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1.
J Neurobiol ; 62(2): 278-88, 2005 Feb 05.
Article in English | MEDLINE | ID: mdl-15514998

ABSTRACT

Neurotrophins are known to regulate dendritic development, but the mechanisms that mediate neurotrophin-dependent dendrite formation are largely unknown. Here we show that brain-derived neurotrophic factor (BDNF) induces the formation of primary dendrites in cortical neurons by a protein synthesis-independent mechanism. BDNF leads to the rapid activation of PI3-kinase, MAP kinase, and PLC-gamma in cortical neurons, and pharmacological inhibition of PI3-kinase and MAP kinase in dissociated cell cultures and cortical slice cultures suppresses the ability of BDNF to induce dendrite formation. A constitutively active form of PI3-kinase, but not MEK, is sufficient to induce primary dendrite formation in cortical neurons. These observations indicate that BDNF induces primary dendrite formation via activation of the PI3-kinase and MAP kinase pathways and provide insight into the mechanisms that mediate the morphological effects of neurotrophin signaling.


Subject(s)
Brain-Derived Neurotrophic Factor/pharmacology , Cerebral Cortex/cytology , Dendrites/drug effects , Extracellular Signal-Regulated MAP Kinases/physiology , Neurons/cytology , Phosphatidylinositol 3-Kinases/physiology , Signal Transduction/physiology , Animals , Blotting, Western/methods , Cell Count/methods , Cells, Cultured , Dendrites/physiology , Drug Interactions , Embryo, Mammalian , Enzyme Inhibitors/pharmacology , Extracellular Signal-Regulated MAP Kinases/antagonists & inhibitors , Fluorescent Antibody Technique/methods , Green Fluorescent Proteins/metabolism , In Vitro Techniques , Neurons/drug effects , Phosphoinositide-3 Kinase Inhibitors , Rats , Rats, Long-Evans , Time Factors , Transfection/methods
2.
Prog Brain Res ; 147: 17-27, 2005.
Article in English | MEDLINE | ID: mdl-15581694

ABSTRACT

The development of cortical dendrites is regulated by both activity-dependent and activity-independent signaling. Activity-dependent dendritic growth involves calcium-dependent gene expression. Both CREB and CREST are transactivators that contribute to calcium-dependent dendritic growth. Dendritic development is also regulated by extracellular factors such as neurotrophins. Neurotrophin-dependent dendritic growth is mediated by the MAP kinase and PI 3-kinase pathways. Selective responsiveness to activity cues and neurotrophins may contribute to morphological diversity in the nervous system.


Subject(s)
Calcium Signaling , Dendrites/physiology , Nerve Growth Factors/physiology , Neuronal Plasticity/physiology , Signal Transduction/physiology , Animals , Humans
3.
Exp Neurol ; 189(2): 303-16, 2004 Oct.
Article in English | MEDLINE | ID: mdl-15380481

ABSTRACT

Following avulsion of a spinal ventral root, motoneurons that project through the avulsed root are axotomized. Avulsion between, for example, L2 and L6 leads to denervation of hind limb muscles. Reimplantation of an avulsed root directed to the motoneuron pool resulted in re-ingrowth of some motor axons. However, most motoneurons display retrograde atrophy and subsequently die. Two neurotrophic factors, glial cell line-derived neurotrophic factor (GDNF) and brain-derived neurotrophic factor (BDNF), promote the survival of motoneurons after injury. The long-term delivery of these neurotrophic factors to the motoneurons in the ventral horn of the spinal cord is problematic. One strategy to improve the outcome of the neurosurgical reinsertion of the ventral root following avulsion would involve gene transfer with adeno-associated viral (AAV) vectors encoding these neurotrophic factors near the denervated motoneuron pool. Here, we show that AAV-mediated overexpression of GDNF and BDNF in the spinal cord persisted for at least 16 weeks. At both 1 and 4 months post-lesion AAV-BDNF- and -GDNF-treated animals showed an increased survival of motoneurons, the effect being more prominent at 1 month. AAV vector-mediated overexpression of neurotrophins also promoted the formation of a network of motoneuron fibers in the ventral horn at the avulsed side, but motoneurons failed to extent axons into the reinserted L4 root towards the sciatic nerve nor to improve functional recovery of the hind limbs. This suggests that high levels of neurotrophic factors in the ventral horn promote sprouting, but prevent directional growth of axons of a higher number of surviving motoneurons into the implanted root.


Subject(s)
Brain-Derived Neurotrophic Factor/genetics , Motor Neurons/metabolism , Nerve Growth Factors/genetics , Nerve Regeneration/genetics , Radiculopathy/therapy , Spinal Cord/metabolism , Animals , Gene Transfer Techniques , Genetic Vectors , Glial Cell Line-Derived Neurotrophic Factor , Growth Cones/metabolism , Growth Cones/ultrastructure , Lumbar Vertebrae , Male , Motor Neurons/cytology , Neuronal Plasticity/genetics , Radiculopathy/metabolism , Radiculopathy/pathology , Rats , Rats, Wistar , Recovery of Function/genetics , Sciatic Nerve/cytology , Sciatic Nerve/physiology , Spinal Cord/pathology , Spinal Nerve Roots/injuries , Spinal Nerve Roots/pathology , Spinal Nerve Roots/surgery
4.
Neurobiol Dis ; 15(2): 394-406, 2004 Mar.
Article in English | MEDLINE | ID: mdl-15006710

ABSTRACT

Rubrospinal neurons (RSNs) undergo marked atrophy after cervical axotomy. This progressive atrophy may impair the regenerative capacity of RSNs in response to repair strategies that are targeted to promote rubrospinal tract regeneration. Here, we investigated whether we could achieve long-term rescue of RSNs from lesion-induced atrophy by adeno-associated viral (AAV) vector-mediated gene transfer of brain-derived neurotrophic factor (BDNF). We show for the first time that AAV vectors can be used for the persistent transduction of highly atrophic neurons in the red nucleus (RN) for up to 18 months after injury. Furthermore, BDNF gene transfer into the RN following spinal axotomy resulted in counteraction of atrophy in both the acute and chronic stage after injury. These novel findings demonstrate that a gene therapeutic approach can be used to reverse atrophy of lesioned CNS neurons for an extended period of time.


Subject(s)
Atrophy/therapy , Brain-Derived Neurotrophic Factor/genetics , Gene Transfer Techniques , Genetic Vectors/genetics , Nerve Regeneration/genetics , Spinal Cord Injuries/therapy , Acute Disease , Animals , Atrophy/metabolism , Atrophy/physiopathology , Axotomy , Brain-Derived Neurotrophic Factor/metabolism , Brain-Derived Neurotrophic Factor/therapeutic use , Chronic Disease , Dependovirus/genetics , Disease Models, Animal , Efferent Pathways/growth & development , Efferent Pathways/pathology , Efferent Pathways/physiopathology , Genetic Vectors/therapeutic use , Male , Nerve Regeneration/drug effects , Neurons/drug effects , Neurons/metabolism , Rats , Reaction Time/genetics , Receptor, trkB/metabolism , Red Nucleus/growth & development , Red Nucleus/pathology , Red Nucleus/physiopathology , Retrograde Degeneration/metabolism , Retrograde Degeneration/physiopathology , Retrograde Degeneration/therapy , Spinal Cord/growth & development , Spinal Cord/pathology , Spinal Cord/physiopathology , Spinal Cord Injuries/metabolism , Spinal Cord Injuries/physiopathology
5.
J Neurosci ; 23(18): 7045-58, 2003 Aug 06.
Article in English | MEDLINE | ID: mdl-12904465

ABSTRACT

The present study uniquely combines olfactory ensheathing glia (OEG) implantation with ex vivo adenoviral (AdV) vector-based neurotrophin gene therapy in an attempt to enhance regeneration after cervical spinal cord injury. Primary OEG were transduced with AdV vectors encoding rat brain-derived neurotrophic factor (BDNF), neurotrophin-3 (NT-3), or bacterial marker protein beta-galactosidase (LacZ) and subsequently implanted into adult Fischer rats directly after unilateral transection of the dorsolateral funiculus. Implanted animals received a total of 2 x 105 OEG that were subjected to transduction with neurotrophin-encoding AdV vector, AdV-LacZ, or no vector, respectively. At 4 months after injury, lesion volumes were smaller in all OEG implanted rats and significantly reduced in size after implantation of neurotrophin-encoding AdV vector-transduced OEG. All OEG grafts were filled with neurofilament-positive axons, and AdV vector-mediated expression of BDNF by implanted cells significantly enhanced regenerative sprouting of the rubrospinal tract. Behavioral analysis revealed that OEG-implanted rats displayed better locomotion during horizontal rope walking than unimplanted lesioned controls. Recovery of hind limb function was also improved after implantation of OEG that were transduced with a BDNF- or NT-3-encoding AdV vector. Hind limb performance during horizontal rope locomotion did directly correlate with lesion size, suggesting that neuroprotective effects of OEG implants contributed to the level of functional recovery. Thus, our results demonstrate that genetic engineering of OEG not only resulted in a cell that was more effective in promoting axonal outgrowth but could also lead to enhanced recovery after injury, possibly by sparing of spinal tissue.


Subject(s)
Adenoviridae/genetics , Genetic Vectors/administration & dosage , Nerve Growth Factors/biosynthesis , Neuroglia/transplantation , Spinal Cord Injuries/therapy , Animals , Cells, Cultured , Disease Models, Animal , Evoked Potentials, Motor/physiology , Female , Gene Expression , Gene Transfer Techniques , Genetic Vectors/genetics , Motor Activity , Neck , Nerve Growth Factors/genetics , Nerve Regeneration , Neuroglia/cytology , Neuroglia/metabolism , Olfactory Bulb/cytology , Rats , Rats, Inbred F344 , Recovery of Function , Red Nucleus/physiology , Spinal Cord/pathology , Spinal Cord Injuries/pathology , Transgenes , Treatment Outcome
6.
Development ; 129(13): 3147-60, 2002 Jul.
Article in English | MEDLINE | ID: mdl-12070090

ABSTRACT

During telencephalic development, cells from the medial ganglionic eminence (MGE) are thought to migrate to the neocortex to give rise to a majority of cortical GABAergic interneurons. By combining time-lapse video-microscopy, immunofluorescence and pharmacological perturbations in a new in vitro migration assay, we find that MGE-derived cells migrate through the entire extent of the cortex and into the CA fields of the hippocampus, but avoid the dentate gyrus. Migrating neurons initially travel within the marginal zone and intermediate zone, and can enter the cortical plate from either location. Tangential migration is strongly stimulated by BDNF and NT4 and attenuated by the Trk-family inhibitor, K252a, suggesting that migration is regulated by TrkB signaling. Furthermore, TrkB-null mice show a significant decrease in the number of calbindin-positive neurons migrating tangentially in the embryonic cortex. BDNF and NT4 cause rapid activation of PI3-kinase in MGE cells, and inhibition of PI3-kinase (but not of MAP kinase or PLCgamma) dramatically attenuates tangential migration. These observations suggest that TrkB signaling, via PI3-kinase activation, plays an important role in controlling interneuron migration in the developing cerebral cortex.


Subject(s)
Cerebral Cortex/embryology , Neurons/metabolism , Phosphatidylinositol 3-Kinases/metabolism , Animals , Brain-Derived Neurotrophic Factor/pharmacology , Carbazoles/pharmacology , Cell Movement/drug effects , Cell Transplantation/methods , Cells, Cultured , Cerebral Cortex/cytology , Cerebral Cortex/metabolism , Chromones/pharmacology , Coculture Techniques/methods , Enzyme Inhibitors/pharmacology , Female , Ganglia, Sensory/cytology , Ganglia, Sensory/embryology , Green Fluorescent Proteins , Indole Alkaloids , Isoenzymes/antagonists & inhibitors , Luminescent Proteins/genetics , Luminescent Proteins/metabolism , Mice , Mice, Mutant Strains , Morpholines/pharmacology , Nerve Growth Factors/pharmacology , Phospholipase C gamma , Receptor, trkB/antagonists & inhibitors , Receptor, trkB/metabolism , Signal Transduction , Type C Phospholipases/antagonists & inhibitors
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