Effects of BDNF and NT-3 on Development of Ia/Motoneuron Functional Connectivity in Neonatal Rats

Seebach, Bradley S.; Arvanov, Viktor L.; Mendell, Lorne M.

doi:10.1152/jn.1999.81.5.2398

Cited by 57 publications

(53 citation statements)

References 47 publications

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“…Postnatal application of NT3 increases the amplitude of Ia-MN EPSPs, both in normal neonates and in mice lacking NT3 expression in muscle spindles (Seebach et al, 1999;Arvanov et al, 2000;Chen et al, 2002;Arvanian et al, 2003Arvanian et al, , 2006. NT3 expression in mlc/NT3 mice continues into adulthood (Taylor et al, 2001), so the aberrant synaptic inputs might result from postnatal exposure to elevated NT3.…”

Section: Discussionmentioning

confidence: 99%

Prenatal Exposure to Elevated NT3 Disrupts Synaptic Selectivity in the Spinal Cord

Wang¹,

Li²,

Taylor³

et al. 2007

J. Neurosci.

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Monosynaptic connections between muscle spindle (Ia) afferents and motoneurons (MNs), the central portion of the stretch reflex circuit, are highly specific, but the mechanisms underlying this specificity are primarily unknown. In this study, we report that embryonic overexpression of neurotrophin-3 (NT3) in muscles disrupts the development of these specific Ia-MN connections, using transgenic (mlc/NT3) mice that express elevated levels of NT3 in muscles during development. In mlc/NT3 mice, there is a substantial increase in the amplitudes of monosynaptic EPSPs evoked by Ia afferents in MNs as measured with extracellular recordings from ventral roots. Despite this increased functional projection of Ia afferents, there is no obvious change in the anatomical density of Ia projections into the ventral horn of the spinal cord. Intracellular recordings from MNs revealed a major disruption in the pattern of Ia-MN connections. In addition to the normal connections between Ia afferents and MNs supplying the same muscle, there were also strong monosynaptic inputs from Ia afferents supplying unrelated muscles, which explains the increase seen in extracellular recordings. There was also a large variability in the strength of Ia input to individual MNs, both from correct and incorrect Ia afferents. Postnatal muscular administration of NT3 did not cause these changes in connectivity. These results indicate that prenatal exposure to elevated levels of NT3 disrupts the normal mechanisms responsible for synaptic selectivity in the stretch reflex circuit.

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Section: Discussionmentioning

confidence: 99%

Prenatal Exposure to Elevated NT3 Disrupts Synaptic Selectivity in the Spinal Cord

Wang¹,

Li²,

Taylor³

et al. 2007

J. Neurosci.

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“…The subcutaneous injection of NT3 on every other day during the first postnatal week increases the EPSP amplitude recorded on P8 intracellularly from antidromically identified motoneurons in rat (Seebach et al 1999). Treatment with trkC-IgG decreases EPSP amplitude just below statistical significance suggesting that this should be re-examined by employing more effective suppression of NT3 signalling.…”

Section: Nts Affect Primary Afferent Connectivity In Spinal Cordmentioning

confidence: 98%

Role of neurotrophin signalling in the differentiation of neurons from dorsal root ganglia and sympathetic ganglia

2009

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Manipulation of neurotrophin (NT) signalling by administration or depletion of NTs, by transgenic overexpression or by deletion of genes coding for NTs and their receptors has demonstrated the importance of NT signalling for the survival and differentiation of neurons in sympathetic and dorsal root ganglia (DRG). Combination with mutation of the proapoptotic Bax gene allows the separation of survival and differentiation effects. These studies together with cell culture analysis suggest that NT signalling directly regulates the differentiation of neuron subpopulations and their integration into neural networks. The high-affinity NT receptors trkA, trkB and trkC are restricted to subpopulations of mature neurons, whereas their expression at early developmental stages largely overlaps. trkC is expressed throughout sympathetic ganglia and DRG early after ganglion formation but becomes restricted to small neuron subpopulations during embryogenesis when trkA is turned on. The temporal relationship between trkA and trkC expression is conserved between sympathetic ganglia and DRG. In DRG, NGF signalling is required not only for survival, but also for the differentiation of nociceptors. Expression of neuropeptides calcitonin gene-related peptide and substance P, which specify peptidergic nociceptors, depends on nerve growth factor (NGF) signalling. ret expression indicative of nonpeptidergic nociceptors is also promoted by the NGFsignalling pathway. Regulation of TRP channels by NGF signalling might specify the temperature sensitivity of afferent neurons embryonically. The manipulation of NGF levels "tunes" heat sensitivity in nociceptors at postnatal and adult stages. Brain-derived neurotrophic factor signalling is required for subpopulations of DRG neurons that are not fully characterized; it affects mechanical sensitivity in slowly adapting, low-threshold mechanoreceptors and might involve the regulation of DEG/ENaC ion channels. NT3 signalling is required for the generation and survival of various DRG neuron classes, in particular proprioceptors. Its importance for peripheral projections and central connectivity of proprioceptors demonstrates the significance of NT signalling for integrating responsive neurons in neural networks. The molecular targets of NT3 signalling in proprioceptor differentiation remain to be characterized. In sympathetic ganglia, NGF signalling regulates dendritic development and axonal projections. Its role in the specification of other neuronal properties is less well analysed. In vitro analysis suggests the involvement of NT signalling in the choice between the noradrenergic and cholinergic transmitter phenotype, in the expression of various classes of ion channels and for target connectivity. In vivo analysis is required to show the degree to which NT signalling regulates these sympathetic neuron properties in developing embryos and postnatally.

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“…To test the hypothesis that upregulated neurotrophins mediate partial recovery, we administered Trk-Fc "receptor bodies" intrathecally to sequester spinal BDNF/NT-4 and NT-3 (Cabelli et al, 1997;Seebach et al, 1999;Chan et al, 2001). An antibody specific for the human Fc moiety was used to assess spinal Trk-Fc penetration (Fig.…”

Section: Continuous Trkb-fc Treatment Improves Mechanosensory Recoverymentioning

confidence: 99%

“…On the other hand, BDNF has been shown to inhibit glutamatergic signaling in the nucleus of the solitatry tract (Balkowiec et al, 2000) and in lateral motor nuclei in the spinal cord (Seebach et al, 1999;Arvanian and Mendell, 2001). It might therefore have been argued that endogenous BDNF prevents complete recovery by inhibiting glutamatergic transmission in the dorsal horn.…”

Section: Potential Mechanisms Of Spontaneous Recovery After Drimentioning

confidence: 99%

“…In neonatal rats, chronic TrkB-Fc treatment has been shown to strengthen the connection between Ia afferents and motoneurons, evident as an increase in the size of EPSPs (Seebach et al, 1999). It might therefore be argued that TrkB-Fc treatment results in larger EPSPs in dorsal horn neurons subsequent to peripheral stimulation of cutaneous mechanosensory axons.…”

Section: Potential Mechanisms Of Spontaneous Recovery After Drimentioning

confidence: 99%

See 1 more Smart Citation

Endogenous TrkB Ligands Suppress Functional Mechanosensory Plasticity in the Deafferented Spinal Cord

Ramer

McPhail²,

Borisoff³

et al. 2007

J. Neurosci.

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Dorsal root injury (DRI) disrupts the flow of sensory information to the spinal cord. Although primary afferents do not regenerate to their original targets, spontaneous recovery can, by unknown mechanisms, occur after DRI. Here, we show that brain-derived neurotrophic factor (BDNF) and neurotrophin-3 (NT-3), but not nerve growth factor or neurotrophin-4, are upregulated in the spinal gray matter after DRI. Because endognous BDNF and NT-3 have well established roles in synaptic and axonal plasticity, we hypothesized that they contributed to spontaneous recovery after DRI. We first developed a model of DRI-induced mechanosensory dysfunction: rat C7/8 DRI produced a deficit in low-threshold cutaneous mechanosensation that spontaneously improved within 10 d but did not recover completely. To determine the effects of endogenous BDNF and NT-3, we administered TrkB-Fc or TrkC-Fc fusion proteins throughout the recovery period. To our surprise, TrkB-Fc stimulated complete recovery of mechanosensation by 6 d after DRI. It also stimulated mechanosensory axon sprouting but prevented deafferentation-induced serotonergic sprouting. TrkC-Fc had no effect on low-threshold mechanosensory behavior or axonal plasticity. There was no mechanosensory improvement with single-bolus TrkB-Fc infusions at 10 d after DRI (despite significantly reducing rhizotomy-induced cold pain), indicating that neuromodulatory effects of BDNF did not underlie mechanosensory recovery. Continuous infusion of the pan-neurotrophin antagonist K252a also stimulated behavioral and anatomical plasticity, indicating that these effects of TrkB-Fc treatment occurred independent of signaling by other neurotrophins. These results illustrate a novel, plasticity-suppressing effect of endogenous TrkB ligands on mechanosensation and mechanosensory primary afferent axons after spinal deafferentation.

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Effects of BDNF and NT-3 on Development of Ia/Motoneuron Functional Connectivity in Neonatal Rats

Cited by 57 publications

References 47 publications

Prenatal Exposure to Elevated NT3 Disrupts Synaptic Selectivity in the Spinal Cord

Prenatal Exposure to Elevated NT3 Disrupts Synaptic Selectivity in the Spinal Cord

Role of neurotrophin signalling in the differentiation of neurons from dorsal root ganglia and sympathetic ganglia

Endogenous TrkB Ligands Suppress Functional Mechanosensory Plasticity in the Deafferented Spinal Cord

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