| 1. |
- Elmer, Eskil, et al.
(författare)
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Suppressed kindling epileptogenesis and perturbed BDNF and TrkB gene regulation in NT-3 mutant mice
- 1997
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Ingår i: Experimental Neurology. - : Elsevier BV. - 0014-4886. ; 145:1, s. 93-103
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Tidskriftsartikel (refereegranskat)abstract
- In the kindling model of epilepsy, repeated electrical stimulations lead to progressive and permanent intensification of seizure activity. We find that the development of amygdala kindling is markedly retarded in mice heterozygous for a deletion of the neurotrophin-3 (NT-3) gene (NT-3+/- mice). These mice did not reach the fully kindled state (3rd grade 5 seizure) until after 28 +/- 4 days of stimulation compared to 17 +/- 2 days in the wild-type animals. The deficit in the NT-3+/- mice reflected dampening of the progression from focal to generalized seizures. The number of stimulations required to evoke focal (grade 1 and 2) seizures did not differ between the groups, but the NT-3 mutants spent a considerably longer period of time (13 +/- 3 days) than wild-type mice (2 +/- 1 days) in grade 2 seizures. As assessed by test stimulation 4-12 weeks after the 10th grade 5 seizure, kindling was maintained in the NT-3 mutants. In situ hybridization showed 30% reduction of basal NT-3 mRNA levels and lack of upregulation of TrkC mRNA expression at 2 h after a generalized seizure in dentate granule cells of the NT-3+/- mice, whereas the seizure-evoked increase in brain-derived neurotrophic factor (BDNF) and TrkB mRNA levels was enhanced. These results indicate that endogenous NT-3 levels can influence the rate of epileptogenesis, and suggest a link between NT-3 and BDNF gene regulation in dentate granule cells.
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| 2. |
- Fundin, Bengt, et al.
(författare)
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Differential dependency of developing mechanoreceptors on neurotrophins, trk receptors, and p75LNGFR
- 1997
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Ingår i: Developmental Biology. - 0012-1606 .- 1095-564X. ; 190:1, s. 94-116
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Tidskriftsartikel (refereegranskat)abstract
- The impact of null mutations of the genes for the NGF family of neurotrophins and their receptors was examined among the wide variety of medium to large caliber myelinated mechanoreceptors which have a highly specific predictable organization in the mystacial pad of mice. Immunofluorescence with anti-protein gene product 9.5, anti-200-kDa neurofilament protein (RT97), and anti-calcitonin gene-related product was used to label innervation in mystacial pads from mice with homozygous null mutations for nerve growth factor (NGF), brain-derived neurotrophic factor (BDNF), neurotrophin-3 (NT-3), neurotrophin-4 (NT-4), the three tyrosine kinase receptors (trkA, trkB, trkC), and the low-affinity nerve growth factor receptor p75. Specimens were sacrificed at birth and at 1, 2, and 4 weeks for each type of mutation as well as at 11 weeks and 1 year for p75 and trkC mutations, respectively. Our results demonstrate several major concepts about the role of neurotrophins in the development of cutaneous mechanoreceptors that are supplied by medium to large caliber myelinated afferents. First, each of the high-affinity tyrosine kinase receptors, trkA, trkB, and trkC, as well as the low-affinity p75 receptor has an impact on at least one type of mechanoreceptor. Second, consistent with the various affinities for particular trk receptors, the elimination of NGF, BDNF, and NT-3 has an impact comparable to or more complex than the absence of their most specific high-affinity receptors: trkA, trkB, and trkC, respectively. These complexities include potential NT-3 signaling through trkA and trkB to support some neuronal survival. Third, most types of afferents are dependent on a different combination of neurotrophins and receptors for their survival: reticular and transverse lanceolate afferents are dependent upon NT-3, NGF, and trkA; Ruffini afferents upon BDNF and trkB; longitudinal lanceolate afferents upon NGF, trkA, BDNF, and trkB; and Merkel afferents on NGF, trkA, NT-3, trkC, and p75. NT-4 has no obvious detrimental impact on the mechanoreceptor development in the presence of BDNF. Fourth, NT-4 and BDNF signaling through trkB may suppress Merkel innervation and NT-3 signaling through trkC may suppress Ruffini innervation. Finally, regardless of the neurotrophin/receptor dependency for afferent survival and neurite outgrowth, NT-3 has an impact on the formation of all the sensory endings. In the context of these findings, indications of competitive and suppressive interactions that appear to regulate the balance of innervation density among the various sets of innervation were evident.
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| 3. |
- Kokaia, Merab, et al.
(författare)
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Suppressed epileptogenesis in BDNF mutant mice
- 1995
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Ingår i: Experimental Neurology. - : Elsevier BV. - 0014-4886. ; 133:2, s. 215-224
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Tidskriftsartikel (refereegranskat)abstract
- Kindling is an animal model of epilepsy in which repeated electrical stimulations lead to progressive and permanent amplification of seizure activity, culminating in generalized convulsions. Each brief period of seizure activity during kindling epileptogenesis causes a marked, transient increase of the synthesis of brain-derived neurotrophic factor (BDNF) in cortical and hippocampal neurons. We find that the development of kindling is markedly suppressed in mice heterozygous for a deletion of the BDNF gene. In contrast, the maintenance of kindling is unaffected. The mutant mice show lower levels of BDNF mRNA in cortical and hippocampal neurons after seizures than do wild-type mice. Hippocampal mossy fiber sprouting is augmented in BDNF mutants but there are no other morphological abnormalities. These results show that BDNF plays an important role in establishing hyperexcitability during epileptogenesis, probably by increasing efficacy in stimulated synapses.
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| 4. |
- Rice, Frank, et al.
(författare)
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Differential dependency of unmyelinated and A delta epidermal and upper dermal innervation on neurotrophins, trk receptors, and p75LNGFR
- 1998
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Ingår i: Developmental Biology. - 0012-1606 .- 1095-564X. ; 198:1, s. 57-81
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Tidskriftsartikel (refereegranskat)abstract
- The impact of the nerve growth factor (NGF) family of neurotrophins and their receptors was examined on the cutaneous innervation in the mystacial pads of mice. Ten sets of unmyelinated and thinly myelinated sensory and autonomic innervation were evaluated that terminated in the epidermis, upper dermis, and upper part of the intervibrissal hair follicles. Mystacial pads were analyzed from newborn to 4-week-old mice that had homozygous functional deletions of the genes for NGF, brain-derived neurotrophic factor (BDNF), neurotrophin-3 (NT-3), neurotrophin-4 (NT-4), tyrosine kinase (trk) A, trkB, trkC, or p75. Mystacial pads were also analyzed in adult transgenic mice that had overproduction of NGF, BDNF, or NT-3 driven by a keratin promoter gene. The innervation was revealed by using immunofluorescence and immunocytochemistry with antibodies for protein gene product (PGP) 9.5, calcitonin gene-related product (CGRP), substance P (SP), galanin (GAL), neuropeptide Y (NPY), tyrosine hydroxylase (TH), and a neurofilament protein. The cumulative results indicated that NGF/trkA signaling plays a major role in the outgrowth and proliferation of sensory axons, whereas NT-3/ trkA signaling plays a major role in the formation of sensory endings. TrkC is also essential for the development of three sets of trkA-dependent sensory innervation that coexpress CGRP, SP, and GAL. Another set of sensory innervation that only coexpressed CGRP and SP was solely dependent upon NGF and trkA. Surprisingly, most sets of trkA-dependent sensory innervation are suppressed by trkB perhaps interacting with p75. BDNF and NT-4 appear to mediate this suppressing effect in the upper dermis and NT-4 in the epidermis. In contrast to sensory innervation, sympathetic innervation to the necks of intervibrissal hair follicles depends upon NGF/trkA signaling interacting with p75 for both the axon outgrowth and ending formation. Although NT-3/trkA signaling is essential for the full complement of sympathetic neurons, NT-3 is detrimental to the formation of sympathetic terminations to the necks of hair follicles. TrkB signaling mediated by BDNF but not NT-4 also suppresses these sympathetic terminations. One sparse set of innervation, perhaps parasympathetic, terminating at the necks of hair follicles is dependent solely upon NT-3 and trkC. Taken together, our results indicate that the innervation of the epidermis, upper dermis, and the upper portion of hair follicles is regulated by a competitive balance between promoting and suppressing effects of the various neurotrophins.
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