Neurotrophin expression by spinal motoneurons in adult and developing rats

Buck, Charles R.; Seburn, Kevin L.; Cope, Timothy C.

doi:10.1002/(sici)1096-9861(20000117)416:3<309::aid-cne3>3.0.co;2-u

Cited by 77 publications

(66 citation statements)

References 56 publications

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“…To provide some validity to our assumption in the mouse, we investigated the expression of these proteins in the L4 DRG in stimulated and unstimulated mice. In contrast to highly immunoreactive motoneurons (Buck et al, 2000;Copray and Kernell, 2000), only about half of the YFP+ DRG neurons in intact mice are immunoreactive for the full length trkB molecule (English et al, 2005a). As others have shown (Michael et al, 1999;Zhou et al, 1999;Karchewski et al, 2002), axotomy results in a change in BDNF expression in DRG neurons from mainly small, presumably trkA containing cells to medium to large size neurons.…”

Section: Discussionsupporting

confidence: 93%

“…English et al Page 11 Even though electrical stimulation might result in an increase in trkB signaling in regenerating axons, our interpretation is complicated by the fact that more than one cellular source of the ligands for that receptor are known. In addition to the production of trkB ligands by most motoneurons (Buck et al, 2000;Copray and Kernell, 2000) and some dorsal root ganglion cells (Mendell, 1996), Schwann cells in the distal stump synthesize both BDNF and NT-4/5, beginning as early as four days after injury (Funakoshi et al, 1993;Griesbeck et al, 1995;Zhang et al, 2000). Thus, the rapid up regulation of the mRNA for trkB in motoneurons described following electrical stimulation could result in an increase in trkB signaling in regenerating axons produced by BDNF of neuronal origin (which acts on the regenerating axons themselves and/or the surrounding axons) or BDNF (or/and NT-4/5) produced by Schwann cells in the surrounding environment (a form of target derived neurotrophin signaling).…”

Section: Discussionmentioning

confidence: 55%

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Electrical stimulation promotes peripheral axon regeneration by enhanced neuronal neurotrophin signaling

et al. 2006

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Electrical stimulation of cut peripheral nerves at the time of their surgical repair results in an enhancement of axon regeneration. Regeneration of axons through nerve allografts was used to evaluate whether this effect is due to an augmentation of cell autonomous neurotrophin signaling in the axons or signaling from neurotrophins produced in the surrounding environment. In the thy-1-YFP-H mouse, a single one hour application of electrical stimulation at the time of surgical repair of the cut common fibular nerve results in a significant increase in the proportion of YFP+ dorsal root ganglion neurons that were also immunoreactive for BDNF or trkB as well as an increase in the length of regenerating axons through allografts from wild type litter mates, both one and two weeks later. Axon growth through allografts from neurotrophin-4/5 knockout mice or grafts made acellular by repeated cycles of freezing and thawing is normally very poor, but electrical stimulation results in a growth of axons through these grafts which is similar to that observed through grafts from wild type mice after electrical stimulation. When cut nerves in NT-4/5 knockout mice were electrically stimulated, no enhancement of axon regeneration was found. Electrical stimulation thus produces a potent enhancement of the regeneration of axons in cut peripheral nerves which is independent of neurotrophin production by cells in their surrounding environment but is dependent on stimulation of trkB and its ligands in the regenerating axons themselves.

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Section: Discussionsupporting

confidence: 93%

Section: Discussionmentioning

confidence: 55%

Electrical stimulation promotes peripheral axon regeneration by enhanced neuronal neurotrophin signaling

et al. 2006

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“…It is therefore likely that, as in the adult animal, BDNF is anterogradely transported to the central terminals of these (presumably nociceptive) neurons and, after a sufficient stimulus, is released into the spinal cord. NT-4 mRNA was found by us and by others (27,28), to be present both in DRG and spinal neurons.…”

Section: Discussionmentioning

confidence: 94%

BDNF but not NT-4 is required for normal flexion reflex plasticity and function

Heppenstall

Lewin²

2001

Proc. Natl. Acad. Sci. U.S.A.

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Neurotrophins can directly modulate the function of diverse types of central nervous system synapses. Brain-derived neurotrophic factor (BDNF) might be released by nociceptors onto spinal neurons and mediate central sensitization associated with chronic pain. We have studied the role of BDNF and neurotrophin-4 (NT-4), both ligands of the trkB tyrosine kinase receptor, in synaptic transmission and reflex plasticity in the mouse spinal cord. We used an in vitro spinal cord preparation to measure monosynaptic and polysynaptic reflexes evoked by primary afferents in BDNF-and NT-4-deficient mice. In situ hybridization studies show that both these neurotrophins are synthesized by sensory neurons, and NT-4, but not BDNF, also is expressed by spinal neurons. BDNF null mutants display selective deficits in the ventral root potential (VRP) evoked by stimulating nociceptive primary afferents whereas the non-nociceptive portion of the VRP remained unaltered. In addition, activity-dependent plasticity of the VRP evoked by repetitive (1 Hz) stimulation of nociceptive primary afferents (termed windup) was substantially reduced in BDNF-deficient mice. This plasticity also was reduced in a reversible manner by the protein kinase inhibitor K252a. Although the trkB ligand NT-4 is normally present, reflex properties in NT-4 null mutant mice were normal. Pharmacological studies also indicated that spinal N-methyl-D-aspartate receptor function was unaltered in BDNF-deficient mice. Using immunocytochemistry for markers of nociceptive neurons we found no evidence that their number or connectivity was substantially altered in BDNF-deficient mice. Our data therefore are consistent with a direct role for presynaptic BDNF release from sensory neurons in the modulation of pain-related neurotransmission.B rain-derived neurotrophic factor (BDNF) and neurotrophin-4 (NT-4) are structurally related neurotrophins that act through a common tyrosine kinase trkB receptor and regulate neuronal survival and differentiation (1). In addition, it is now known that neurotrophins are powerful modulators of both peripheral and central nervous system synapses (2). Thus both basal synaptic transmission and long-term synaptic plasticity can be regulated by neurotrophins (3).In the spinal cord, a form of synaptic plasticity termed central sensitization underlies many forms of hyperalgesia, and neurotrophins play an important role in this process (4, 5). For example, the hyperalgesia and pain associated with peripheral inflammation depends on up-regulation of nerve growth factor (NGF) in inflamed tissues (6-8). NGF can directly sensitize primary afferent nociceptors expressing the trkA receptor and also indirectly increase primary afferent connectivity in the spinal cord (6, 9, 10, 11). BDNF is synthesized by trkA-positive sensory neurons, and NGF treatment dramatically increases levels of BDNF in these neurons (12). Furthermore, BDNF is anterogradely transported to the spinal terminals of nociceptive neurons where it is localized in dense core vesicles and pres...

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“…The formation of specific patterns of synaptic connections is likely to require the expression of recognition molecules such as cadherins or protocadherins (Obst-Pernberg and Redies, 1999;Shapiro and Colman, 1999;Takai et al, 2003;Takeichi, 2007) in both presynaptic and postsynaptic neurons. TrkC, the specific receptor for NT3, is expressed in both Ia sensory neurons and MNs (Schecterson and Bothwell, 1992;McMahon et al, 1994;Wright and Snider, 1995;Copray and Kernell, 2000;Stephens et al, 2005), and NT3 is transported retrogradely back to their cell bodies (Buck et al, 2000). Elevated NT3 levels in muscle could therefore misregulate the expression of these recognition proteins in both cell classes.…”

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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Neurotrophin expression by spinal motoneurons in adult and developing rats

Cited by 77 publications

References 56 publications

Electrical stimulation promotes peripheral axon regeneration by enhanced neuronal neurotrophin signaling

Electrical stimulation promotes peripheral axon regeneration by enhanced neuronal neurotrophin signaling

BDNF but not NT-4 is required for normal flexion reflex plasticity and function

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

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