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Secreted forms of beta-amyloid precursor protein protect hippocampal neurons against amyloid beta-peptide-induced oxidative injury.

Alternative processing of the beta-amyloid precursor protein (beta APP) can result in liberation of either secreted forms of beta APP (APPSs), which may play roles in neuronal plasticity and survival, or amyloid beta-peptide (A beta), which can be neurotoxic. In rat hippocampal cell cultures A beta 1-40 caused a time- and concentration-dependent reduction in neuronal survival. APPS695 and APPS751 significantly reduced A beta-induced injury in a concentration-dependent manner. A beta caused an elevation of intracellular calcium levels ([Ca2+]i) which was significantly attenuated by APPSs. A beta also caused induction of reactive oxygen species (measured using the oxidation-sensitive fluorescent dye 2,7-dichlorofluorescein) which was also attenuated by APPSs. A beta-induced neurotoxicity and elevations of [Ca2+]i were attenuated by vitamin E, suggesting the involvement of free radicals in A beta-induced loss of calcium homeostasis and neuronal injury. The APPSs protected neurons against oxidative injury caused by exposure to iron. Taken together, the data indicate that A beta kills neurons by causing free radical production and increased [Ca2+]i. APPSs can protect neurons against such free radical- and Ca(2+)-mediated injury. These findings support the hypothesis that altered processing of beta APP contributes to neuronal injury in Alzheimer's disease.

Amyloid beta-Peptides↗

The monosynaptic connection: modulating influence of opioid peptides on the plasticity of presynaptic neurons and identified synapses.

An investigation of the effect of opioid peptides (leucine-enkephalin and methionine-enkephalin) on the plastic properties of the system of monosynaptically connected LPa7-LPa3 and RPa3, and LPa8-LPa3 and RPa3, neurons in the brain of the edible snail was carried out. It was demonstrated that all three elements in the system under investigation (the presynaptic neuron, the postsynaptic neuron, and the synapse) display the same type of plasticity, i.e., habituation to rhythmic stimulation. The enkephalins exert a modulating effect on the plastic properties of the presynaptic neuron and synapse: they slow down the habituation of the presynaptic neuron in response to intracellular stimulation and the development of habituation at a level of the synapse as well. However, the changes in the character of the postsynaptic response in the presence of enkephalins are not the direct consequence of their influence on the plastic properties of the presynaptic neuron. In addition, the enkephalins decrease the efficiency of synaptic transmission in this system: they decrease the duration of the EPSP in the postsynaptic neuron.

Animals↗

Extensive cortical reorganization following sciatic nerve injury in adult rats versus restricted reorganization after neonatal injury: implications for spatial and temporal limits on somatosensory plasticity.

Expansion of the saphenous representation in rat S-I cortex following sciatic nerve injury, examined at different times after injury and following injury at different developmental stages, has contributed to the beginnings of a comprehensive view of spatial and temporal patterns of cortical reorganization. In the first few days or weeks after deafferentation in adult animals, cortical reorganization may be spatially constrained to convergence zones between central representations of peripheral nerves (Wall and Cusick, 1984; Garraghty et al., 1994a; Schroeder et al., 1995). The apparent steady state of the rat hindpaw system up to 5-6 months after sciatic nerve injury contrasts with the additional, nearly complete reorganization shown at times longer than 7-8 months. The late reorganization supports the concept that reorganized cortical maps can continue to be altered throughout life. The prolonged time course of change in the rat hindpaw system suggests that studies of "chronic" nerve injuries need to carefully define the reorganizational state of the system at the time intervals studied. For humans with peripheral nerve or amputation injuries, the results imply that the short term postinjury status can be further altered at longer times, perhaps decades later. To characterize the neurochemical consequences or mechanisms of cortical reorganization, it is necessary to consider possible differences between early versus late changes. Time dependent changes in neurotransmitters and their receptors have been described following peripheral injury (e.g., Avendaño et al., 1995). In addition, both early and late mechanisms or consequences of reorganization may differ spatially. In the example of changes in rat hindpaw cortex after sciatic nerve transection, neurochemical changes in "expansion" cortex may differ quantitatively or qualitatively from changes in the deafferented "sciatic dominant" zone. To accurately define neurochemical changes, it may thus be necessary to characterize sample zones as having intact or reorganized inputs, or as deprived of inputs. The studies of cortical reorganization following neonatal sciatic nerve injury underscore the importance of developmental age at time of injury. Most studies of critical periods in the central nervous system have emphasized greater plasticity in developing as opposed to adult animals. Early lesions or deprivation, however, not only result in connectional alterations, but can produce dramatically more atrophy or cell loss (e.g., see Cunningham, 1982; Waite, 1984; Himes and Tessler, 1989). A number of authors have commented on the seeming paradox of greater transneuronal and retrograde cell death, yet greater neuronal plasticity, in infant animals. How developmental stage influences plastic responses to peripheral injury in the somatosensory system is not completely understood. Early peripheral lesions may deprive central neurons of necessary trophic factors, accentuate naturally occurring central cell death, and thereby result in smaller central representations. Or, smaller central representations may be produced by competitive interactions of deprived with adjacent intact pathways. In addition, throughout all stages of development, the capacity for reorganization may be spatially limited and depend on the size or pattern of the peripheral injury.

Animals↗

N-methyl-D-aspartate receptors are transiently expressed in the developing spinal cord ventral horn.

Quantitative receptor autoradiography was used to map the distribution of N-methyl-D-aspartate (NMDA) receptors in the developing rat spinal cord. Three different specific ligands, which label partially overlapping subpopulations of NMDA receptors, were used: an agonist (L-[3H]glutamate), a noncompetitive antagonist ([3H]MK-801), and a competitive antagonist ([3H]CGP-39653). In the adult, NMDA receptors labeled with all three ligands are restricted to the substantia gelatinosa in the spinal dorsal horn. In marked distinction, at postnatal day 7 NMDA receptors labeled with L-[3H]glutamate and [3H]MK-801 are present throughout the spinal gray matter. NMDA receptors in the neonatal spinal ventral horn have a higher affinity for L-[3H]glutamate than those in the adult substantia gelatinosa. Over the second and third postnatal weeks, NMDA receptors are lost from all areas of the spinal gray matter except for the substantia gelatinosa. Neonatal NMDA receptors identified with [3H]CGP-39653 are restricted to the substantia gelatinosa. These results show that the immature ventral horn contains a subpopulation of NMDA receptors and raise the possibility that motor neurons transiently express NMDA receptors in early postnatal life. Ventral horn NMDA receptors may be a component of the mechanisms by which the mature phenotype of motor neurons is acquired through activity-dependent processes. The loss of NMDA receptors over the course of development may play a role in limiting the period of motor neuron plasticity.

2-Amino-5-phosphonovalerate↗

Metabotropic suppression of excitation in murine autaptic hippocampal neurons.

Depolarization-induced suppression of excitation (DSE) and inhibition (DSI) are forms of short-term neuronal plasticity involving postsynaptic release of an endocannabinoid and the activation of presynaptic cannabinoid CB1 receptors. We have recently reported that CB1-dependent DSE can be elicited in autaptic cultures of excitatory hippocampal neurons of the mouse. We now report that the same preparation exhibits a parallel G(q)-coupled receptor-dependent production of endocannabinoids causing retrograde inhibition, also via CB1 receptors, which we will refer to as metabotropic suppression of excitation (MSE). We tested a spectrum of G(q)-coupled receptor agonists and found that both muscarinic and metabotropic glutamate receptors (group I) mediate retrograde inhibition via CB1 receptors in autaptic hippocampal neurons. Thus these neurons possess not only the pre- and postsynaptic machinery necessary for DSE but also that for MSE. This permitted a closer examination of MSE and its interaction with other aspects of the endocannabinoid retrograde signalling machinery: MSE mimics and occludes DSE and is itself occluded by the endocannabinoid 2-arachidonoyl glycerol (2-AG), consistent with 2-AG as a likely mediator of MSE. In contrast to DSE, MSE undergoes heterologous desensitization over the time course of minutes. In keeping with data reported for metabotropic suppression of inhibition (MSI) and DSI in the hippocampus, subthreshold MSE and DSE act synergistically. We additionally found that Delta9-tetrahydrocannabinol, which has been shown to attenuate DSE, antagonizes MSE. Finally, we have distinguished a neuronal subpopulation that exhibits DSE and a differential complement of MSE-mediating Gq-coupled receptors, making possible contrasting studies of MSE. Autaptic endocannabinoid signalling is rich, robust and complex in a deceptively simple package, including a previously unreported postsynaptic mechanism of adaptation in addition to known presynaptic CB1 desensitization. These adaptive sites offer novel targets for modulation of endogenous cannabinoid signalling.

Animals↗

Regulation of heme oxygenase expression by cyclopentenone prostaglandins.

Prostaglandins (PGs) originate from the degradation of membranar arachidonic acid by cyclooxygenases (COX-1 and COX-2). The prostaglandin actions in the nervous system are multiple and have been suggested to play a significant role in neurodegenerative disorders. Some PGs have been reported to be toxic and, interestingly, the cyclopentenone PGs have been reported to be cytoprotective at low concentration and could play a significant role in neuronal plasticity. They have been shown to be protective against oxidative stress injury; however, the cellular mechanisms of protection afforded by these PGs are still unclear. It is postulated that the cascade leading to neuronal cell death in acute and chronic neurodegenerative conditions, such as cerebral ischemia and Alzheimer's disease, would be mediated by free radical damage. We tested the hypothesis that the neuroprotective action of cyclopentanone could be caused partially by an induction of heme oxygenase 1 (HO-1). We and others have previously reported that modulation of HO total activity may well have direct physiological implications in stroke and in Alzheimer's disease. HO acts as an antioxidant enzyme by degrading heme into iron, carbon monoxide, and biliverdin that is rapidly converted into bilirubin. Using mouse primary neuronal cultures, we demonstrated that PGs of the J series induce HO-1 in a dose-dependent manner (0, 0.5, 5, 10, 20, and 50 micro g/ml) and that PGJ(2) and dPGJ(2) were more potent than PGA(2), dPGA(2), PGD(2), and PGE(2). No significant effects were observed for HO-2 and actin expression. In regard to HO-3 expression found in rat, with its protein deducted sequence highly homologous to HO-2, no detection was observed in HO-2(-/-) mice, suggesting that HO-3 protein would not be present in mouse brain. We are proposing that several of the protective effects of PGJ(2) could be mediated through beneficial actions of heme degradation and its metabolites. The design of new mimetics based on the cyclopentenone structure could be very useful as neuroprotective agents and be tested in animal models of stroke and Alzheimer's disease.

Animals↗

Two alternative promoters direct neuron-specific expression of the rat microtubule-associated protein 1B gene.

Microtubule-associated protein 1B (MAP1B) is a major constituent of the neuronal cytoskeleton that is expressed at high levels during early brain development and plays a role in axonal growth and neuronal plasticity. Previous studies suggested that the regulation of its gene expression is primarily at the transcriptional level. Thus, the characterization of the promoter region should help to define regulatory elements that control neuron-specific and developmental expression of the MAP1B gene. We have isolated genomic clones containing up to 11 kb of the upstream region of the rat MAP1B gene, sequenced approximately 1.8 kb upstream from the translation start codon, and identified several consensus sequences. These sequences include a consensus element common to several neuronal genes, a TCC repeat, a cAMP response element, and two TATA boxes that were 134 nucleotides apart from each other. S1 nuclease and RNase protection assays identified two corresponding groups of transcription initiation sites that were used selectively in distinct regions of the nervous system and during different stages of development. Transient transfection assays with neuronal and non-neuronal cell lines demonstrated that each TATA sequence and its corresponding adjacent region could independently direct neuron-specific expression of a reporter gene. Furthermore, the transcription of the reporter gene was initiated from the same sites as those of the MAP1B gene in vivo. These results suggest that two alternative and overlapping promoters, one inducible and the other constitutive, regulate the temporal and tissue-specific expression of the rat MAP1B gene.

Amino Acid Sequence↗

Nogo A expression in the adult enteric nervous system.

Neuronal plasticity plays an important role in physiological and pathological processes within the gastrointestinal (GI) tract. Nogo A is a major contributor to the negative effect central nervous system (CNS) myelin has on neurite outgrowth after injury and may also play a role in maintaining synaptic connections in the healthy CNS. Nogo A is highly expressed during neuronal development but in the CNS declines postnatally concomitantly with a loss of regenerative potential while ganglia of the Peripheral Nervous System (PNS) retain Nogo A. The enteric nervous system shares a number of features in common with the CNS, thus the peripheral distribution of factors affecting plasticity is of interest. We have investigated the distribution of Nogo in the adult mammalian gastrointestinal tract. Nogo A mRNA and protein are detectable in the adult rat GI tract. Nogo A is expressed heterogeneously in enteric neurons throughout the GI tract though expression levels appear not to be correlated with neuronal sub-type. The pattern of expression is maintained in cultured myenteric plexus from the guinea-pig small intestine. As is seen in developing neurons of the CNS, enteric Nogo A is present in both neuronal cell bodies and axons. Our results point to a hitherto unsuspected role for Nogo A in enteric neuronal physiology.

Animals↗

Reduced neuritic outgrowth and cell adhesion in neuronal cells transfected with human alpha-synuclein.

Since recent reports have suggested that alpha-synuclein might play a role in neuronal plasticity, the main objective of this study was to determine the effects of alpha-synuclein on neuritic outgrowth. We stably transfected either human (h) alpha- or beta-synuclein cDNA in B103 rat neuronal cells. Expression of h(alpha)-synuclein resulted in reduced neurite extension and weak adhesion compared to vector-transfected and h(beta)-synuclein expressing cells. To investigate the potential pathways involved, we studied the effects of reagents known to modulate B103 proliferation and differentiation. Neither phorbol 12-myristate 13-acetate nor forskolin or antioxidants (catalase, superoxide dismutase, or vitamin E) were able to restore the reduced length of neurites in h(alpha)-synuclein-expressing cells. These results suggest that reduced neuritic activity in the h(alpha)-synuclein-expressing cells might be due, in part, to alterations in cell adhesion capacity. This might be attributed to alpha-synuclein affecting a signal transduction pathway distinct from protein kinase C and protein kinase A.

Animals↗

Bone marrow stromal cells mediate protection through stimulation of PI3-K/Akt and MAPK signaling in neurons.

Application of adult bone marrow stromal cells (BMSC) improves functional outcome in animal models of cerebral ischemia, traumatic brain injury, and spinal cord injury. Accumulating evidence suggests that such functional recovery after BMSC treatment is mediated by enhanced trophic support of the injured neurons and improved neuronal plasticity rather than tissue replacement by bone marrow-derived stem cells. Therefore, the aim of the present study was to explore the potential of non-hematopoietic BMSC to stimulate signaling pathways in neurons that mediate trophic effects and neuroprotection. In primary embryonic rat neurons, BMSC conditioned medium (CM) attenuated staurosporine (STS) or amyloid-beta peptide-induced apoptosis in a concentration-dependent manner. The neuroprotective effect of CM required several hours of pretreatment and was abolished by heating over 90 degrees C. Immunoblot analyses revealed that CM enhanced Erk1/2 and Akt phosphorylation in neurons, and the specific MEK1 inhibitor PD98059 or the phosphoinositide-3 kinase (PI3-K) inhibitor Ly294002 abolished the neuroprotective effect of CM. Further, double-conditioned medium (DCM) obtained from BMSC previously stimulated by medium from STS-challenged neurons showed a more potent anti-apoptotic effect compared to the single-conditioned medium. Overall, these findings demonstrate that BMSC trigger endogenous survival signaling pathways in neurons that mediate protection against apoptotic insults. Moreover, the interaction between stressed neurons and BMSC further amplifies the observed neuroprotective effect.

Animals↗

In vitro and in vivo characterization of hNT neuron neurotransmitter phenotypes.

The hNT neuron exhibits many characteristics of neuroepithelial precursor cells, making them an excellent model to study neuronal plasticity in vitro and in vivo. These cells express a number of neurotransmitters in vitro, including dopamine, gamma-aminobutyric acid and acetylcholine. However, there have been few reports of the neurotransmitters that hNT neurons express in vivo. The present study examined whether hNT neurons express the same neurotransmitters in vivo as they do in vitro. First, the expression of tyrosine hydroxylase (TH), glutamic acid decarboxylase (GAD), choline acetyltransferase (ChAT) and the human specific nuclear marker NuMA by hNT neurons was confirmed. Nineteen normal animals were then transplanted with 80,000 hNT neurons aimed at the striatum, hippocampus or cerebral cortex. Five additional animals received injections of medium. All animals received daily intraperitoneal injections of cyclosporine (10 mg/kg) and survived 30 days. Sections through the transplants were examined for NuMA-positive hNT neurons, and for the presence of the three neurotransmitter markers: TH, GAD and ChAT. The hNT neurons were found in the striatum and cortex. Of the hNT neurons found within the rat striatum, 33% were ChAT-positive. In the cortex, only 4% of the neurons expressed ChAT. No GAD-positive hNT neurons were detected at either site. No NuMA-positive neurons were found in the hippocampus. The implanted hNT neurons did not induce activation of astrocytes as determined by immunocytochemistry for glial fibrillary acidic protein (GFAP). Moreover, no hNT neuron was found to express GFAP in vivo. Together, these data suggest that the hNT neurons engraft in the new host tissue, maintain their neuronal identity and may be guided in differentiation according to local environmental cues.

Animals↗

Regulation of NMDA receptor subunit mRNA expression in the guinea pig vestibular nuclei following unilateral labyrinthectomy.

The localization of neurons expressing mRNAs for the NR1 and NR2A-D subunits of the glutamatergic NMDA receptor was examined by non-radioactive in situ hybridization throughout the guinea pig vestibular nuclei. After deafferentation of the vestibular nuclei by unilateral labyrinthectomy, modifications of the mRNA distributions were followed for 30 days. A quantitative analysis was performed in the medial vestibular nucleus by comparison of the labelled neurons in the ipsi- and contra-lateral nuclei. In vestibular nuclei, the NR1 subunit mRNA was found in various populations of neurons. The NR2A and NR2C subunit mRNAs were less widely distributed, whereas little NR2D mRNA was detected and only rare cells contained NR2B mRNA. NR1 and NR2A-D mRNAs were colocalized in some but not other neuronal types. Twenty hours after the lesion, there was a transient ipsilateral increase of NR1 mRNA level in the medial vestibular nucleus, followed by a decrease 48 h after the lesion and, at 3 days, by recovery to the control level. An ipsilateral increase in the mRNA level of NR2C subunit was detected 20 h after lesion and maintained at 48 h. No significant changes were apparent in NR2A, NR2B and NR2D mRNA levels. The distributions and the differential signal intensities of NR2A-D mRNAs suggest various subunit organizations of the NMDA receptors in different neurons of the vestibular nuclei. Neuronal plasticity reorganizations in the vestibular nuclei following unilateral labyrinthectomy appear to include only changes in NR1 and NR2C mRNA levels modifying the functional diversity of the NMDA receptor in the ipsilateral medial vestibular nucleus neurons. The transient changes in NR1 and the NR2C subunit mRNA expressions in response to sensory deprivation are consistent with an active role for NMDA receptors in the appearance and development of the vestibular compensatory process.

Animals↗

Nitric oxide and cGMP regulate gene expression in neuronal and glial cells by activating type II cGMP-dependent protein kinase.

Nitric oxide (NO) and cGMP have been implicated in many neuronal functions, including regulation of gene expression, but little is known about the downstream targets of NO/cGMP in the nervous system. We found that type II cGMP-dependent protein kinase (G-kinase), which is widely expressed in the brain, mediated NO- and cGMP-induced activation of the fos promoter in cells of neuronal and glial origin; the enzyme was ineffective in regulating gene expression in fibroblast-like cells. The effect of G-kinase II on gene expression did not require calcium uptake but was synergistically enhanced by calcium. G-kinase II was membrane associated and did not translocate to the nucleus; however, a soluble G-kinase II mutant translocated to the nucleus and regulated gene expression in fibroblast-like cells. Soluble G-kinase I also regulates fos promoter activity, but membrane targeting of G-kinase I prevented the enzyme from translocating to the nucleus and regulating transcription in multiple cell types, including glioma cells; this suggests that cell type-specific factor(s) that mediate the transcriptional effects of extranuclear G-kinase II are not regulated by G-kinase I. Our results suggest that G-kinase I and II control gene expression by different mechanisms and that NO effects on neuronal plasticity may involve G-kinase II regulation of gene expression.-Gudi, T., Hong, G. K.-P., Vaandrager, A. B., Lohmann, S. M., Pilz, R. B. Nitric oxide and cGMP regulate gene expression in neuronal and glial cells by activating type II cGMP-dependent protein kinase.

3T3 Cells↗

A biochemical and immunohistological study of calmodulin in rat brain structures.

Calmodulin content and immunoreactivity in rat brain structures, believed to be essential site involved in plasticity events, were determined by using biochemical and immunohistochemical methods, respectively. The levels of cytosolic and membrane-bound calmodulin paralleled the overall distribution pattern of calmodulin immunoreactivity. Very intense immunoreactivity was observed in neuronal structures of hippocampus, striatum and mesencephalon. White matter structures and, especially, myelinated nerve fibres did not reveal calmodulin immunoreactivity. Thus, the present findings are consistent with data reported in the literature that calmodulin, unlike to other calcium-binding proteins, is primarily associated with neuronal elements. The present findings support the usefulness of calmodulin studies in elucidating of cellular mechanisms underlying neuronal plasticity.

Animals↗

Lesion-induced expression of low-affinity nerve growth factor receptor-immunoreactive protein in Purkinje cells of the adult rat.

Normal adult cerebellar Purkinje cells in the rat rarely express low-affinity nerve growth factor receptor immunoreactivity. However, intense anti-low-affinity nerve growth factor receptor immunostaining was observed as early as one day after a lesion of the cerebellar cortex. Low-affinity nerve growth factor receptor immunoreactivity was confined to a selected group of Purkinje cells, the number of which reached a maximum at three days postlesion, and, in some neurons, persisted up to 10 days after damage. The intensity of Purkinje cell immunolabeling decayed abruptly with distance from the lesion site. Reactive Purkinje cells exhibited deposition of immunoreaction product in the cell soma, dendrites and axons. Characteristically, most Purkinje cell axons exhibiting intense low-affinity nerve growth factor receptor immunoreactivity had beaded, varicose morphology. Varicose fibres with the appearance of recurrent collaterals of Purkinje cell axons were also low-affinity nerve growth factor receptor-positive. Our results indicate that adult rat Purkinje cells increase low-affinity nerve growth factor receptor-immunoreactive protein in response to injury, suggesting that, in the cerebellum, low-affinity nerve growth factor receptor or low-affinity nerve growth factor receptor-like molecules may be involved in regulating neuronal plasticity during adulthood.

Animals↗

The angiotensin type 2 receptor of angiotensin II and neuronal differentiation: from observations to mechanisms.

The angiotensin II (Ang II) type 2 receptor (AT(2)) is a member of the seven-transmembrane domain, G-protein coupled receptor family. This receptor is ubiquitously distributed in the fetus but, in most tIssues, its expression dramatically falls in the first few hours after birth. Based on this observation, the hypothesis that this receptor could be involved in fetal development was raised and, over the past ten Years, many studies have tried to identify a role for the AT(2) receptor using many different tIssues and cell lines. To date, one of the major roles associated with the Ang II AT(2) receptor concerns its ability to induce neuronal differentiation. Indeed, in cells of neuronal origin, activation of the AT(2) receptor was shown to induce neurite outgrowth and elongation, modulate neuronal excitability, promote cellular migration and, in particular conditions, induce neuronal cell death. Regarding its signaling mechanisms, the AT(2) receptor still represents one of the most controversial G-protein coupled receptors since it does not stimulate the production of any of the classical second messengers. This review summarizes knowledge of the functions and the signaling mechanisms involved in the actions of the AT(2) receptor in neurons and cells of neuronal origin. Based on its altered expression in neurological disorders, a role for the AT(2) receptor in control of neuronal plasticity is proposed.

Angiotensin II↗

Constitutive Ras activity induces hippocampal hypertrophy and remodeling of pyramidal neurons in synRas mice.

The small G protein Ras, which is involved critically in neurotrophic signal transduction, has been implicated in neuronal plasticity of both the developing and the adult nervous systems. In the present study, the cumulative effects of constitutive Ras activity from early in postnatal development into the adult upon the morphology of hippocampal pyramidal neurons were investigated in synRas mice overexpressing Val12-Ha-Ras postmitotically under the control of the rat synapsin I promoter. In synRas mice, stereologic investigations revealed hypertrophy of the hippocampus associated with an increase in perikaryal size of pyramidal neurons within the CA2/CA3 region and the gyrus dentatus. Morphometric analyses of Lucifer Yellow-filled CA1 pyramidal neurons, in addition, demonstrated considerable expansion of dendritic arbors. The increase in basal dendritic size was caused primarily by alterations of intermediate and distal segments and was associated with an enlarged dendritic surface. Apical dendrites showed similar but more moderate changes, which were attributed mainly to elongation of terminal segments. Sholl analyses illustrated higher complexity of both basal and apical trees. Despite significant morphologic alterations, dendritic arbors preserve their major design principles. The synaptic density within the stratum radiatum of CA1 remained unchanged; however, increases in the total hippocampal volume and in apical dendritic size imply an increment in the absolute number of synaptic contacts. The data presented here suggest a critical involvement of Ras dependent signaling in morphoregulatory processes during the maturation and in the maintenance of hippocampal pyramidal neurons.

Animals↗

The differential expression patterns of messenger RNAs encoding Nogo-A and Nogo-receptor in the rat central nervous system.

Nogo-A and Nogo-receptor have been considered to play pivotal roles in controlling axonal regeneration and neuronal plasticity. We investigated the total distribution of Nogo-A and Nogo-receptor mRNAs in the adult rat central nervous system using in situ hybridization histochemistry. Nogo-A is abundantly expressed in both neurons and oligodendrocytes throughout the central nervous system. Interestingly, we could not find any neuron which lacks Nogo-A mRNA expression, indicating that Nogo-A mRNA is universally expressed in all neurons. In contrast, Nogo-R mRNA expression was very restricted. Nogo-R mRNA was expressed in the olfactory bulb, hippocampus, tentia tecta, some amygdala nuclei, cerebral cortex, some thalamic nuclei, medial habenular, whereas we could not detect it in the other regions. Interestingly, we did not detect Nogo-R mRNA in monoaminergic neurons, which are known to have high regenerative capacity, in the substantia nigra, ventral tegmental area, locus caeruleus, and raphe nuclei. In addition, although neurons in the reticular thalamus and cerebellar nuclei are also known to show high capacity for regeneration, Nogo-R mRNA was not detected there. These data indicate that Nogo-A and Nogo-R mRNAs were differentially expressed in the central nervous system, and suggest that the lack of Nogo-R expression in a given neuron might be necessary to keep its high regenerative capacity.

Animals↗