Absence of the p75 neurotrophin receptor alters the pattern of sympathosensory sprouting in the trigeminal ganglia of mice overexpressing nerve growth factor

Sympathetic axons invade the trigeminal ganglia of mice overexpressing nerve growth factor (NGF) (NGF/p75(+/+) mice) and surround sensory neurons having intense NGF immunolabeling; the growth of these axons appears to be directional and specific (). In this investigation, we provide new insight into the neurochemical features and receptor requirements of this sympathosensory sprouting. Using double-antigen immunohistochemistry, we demonstrate that virtually all (98%) trigeminal neurons that exhibit a sympathetic plexus are trk tyrosine kinase receptor (trkA)-positive. In addition, the majority (86%) of those neurons enveloped by sympathetic fibers is also calcitonin gene-related peptide (CGRP)-positive; a smaller number of plexuses (14%) surrounded other somata lacking this neuropeptide. Our results show that sympathosensory interactions form primarily between noradrenergic sympathetic efferents and the trkA/CGRP-expressing sensory somata. To assess the contribution of the p75 neurotrophin receptor (p75(NTR)) in sympathosensory sprouting, a hybrid strain of mice was used that overexpresses NGF but lacks p75(NTR) expression (NGF/p75(-/-) mice). The trigeminal ganglia of NGF/p75(-/-) mice, like those of NGF/p75(+/+) mice, have increased levels of NGF protein and display a concomitant ingrowth of sympathetic axons. In contrast to the precise pattern of sprouting seen in the ganglia of NGF/p75(+/+) mice, sympathetic axons course randomly throughout the ganglionic neuropil of NGF/p75(-/-) mice, forming few perineuronal plexuses. Our results indicate that p75(NTR) is not required to initiate or sustain the growth of sympathetic axons into the NGF-rich trigeminal ganglia but rather plays a role in regulating the directional patterns of axon growth.     

Neurotrophin receptor expression is induced in a subpopulation of trigeminal neurons that label by retrograde transport of NGF or fluoro-gold following tooth injury

Tissue responses to injury are regulated by neurotrophins and neurotrophin receptor levels and can involve both retrograde and paracrine/autocrine trophic signaling. To determine how neurotrophins may contribute to the injury response, the timing and the extent of the up-regulation of neurotrophins and their receptors was examined in a model system which is particularly well suited for the analysis of trophic signaling pathways in response to injury. Injury to the occlusal surfaces of rat molar cusps induces a localized increase in nerve growth factor (NGF) expression in the dental pulp within 4-6 h. Radiolabeled NGF was transported in a receptor-mediated fashion from the teeth to a subset of neurons in the trigeminal ganglion within 15 h, indicating that these neurons possess NGF receptors (trk A and/or p75NTR). To test for NGF responses in the tooth sensory afferent neurons, levels of expression of neurotrophins and their receptors were examined by in situ hybridization in the trigeminal ganglion at 0, 4, 12, 20, 28 and 52 h post-injury. Within the maxillary division of the trigeminal ganglion, trk A expression was elevated at 4 h post-injury, with a maximum increase (2-fold) after 52 h. p75NTR was increased by 28 h post-injury and was increased 1.35-fold by 52 h. BDNF mRNA was increased 12 h after injury (1.8-fold), and 2.5-3-fold at 52 h post-injury. The trk B expression was increased only late after injury (28 and 52 h). To determine the receptor/neurotrophin phenotype of trigeminal neurons with projections to the molar teeth, these neurons were double-labeled with the retrograde tracer fluoro-gold and probes for either BDNF or trk B. The results show that tooth-innervating trigeminal neurons express BDNF, but not trk B. The timing of mRNA expression after injury and the phenotype of identified trigeminal neurons suggests a complex signaling cascade in which NGF at the injury site regulates NGF receptor expression at the levels of the cell body as well as increases in BDNF expression. Upregulated BDNF may act in a paracrine fashion on neighboring trigeminal cells expressing trk B. This signaling cascade may be a common feature of the response to mild peripheral inflammatory injuries within nociceptive pathways.     

Neurotrophin-like immunoreactivity in the human trigeminal ganglion

The localization of the neurotrophins nerve growth factor (NGF), brain-derived neurotrophic factor (BDNF), neurotrophin-4 (NT-4), and neurotrophin-3 (NT-3) was demonstrated immunohistochemically in discrete neuronal subsets of the human trigeminal ganglion at ages ranging from 23 weeks of gestation to adulthood. Neurotrophin-containing subpopulations partially overlapped with each other and with those immunoreactive for the relevant trk receptor. Glial elements could also be immunostained, labelled satellite cells being particularly abundant in NT-3 stained sections. These results suggest that the neurotrophins are of functional significance for the human trigeminal primary sensory neurones throughout life. Their localization in the ganglion cellular components supports their function as target-derived trophic factors and as molecules effective in autocrine/paracrine interactions.     

Biochemical and functional interactions between the neurotrophin receptors trk and p75NTR

Neurotrophins bind to two structurally unrelated receptors, the trk tyrosine kinases and the neurotrophin receptor p75(NTR). Ligand activation of these two types of receptor can lead to opposite actions, in particular the prevention or activation of programmed cell death. Many cells co-express trk receptors and p75(NTR), and we found that p75(NTR) was co-precipitated with trkA, trkB and trkC in cells transfected with both receptor types. Co-precipitation of p75(NTR) was not observed with the epidermal growth factor receptor. Experiments with deletion constructs of trkB (the most abundant trk receptor in the brain) and p75(NTR) revealed that both the extracellular and intracellular domains of trkB and p75(NTR) contribute to the interaction. Blocking autophosphorylation of trkB substantially reduced the interactions between p75(NTR) and trkB constructs containing the intracellular, but not the extracellular, domains. We also found that co-expression of p75(NTR) with trkB resulted in a clear increase in the specificity of trkB activation by brain-derived neurotrophic factor, compared with neurotrophin-3 and neurotrophin-4/5. These results indicate a close proximity of the two neurotrophin receptors within cell membranes, and suggest that the signalling pathways they initiate may interact soon after their activation.     

Differential dependency of cutaneous mechanoreceptors on neurotrophins, trk receptors, and P75 LNGFR

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.     

Neurotrophins regulate sequential changes in neurotrophin receptor expression by sympathetic neuroblasts

We have examined the mechanisms controlling the induction of the two NGF receptors, trkA and p75, in proliferating neuroblasts immuno-isolated from thoracolumbar embryonic sympathetic ganglia. Contrary to prior studies, we find that induction of p75 follows rather than precedes that of trkA; this late induction is consistent with the fact that p75 functions at relatively late stages of sympathetic development. trkA induction is apparently not controlled by a cell-intrinsic mechanism. Rather, this receptor is induced by environmental signals including NT-3, which also acts as an interim survival factor for these neuroblasts. trkA induction by NT-3 is consequent to its promotion of mitotic arrest, as anti-mitotic drugs also efficiently induce trkA. p75 expression is induced in trkA-expressing cells by NGF. Thus, the development of sympathetic neurons involves sequential actions of different neurotrophins, which also regulate the expression of their own and each other's receptors.     

Expression of neurotrophins and their receptors in the developing and adult rat adrenal gland

We have studied the postnatal expression of neurotrophins, their cognate high-affinity trk receptors and the low-affinity NGF receptor (p75LNGFR) in the rat adrenal gland using RT-PCR. Neurotrophin mRNAs were detectable during the whole postnatal period. Strongest signals were obtained for BDNF and NT4/5. Expression of trkA, trkB, trkC and p75LNGFR was found at all ages studied. Signals for trkA were highest in the adult adrenal medulla, whereas signals for p75LNGFR were highest in the adult adrenal cortex. Cur data suggest still largely enigmatic roles for neurotrophins in functions of the adrenal medulla and possibly also the cortex.     

NGF binding to p75 enhances the sensitivity of sensory and sympathetic neurons to NGF at different stages of development

To clarify the role of the common neurotrophin receptor p75 in modulating the survival response of sensory and sympathetic neurons to NGF at different stages of development, we compared the actions of wild-type NGF with a mutated NGF protein that binds normally to TrkA, the NGF receptor tyrosine kinase, but has greatly reduced binding to p75. At saturating concentrations, the NGF mutant promoted the survival of similar numbers of trigeminal sensory and sympathetic neurons as NGF. At subsaturating concentrations, the NGF mutant was less effective than wild-type NGF in promoting the survival of embryonic sensory neurons and postnatal sympathetic neurons but was equally effective as wild-type NGF in promoting the survival of embryonic sympathetic neurons. Whereas the levels of trkA and p75 were similar in embryonic sensory neurons and postnatal sympathetic neurons, the level of p75 was significantly lower than that of trkA in embryonic sympathetic neurons. These results indicate that binding of NGF to p75 enhances the sensitivity of NGF-dependent neurons to NGF at stages in their development when the levels of p75 and TrkA are similar.     

Bone morphogenetic protein-2 and retinoic acid induce neurotrophin-3 responsiveness in developing rat sympathetic neurons

Expression of the receptor tyrosine kinase, Trk, determines the specificity of neurotrophin responsiveness of different neuronal populations during development. Recently it has become apparent that sympathetic neurons of rat superior cervical ganglia (SCG) acquire sensitivity to neurotrophin-3 (NT3) before they become dependent on the target-derived nerve growth factor (NGF) for their survival by sequential induction of TrkC and TrkA. The mechanism controlling the expression of TrkC as well as the source of NT3 at their initial developmental stage has, however, not been clarified. Here we show that the treatment of the perinatal rat SCG neurons which express high levels of trkA mRNA with bone morphogenetic protein-2 (BMP2) induced the expression of trkC mRNA. Induction of the functional TrkC receptor by BMP2 was confirmed by the enhancement of the survival response of these neurons to NT3. Treatment of SCG neurons with retinoic acid (RA) promoted the effect of BMP2 on the induction of trkC mRNA levels. BMP2 treatment, on the other hand, promoted the effect of RA on the suppressions of trkA mRNA levels and the NGF-dependent survival of the SCG neurons. Furthermore, BMP2/RA treatment induced the endogenous expression of NT3. These results indicate that specific environmental signals can regulate neurotrophin responsiveness of developing sympathetic neurons by differential alteration of the trk and neurotrophin expressions.     

High affinity nerve growth factor binding displays a faster rate of association than p140trk binding. Implications for multi-subunit polypeptide receptors

Nerve growth factor (NGF) binds to two cell surface receptors, p140trk and p75NGFR, which are both expressed in responsive sensory, sympathetic, and basal forebrain cholinergic neurons. While p140trk belongs to the family of receptor tyrosine kinases, p75NGFR is a member of the TNF/Fas/CD40/CD30 family of receptors. Current views of neurotrophin receptor function have tended to interpret p140trk as the high affinity NGF-binding site. To assess if the binding of NGF to p140trk was distinguishable from binding to high affinity sites on neuronal cells, PC12 cell sublines were generated which expressed p140trk alone, or coexpressed both p140trk and p75NGFR. Kinetic analysis of 125I-NGF binding indicates that it has an unusually slow rate of association with p140trk (k + 1 = 8 x 10(5) M-1 s-1). When both p140trk and p75NGFR receptors are coexpressed, the rate of association of NGF is increased 25-fold to produce a higher affinity binding site. An increase in the rate of internalization was also observed. Since high affinity binding and internalization are believed to be prerequisite for the biological activities of NGF, these results suggest that the biological effects by NGF are derived from a novel kinetic binding site that requires the expression of both receptors. The implications of these results with respect to multisubunit polypeptide receptors are discussed.     

Diabetes and axotomy-induced deficits in retrograde axonal transport of nerve growth factor correlate with decreased levels of p75LNTR protein in lumbar dorsal root ganglia

The effect of sensory neurone axotomy on the level of retrograde axonal transport of nerve growth factor (NGF) was studied in the sciatic nerve of age-matched normal and 8-week streptozocin-diabetic rats. In normal rats a 10-day sciatic nerve crush induced a 41% decrease in transported NGF, however, axotomy of sensory neurones of diabetic rats did not significantly effect the already deficient levels of NGF undergoing retrograde transport. At first sight, this result indicated that transported NGF levels in the sciatic nerve of diabetic rats are at a residual level due to deficient availability of target-derived NGF. To confirm this, the relationship of the transported NGF to the level of sensory neurone expression of the NGF receptor proteins was analysed. Western blots of L4 and L5 dorsal root ganglia (DRG) homogenates revealed no effect of axotomy and/or diabetes on the levels of the 145-kDa tyrosine kinase form of trkA. However, the expression of p75LNTR protein in the intact DRG was reduced in diabetic compared with normal rats (56%; P < 0.01), and axotomy reduced the levels in the ipsilateral ganglia of normal but not diabetic rats - as seen for NGF axonal transport. Reductions in retrograde axonal transport of NGF in both diabetes and/or axotomy were associated with the levels of p75LNTR within the lumbar DRG.     

p75 and TrkA receptor signaling independently regulate amyloid precursor protein mRNA expression, isoform composition, and protein secretion in PC12 cells

The pheochromocytoma PC12 cell line was used as a model system to characterize the role of the p75 neurotrophin receptor (p75NTR) and tyrosine kinase (Trk) A nerve growth factor (NGF) receptors on amyloid precursor protein (APP) expression and processing. NGF increased in a dose-dependent fashion neurite outgrowth, APP mRNA expression, and APP secretion with maximal effects at concentrations known to saturate TrkA receptor binding. Displacement of NGF binding to p75NTR by addition of an excess of brain-derived neurotrophic factor abolished NGF's effects on neurite outgrowth and APP metabolism, whereas addition of brain-derived neurotrophic factor alone did not induce neurite outgrowth or affect APP mRNA or protein processing. However, treatment of PC12 cells with C2-ceramide, an analogue of ceramide, the endogenous product produced by the activity of p75NTR-activated sphingomyelinase, mimicked the effects of NGF on cell morphology and stimulation of both APP mRNA levels and APP secretion. Specific stimulation of TrkA receptors by receptor cross-linking, on the other hand, selectively stimulated neurite outgrowth and APP secretion but not APP mRNA levels, which were decreased. These findings demonstrate that in PC12 cells expressing p75NTR and TrkA receptors, binding of NGF to the p75NTR is required to mediate NGF effects on cell morphology and APP metabolism. Furthermore, our data are consistent with NGF having specific effects on p75NTR not shared with other neurotrophins. Lastly, we have shown that specific activation of TrkA receptors--in contrast to p75NTR-associated signaling--stimulates neurite outgrowth and increases nonamyloidogenic secretory APP processing without increases in APP mRNA levels.     

Effect of neurocatin on the activity of monoamine oxidase B in rat brain synaptosomes

When the phenotype of neurons in pre- and paravertebral sympathetic ganglia are compared, there are marked differences in NGF dependence, neuropeptide content, connectivity and electrophysiological properties. The trophic interactions that induce these differences are currently poorly understood. One explanation is that prevertebral neurons receive a second neurotrophic signal, other than NGF, from their target of innervation. If this is the case, neurons in the prevertebral ganglia should express another neurotrophin receptor, in addition to the NGF receptor (trkA). To test this prediction, the level of expression of three neurotrophin receptors, trkA, trkB and trkC, were examined in one paravertebral sympathetic ganglia, the SCG, and two prevertebral ganglia, the celiac and superior mesenteric ganglia. It was found that mRNA encoding the full-length form of the trkB receptor was barely expressed in the SCG. Significantly higher levels of full-length trkB mRNA expression were found in the prevertebral ganglia. Ligands of the trkB receptor may, therefore, contribute to the differentiation and/or survival of some prevertebral sympathetic neurons.     

Rapid suppression of free radical formation by nerve growth factor involves the mitogen-activated protein kinase pathway

Neurotrophins such as nerve growth factor (NGF) regulate neuronal survival during development and are neuroprotective in certain models of injury to both the peripheral and the central nervous system. Although many effects of neurotrophins involve long-term changes in gene expression, several recent reports have focused on rapid effects of neurotrophins that do not involve synthesis of new gene products. Because enhanced formation of reactive oxygen species (ROS) represents one consequence of many insults that produce neuronal death, we hypothesized that neurotrophins might influence neuronal function and survival through acute alterations in the production of ROS. Using an oxidation-sensitive compound, dihydrorhodamine, we measured ROS formation in a central nervous system-derived neuronal cell line (GT1-1 trk) and in superior cervical ganglion neurons, both of which express the transmembrane NGF receptor tyrosine kinase, trkA. There was enhanced production of ROS in both cell types in the absence of NGF that was rapidly inhibited by application of NGF; complete inhibition of ROS generation in GT1-1 trk cells occurred within 10 min. NGF suppression of ROS formation was prevented by PD 098059, a specific inhibitor of MEK (mitogen/extracellular receptor kinase, which phosphorylates mitogen-activated protein kinase). The observation that NGF acutely blocks ROS formation in neurons through activation of the mitogen-activated protein kinase pathway suggests a novel mechanism for rapid neurotrophin signaling, and has implications for understanding neuroprotective and other effects of neurotrophins.     

Transgenic mice expressing the intracellular domain of the p75 neurotrophin receptor undergo neuronal apoptosis

We have asked whether p75(NTR) may play a role in neuronal apoptosis by producing transgenic mice that express the p75(NTR) intracellular domain within peripheral and central neurons. These animals showed profound reductions in numbers of sympathetic and peripheral sensory neurons as well as cell loss in the neocortex, where there is normally little or no p75(NTR) expression. Developmental loss of facial motor neurons was not observed, but induced expression of the p75(NTR) intracellular domain within adult animals led to increased motor neuron death after axotomy. Biochemical analyses suggest that these effects were not attributable to a p75(NTR)-dependent reduction in trk activation but instead indicate that the p75(NTR) intracellular domain may act as a constitutive activator of signaling cascades that regulate apoptosis in both peripheral and central neurons.     

Co-localization of high-affinity neurotrophin receptors in nucleus basalis of Meynert neurons and their differential reduction in Alzheimer's disease

It has been suggested that degeneration of neurons in Alzheimer's disease is the result of diminished trophic support. However, so far no evidence has been forwarded that neuronal degeneration in Alzheimer's disease is causally related to insufficient production of neurotrophins. The present study deals with (i) the expression and co-localization of tyrosine kinase receptors (trks) in the human nucleus basalis of Meynert and (ii) alterations of these receptors in Alzheimer's disease in the nucleus basalis of Meynert, an area severely affected in Alzheimer's disease. The expression of trkA, trkB and trkC in the nucleus basalis of Meynert of control and Alzheimer's disease brains was studied using three polyclonal antibodies specifically recognizing the extracellular domain of trkA, trkB and trkC. Brain material of eight controls and seven Alzheimer's disease patients was obtained at autopsy, embedded in paraffin and stained immunocytochemically. Using an image analysis system, we determined the proportion of trk neurons expressing the different trk receptors in controls and Alzheimer's disease patients. In control brains, trkA, trkB and trkC were differentially expressed in numerous nucleus basalis of Meynert neurons. The highest proportion of neurons was found to express trkB (75%), followed by trkC (58%) and trkA (54%). Furthermore, using consecutive sections, a clear co-localization of trk receptors was observed in the same neurons. The highest degree of co-localization was observed between trkA and trkB. In Alzheimer's disease patients, the number of immunoreactive neurons and the staining intensity of individual neurons was reduced dramatically. Reduction in the proportion of neurons expressing trkA was 69%, in trkB 47% and in trkC 49%, which indicated a differential reduction in the amount of trk receptors in Alzheimer's disease. These observations indicate that nucleus basalis of Meynert neurons can be supported by more than one neurotrophin and that the degeneration of these neurons in Alzheimer's disease is associated with a decreased expression of trk receptors, suggesting a decreased neurotrophin responsiveness of nucleus basalis of Meynert neurons in Alzheimer's disease.     

Dorsal root ganglion neurons require functional neurotrophin receptors for survival during development

Neurotrophins are the most profound known regulators of survival in the developing peripheral nervous system. Within dorsal root ganglia, the signalling receptors for the different members of the neurotrophin family are distributed in distinct patterns suggesting regulation of different functional classes of sensory neurons. Abnormalities observed in neurotrophin receptor mutant mice have confirmed this idea. Both trkA (-/-) and trkC (-/-) mice have striking neurological defecits referrable to subpopulations of DRG neurons which have distinct axon projections in the periphery. These results thus generalize concepts of dependence on target-derived factors based on extensive work with the prototypical neurotrophin, nerve growth factor. Further analysis of these animals also provides evidence for more complex developmental mechanisms including dependence on locally synthesized neurotrophins at early developmental stages and plasticity of neurotrophin receptor expression.     

Differential regulation of substance P by all members of the nerve growth factor family of neurotrophins in avian dorsal root ganglia throughout development

This study examined the effects of nerve growth factor, brain-derived neurotrophic factor, neurotrophin-3 and neurotrophin-4/5 on substance P levels in dorsal root ganglia of the quail shortly after ganglia formation (stage 26, embryonic day 4.5), during the middle of development (stage 33, embryonic day 7.5) and during late development (stage 44, embryonic day 14). It has already been shown that nerve growth factor increases levels of substance P during the middle and late stages of development, and that messenger RNA for the neurotrophin receptors, trkA, trkB and trkC is present at all of these stages. Dorsal root ganglia were isolated, rinsed with defined medium to dilute endogenous neurotrophins and exposed to one of the neurotrophins for either 4 or 20 h. Substance P levels were quantitated using enzyme immunoassay. None of the neurotrophins had any effect on substance P levels in dorsal root ganglia obtained at stage 26 after either a 4 or 20 h exposure time. Nerve growth factor, brain-derived neurotrophic factor, neurotrophin-3 and neurotrophin-4/5 all significantly increased levels of substance P after either a 4 h or 20 h incubation in ganglia obtained at stages 33 and 44. The effects of nerve growth factor and neurotrophin-3 were specific: increases in substance P were completely blocked by simultaneous exposure to antibodies against either nerve growth factor or neurotrophin-3. The absence of any effect of neurotrophins on substance P expression during early development was unexpected, since dorsal root ganglia exhibit substantial levels of substance P and receptors for the neurotrophins are present and are apparently functional. It was also surprising that brain-derived neurotrophic factor, neurotrophin-3 and neurotrophin-4/5 induced increases in substance P levels during the middle and late stages of development, since substance P was thought to be exclusively localized to small TrkA neurons in dorsal root ganglia. However, immunocytochemical examination of dorsal root ganglia at stages 33 and 44 revealed substance P-like immunoreactivity in larger neurons as well as in small neurons. The results of this study have shown that different cellular responses to neurotrophins, such as effects on survival and/or peptide expression, may be acquired with differing temporal patterns not strictly related to expression of their receptors. Further, the regulation of neuropeptide synthesis in dorsal root ganglia is not due to any one neurotrophic factor. and the factors that regulate expression during early development are still unknown.     

The nu1 + 5nu3 Dyad of 12CO2 and 13CO2

It has been recently shown that intraventricular injections of nerve growth factor (NGF) prevent the effects of monocular deprivation in the rat. We have tested the localization and the molecular nature of the NGF receptor(s) responsible for this effect by activating cortical trkA receptors in monocularly deprived rats by cortical infusion of a specific agonist of NGF on trkA, the bivalent antirat trkA IgG (RTA-IgG). TrkA protein was detected by immunoblot in the rat visual cortex during the critical period. Rats were monocularly deprived for 1 week (P21-28) and RTA-IgG or control rabbit IgG were delivered by osmotic minipumps. The effects of monocular deprivation on the ocular dominance of visual cortical neurons were assessed by extracellular single cell recordings. We found that the shift towards the ipsilateral, non-deprived eye was largely prevented by RTA-IgG. Infusion of RTA-IgG combined with antibody that blocks p75NTR (REX), slightly reduced RTA-IgG effectiveness in preventing monocular deprivation effects. These results suggest that NGF action in visual cortical plasticity is mediated by cortical TrkA receptors with p75NTR exerting a facilitatory role.