: 1608-1614.[Abstract] [Full Text] - Genetic Enhancement of Thalamocortical Network Activity by Elevating
1G-Mediated Low-Voltage-Activated Calcium Current Induces Pure Absence Epilepsy
- Wayne L. Ernst, Yi Zhang, Jong W. Yoo, Sara J. Ernst, and Jeffrey L. Noebels
J. Neurosci. 2009 29: 1615-1625.[Abstract] [Full Text] - Hippocampal and Cognitive Aging across the Lifespan: A Bioenergetic Shift Precedes and Increased Cholesterol Trafficking Parallels Memory Impairment
- Inga Kadish, Olivier Thibault, Eric M. Blalock, Kuey-C. Chen, John C. Gant, Nada M. Porter, and Philip W. Landfield
J. Neurosci. 2009 29: 1805-1816.[Abstract] [Full Text]
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