Biomedical subjects

Eduardo Soriano

Publications and source records attributed to Eduardo Soriano.

At least 19 recordsLinked to original sources

PubMed2006

Involvement of the myelin-associated inhibitor Nogo-A in early cortical development and neuronal maturation.

Nogo-A is a myelin-associated protein expressed by neurons and myelinating mature oligodendrocytes in the central nervous system. Although most research has focused on the participation of Nogo-A in the prevention of axonal regeneration and plasticity in the adult, little attention has been paid to the putative functions of Nogo-A during embryonic development. Here we examined the general pattern and cell-specific distribution of Nogo-A in the prenatal mouse telencephalon. In addition, we studied the development of the major axon tracts and radial and tangential migration in Nogo-A/B/C knockout mice. The pattern of Nogo-A showed distinct distribution in radial glia and postmitotic neurons, in which it is particularly enriched in developing axons. Similarly, Nogo-A was enriched at the leading process of tangentially migrating interneurons but not detectable in radial migrating neurons. Although a low level of Nogo-A appears to be on the surface of many cortical neurons, most proteins have intracellular localization. In Nogo-deficient background, neurons displayed early polarization and increased branching in vitro, probably reflecting a cell-intrinsic role of Nogo proteins in branching reduction, and early tangential migration was delayed. On the basis of these observations, we propose that Nogo proteins, particularly Nogo-A, are involved in multiple processes during cortical development.

Aging↗

PubMed2006

Semaphorin 6C leads to GSK-3-dependent growth cone collapse and redistributes after entorhino-hippocampal axotomy.

We studied the changes in the distribution of a specific variant of Semaphorin Y/6C (Sema6C) in mouse forebrain after axotomy of the entorhino-hippocampal perforant pathway. We found this isoform to be widely expressed during development, remaining in the adult and showing variations in distribution when the perforant pathway was axotomized. These changes were detected in both the hippocampal and entorhinal cortices. Sema6C1 immunoreactivity (IR) was high in the stratum radiatum of the hippocampus proper and the inner molecular layer of the dentate gyrus; the entorhinal cortex showed Sema6C1 IR in both cell bodies and in fibers of the II/III and V/VI layers. In axotomized animals, the IR of the ipsilateral, but not the contralateral, hemisphere showed that IR had moved into the stratum lacunosum-moleculare, the medial molecular layer of the dentate gyrus and the fibers, but not the cell bodies, of the entorhinal cortex. These results were not reproduced after lateral axotomy of the fimbria fornix, indicating a specific role for Sema6C variants in the generation and/or stability of entorhino-hippocampal synapses. Growth cone collapse of entorhinal and pyramidal neurons, as well as activation of glycogen synthase kinase-3 (GSK-3) through depletion of the inactive pool, induced by diffusible Sema6C1 further supports this view.

Analysis of Variance↗

PubMed2006

Netrin1 exerts a chemorepulsive effect on migrating cerebellar interneurons in a Dcc-independent way.

Few studies have addressed the issue of how GABAergic interneurons in the cerebellar cortex migrate or what guidance cues steer them. Recent data show that their development starts at the cerebellar germinal epithelium on top of the fourth ventricle. These interneurons continue to proliferate in the postnatal cerebellar white matter and later migrate to their final position in the cerebellar cortex. Here we report the chemorepulsive action of Netrin1 on postnatal cerebellar interneurons in vitro and also show the expression pattern of Netrin1 and its receptors Dcc and Unc5. Our expression results further suggest that Netrin1 is involved in the migration of GABAergic interneurons in vivo. Moreover, our data point to Bergmann glial fibers as possible tracks for these cells en route to the molecular layer. Finally, experiments using blocking antibodies allow us to conclude that Dcc, although expressed by postnatal cerebellar interneurons, is not involved in the repulsive response triggered by Netrin1 in these cells.

Age Factors↗

PubMed2006

Expression pattern of ACK1 tyrosine kinase during brain development in the mouse.

Ack1 is a non-receptor tyrosine kinase that is highly expressed in the adult central nervous system (CNS). Here, we studied the distribution of Ack1 mRNA throughout the development of mouse CNS. Expression was detected in all areas of the brain but especially high levels were observed in the neocortex, hippocampus, and cerebellum. Interestingly, expression levels were prominent in areas of proliferation such as the subventricular zone and areas that originate other structures such the pontine nucleus and the ganglionic eminence. During development, several areas showed an increase in Ack1 expression, especially the dentate gyrus and CA3 in the hippocampus, layer V in the neocortex, and the Purkinje cell layer in the cerebellum. These results demonstrate that this kinase is up-regulated during development and that it is expressed in proliferative areas and in migratory pathways in the developing brain.

Animals↗

PubMed2006

Reelin expression and glycosylation patterns are altered in Alzheimer's disease.

Reelin is a glycoprotein that is essential for the correct cytoarchitectonic organization of the developing CNS. Its function in the adult brain is less understood, although it has been proposed that Reelin is involved in signaling pathways linked to neurodegeneration. Here we analyzed Reelin expression in brains and cerebrospinal fluid (CSF) from Alzheimer's disease (AD) patients and nondemented controls. We found a 40% increase in the Reelin protein levels in the cortex of AD patients compared with controls. Similar increases were detected at the Reelin mRNA transcriptional level. This expression correlates with parallel increases in CSF but not in plasma samples. Next, we examined whether CSF Reelin levels were also altered in neurological diseases, including frontotemporal dementia, progressive supranuclear palsy, and Parkinson's disease. The Reelin 180-kDa band increased in all of the neurodegenerative disorders analyzed. Moreover, the 180-kDa Reelin levels correlated positively with Tau protein in CSF. Finally, we studied the pattern of Reelin glycosylation by using several lectins and the anti-HNK-1 antibody. Glycosylation differed in plasma and CSF. Furthermore, the pattern of Reelin lectin binding differed between the CSF of controls and in AD. Our results show that Reelin is up-regulated in the brain and CSF in several neurodegenerative diseases and that CSF and plasma Reelin have distinct cellular origins, thereby supporting that Reelin is involved in the pathogenesis of a number of neurodegenerative diseases.

Alzheimer Disease↗

PubMed2006

Reelin induces the detachment of postnatal subventricular zone cells and the expression of the Egr-1 through Erk1/2 activation.

Reelin binds to very low-density lipoprotein receptor and apolipoprotein E receptor 2, thereby inducing mDab1 phosphorylation and activation of the phosphatidylinositide 3 kinase (PI3K) pathway. Here we demonstrate that Reelin activates the mitogen-activated protein kinase/extracellular signal-regulated kinase (ERK) pathway, which leads to the phosphorylation of Erk1/2 proteins. The inhibition of Src family kinases (SFK) blocked Reelin-dependent Erk1/2 activation. This was also shown in neuronal cultures from mDab1-deficient mice. Although rat sarcoma viral oncogene was weakly activated upon Reelin treatment, pharmacological inhibition of the PI3K pathway blocked Reelin-dependent ERK activation, which indicates cross talk between the ERK and PI3K pathways. We show that blockade of the ERK pathway does not prevent the chain migration of neurons from the subventricular zone (SVZ) but does inhibit the Reelin-dependent detachment of migrating neurons. We also show that Reelin induces the transcription of the early growth response 1 transcription factor. Our findings demonstrate that Reelin triggers ERK signaling in an SFK/mDab1- and PI3K-dependent manner and that ERK activation is required for Reelin-dependent transcriptional activation and the detachment of neurons migrating from the SVZ.

Animals↗

PubMed2006

Regeneration of lesioned entorhino-hippocampal axons in vitro by combined degradation of inhibitory proteoglycans and blockade of Nogo-66/NgR signaling.

Damaged axons do not regenerate after axotomy in the adult mammalian central nervous system (CNS). This may be due to local inhibitory factors at the site of injury, such as overexpression of chondroitin sulfate (CS) proteoglycans (CSPG), and the presence of myelin-associated inhibitors (MAI). To overcome CSPG- or myelin-induced inhibition, strategies based on extrinsic and intrinsic treatments have been developed. For example, NEP1-40 is a synthetic peptide that promotes axonal regeneration by blocking Nogo-66/NgR interaction and chondroitinase ABC (ChABC), which degrades CS, thereby also promoting axon regrowth. Here, we examined whether the combination of these complementary strategies facilitates regeneration of the lesioned entorhino-hippocampal pathway (EHP) in slice cultures. In this model, overexpressed CSPG and MAI impaired axon regrowth, which mimics regeneration failure in vivo. Both CS cleavage with ChABC and NEP1-40 strongly facilitated the regrowth of entorhinal axons after axotomy, permitting the re-establishment of synaptic contacts with target cells. However, the combined treatment did not improve the regeneration induced by ChABC alone, and the delayed treatment of ChABC, but not NEP1-40, had a less pronounced effect on axonal regrowth compared with acute treatment. These results provide insight into the development of new assays and strategies to enhance axon regeneration in injured cortical connections.

Animals↗

PubMed2006

Nogo-A expression in the human hippocampus in normal aging and in Alzheimer disease.

Myelin-associated proteins are involved in the formation and stabilization of myelin sheaths. In addition, they prevent axon regeneration and plasticity in the adult brain. Recent evidence suggests that the expression of certain myelin-associated proteins (e.g. Nogo-A) can be regulated by synaptic activity or by over-expression after neural lesions in brain syndromes such as temporal lobe epilepsy. However, no studies on Alzheimer disease (AD) have been reported in which cell loss and significant synaptic reorganization occurs. In the present study, we analyze in detail the expression of Nogo-A in the hippocampal formation in normal human aging and in AD. Our results indicate that Nogo-A is expressed by oligodendrocytes and neurons in the aged hippocampal formation. In addition, both granule cells and mossy fiber connections are also labeled in the old-aged hippocampi. Interestingly, Nogo-A is over-expressed by hippocampal neurons in AD and is associated with beta-amyloid deposits in senile plaques. Taken together, our results reinforce the hypothesis that Reticulon proteins such as Nogo-A participate in the neuronal responses stemming from hippocampal formation during senescence, and particularly in AD. These findings also indicate that Reticulon proteins could be considered as new putative drug targets in therapies of neurodegenerative disorders.

Adult↗

PubMed2005

Expression, synaptic localization, and developmental regulation of Ack1/Pyk1, a cytoplasmic tyrosine kinase highly expressed in the developing and adult brain.

Cytosolic tyrosine kinases play a critical role both in neural development and in adult brain function and plasticity. Here we isolated a cDNA with high homology to human Ack1 and mouse Tnk2. This cDNA directs the expression of a 125-kD protein that can be autophosphorylated in tyrosines. Initially, this clone was named Pyk1 for proline-rich tyrosine kinase (Lev et al., 1995); however, since it corresponds to the mouse homolog of Ack1, here we called it Ack1/Pyk1. In this study we show that Ack1/Pyk1 mRNA and protein is highly expressed in the developing and adult brain. The highest levels of Ack1/Pyk1 expression were detected in the hippocampus, neocortex, and cerebellum. Electron microscopy studies showed that Ack1/Pyk1 protein is expressed in these regions both at dendritic spines and presynaptic axon terminals, indicating a role in synaptic function. Furthermore, we demonstrate that Ack1/Pyk1 mRNA levels are strongly upregulated by increased neural activity, produced by intraperitoneal kainate injections. During development, Ack1/Pyk1 was also expressed in the proliferative ventricular zones and in postmitotic maturing neurons. In neuronal cultures, Ack1/Pyk1 was detected in developing dendrites and axons, including dendritic tips and growth cones. Moreover, Ack1/Pyk1 colocalized with Cdc42 GTPase in neuronal cultures and coimmunoprecipitated with Cdc42 in HEK 293T cells. Altogether, our findings indicate that Ack1/Pyk1 tyrosine kinase may be involved both in adult synaptic function and plasticity and in brain development.

Animals↗

PubMed2005

PrP(106-126) activates neuronal intracellular kinases and Egr1 synthesis through activation of NADPH-oxidase independently of PrPc.

Prion diseases are characterised by severe neural lesions linked to the presence of an abnormal protease-resistant isoform of cellular prion protein (PrPc). The peptide PrP(106-126) is widely used as a model of neurotoxicity in prion diseases. Here, we examine in detail the intracellular signalling cascades induced by PrP(106-126) in cortical neurons and the participation of PrPc. We show that PrP(106-126) induces the activation of subsets of intracellular kinases (e.g., ERK1/2), early growth response 1 synthesis and induces caspase-3 activity, all of which are mediated by nicotinamide adenine dinucleotide phosphate hydrogen-oxidase activity and oxidative stress. However, cells lacking PrPc are similarly affected after peptide exposure, and this questions the involvement of PrPc in these effects.

Animals↗

PubMed2005

BDNF-modulated spatial organization of Cajal-Retzius and GABAergic neurons in the marginal zone plays a role in the development of cortical organization.

The present study utilizes nestin-BDNF transgenic mice, which offer a model for early increased brain-derived neurotrophic factor (BDNF) signalling, to examine the role of BDNF in the development of cortical architecture. Our results demonstrate that the premature and homogeneous expression of BDNF, while preserving tangential migration from the ganglionic eminence to the cortex, impairs the final radial migration of GABAergic neurons, as well as their integration in the appropriate cortical layers. Moreover, Cajal-Retzius (CR) cells and GABAergic neurons segregate in the cortical marginal zone (MZ) in response to BDNF signalling, leading to an alternating pattern and a columnar cortical organization, within which the migration of different neuronal populations is specifically affected. These results suggest that both CR and GABAergic neurons play a role in directing the radial migration of late-generated cortical neurons, and that the spatial distribution of these cells in the MZ is critical for the development of correct cortical organization. In addition, reelin secreted by CR cells in the MZ is not sufficient to direct the migration of late-born neurons to the upper cortical layers, which most likely requires the presence of reelin-secreting interneurons in layers V-VI. We propose that in addition to modulating reelin expression, BDNF regulates the patched distribution of CR and GABAergic neurons in the MZ, and that this spatial distribution is involved in the formation of anatomical and/or functional columns and convoluted structures.

Animals↗

PubMed2005

Cell proliferation in the adult hippocampal formation of rodents and its modulation by entorhinal and fimbria-fornix afferents.

New granule neurons are produced in the dentate gyrus (DG) of rodents throughout adult life. Recent studies have also reported adult neurogenesis in the cerebral cortex in normal animals or after brain injury. However, few of these studies focused on the hippocampal formation (HF), a cortical area involved in learning and memory in which extensive cell death occurs in neurodegenerative diseases. Thus, we studied cell proliferation in the HF of rodents and the intrinsic putative neurogenic potential of entorhinal cortex (EC) progenitors. We show that only the DG generates new neurons in the HF. In addition, neurospheres from the EC differentiate into neurons and glia in vitro and after transplantation in the adult DG. We also analyzed whether the absence of the synaptic input from the main hippocampal afferents induces neuronal generation in the HF outside the DG and/or regulates the proliferation of DG neuroprogenitors. We show that the denervation of the hippocampus does not induce neurogenesis in HF regions other than the DG. However, neuroprogenitor proliferation in the DG is reduced after fimbria-fornix lesions but not after entorhinal deafferentation, which supports the view that neuroprogenitor proliferation and/or differentiation in the DG are controlled from basal forebrain/septal neurons.

Adaptation, Physiological↗

PubMed2005

The cells of cajal-retzius: still a mystery one century after.

Cajal-Retzius (CR) cells are an enigmatic class of neurons located at the surface of the cerebral cortex, playing a major role in cortical development. In this review, we discuss several distinct features of these neurons and the mechanisms by which they regulate cortical development. Many CR cells likely have extracortical origin and undergo cell death during development. Recent genetic studies report unique patterns of gene expression in CR cells, which may help to explain the developmental processes in which they participate. Moreover, a number of studies indicate that CR cells, and their secreted gene product, reelin, are involved in neuronal migration by acting on two key partners, migrating neurons and radial glial cells. Emerging data show that these neurons are a critical part of an early and complex network of neural activity in layer I, supporting the notion that CR cells modulate cortical maturation. Given these key and complex developmental properties, it is therefore conceivable for CR cells to be implicated in the pathogenesis of a variety of neurological disorders.

Animals↗

PubMed2005

Age-dependent spontaneous hyperexcitability and impairment of GABAergic function in the hippocampus of mice lacking trkB.

Patterned intrinsic network activity plays a central role in shaping immature neuronal networks into functional circuits. However, the long-lasting signals that regulate spontaneous activity of developing circuits have not been identified. Here we study the net impact of TrkB signaling on early network activity of identified neuronal populations by analyzing postnatal hippocampi from trkB null mice. Ca2+ imaging showed that pyramidal neurons of trkB-/- mice displayed a decrease in intrinsic synchronous activity in neonatal animals but an increase in juveniles. Strikingly, alterations in network activity in trkB-/- hippocampus were associated with an aberrant induction of the transcription factor Fos. In contrast to pyramidal neurons, spontaneous [Ca2+]i oscillations in trkB-/- interneurons were consistently impaired throughout postnatal development. Moreover, the number of GABAergic synapses and the expression levels of GAD65 and KCC2 were decreased in mutant hippocampi, indicating that pre- and post-synaptic GABAergic components were impaired in trkB-/- mice. Finally, the partial blockade of GABA(A) receptor in postnatal slices revealed that mutant hippocampi displayed an increased susceptibility to network hyperexcitability. These results indicate that the lack of TrkB signaling during development impairs GABAergic neurotransmission, thereby leading to an age-dependent decrease followed by an increase in the intrinsic excitability of neuronal circuits. Furthermore, the present study indicates that long-lasting TrkB signaling may contribute to the construction of CNS circuits by modulating patterns of spontaneous [Ca2+]i oscillations.

Aging↗

PubMed2005

Functions of ephrin/Eph interactions in the development of the nervous system: emphasis on the hippocampal system.

Ephrins and their Eph receptors are membrane-anchored proteins that have key roles in the development of the Central Nervous System. The main characteristics of ephrin/Eph interactions are that their effect is mediated by cell-to-cell contacts and that they can propagate bidirectional signals downstream of the ligand-receptor complex. These characteristics make ephrins and Eph receptors critical cues in the regulation of migrating cells or axons, and in the establishment of tissue patterns and topographic maps in distinct regions of the developing brain. In addition, ephrins and Eph receptors regulate synapse formation and plasticity. These roles would be promoted by complementary gradual expression of receptors and ligands in the neurons involved. Although, historically, ephrins and Eph receptors have been considered as repulsion signals through barriers or gradients, new evidence indicates that they may be both inhibitory and permissive/active cues depending on expression levels. The expression of distinct ligands and receptors in the developing and mature hippocampus suggests that these proteins are involved in distinct processes during the development and maturation of the hippocampal region. In fact, recent studies have shown that ephrin/Eph signaling participates in the formation of the layer-specific patterns of hippocampal afferents, in synaptogenesis and in plasticity. Therefore, ephrin/Eph interactions should be considered a crucial system in the development and maturation of the brain regions, including the hippocampus.

Animals↗

PubMed2005

Lack of TrkB and TrkC signaling alters the synaptogenesis and maturation of mossy fiber terminals in the hippocampus.

We have studied the role of endogenous neurotrophins in the formation and maturation of intrinsic hippocampal connections in vivo and analyzed the dentate granule cell projections in both trkB-/- and trkC-/- mice. Immunohistochemistry against calbindin did not show major alterations in the distribution of granule cell axons, which were located exclusively in the hilus and the stratum lucidum. However, the thickness of the stratum lucidum (mossy fiber termination zone) and the density of mossy fiber terminals were reduced in the absence of TrkB signaling. Electron-microscopic analyses showed that the fine structure of mossy terminals was altered in both trkB-/- and trkC-/- mice. Mutant granule cell terminals were smaller than those in wild-type animals and showed a reduction in both the number of synaptic contacts and synaptic vesicles. Immunofluorescence assays demonstrated that the expression levels of most synaptic-associated proteins (v-SNAREs and t-SNAREs) were altered in the mossy fibers of trkB- and trkC-deficient mice. Our results therefore reveal that TrkB and TrkC signaling is required for the maturation of granule cell axons.

Animals↗

PubMed2005

The Netrin family of guidance factors: emphasis on Netrin-1 signalling.

During the development of the nervous system, neurons respond to the coordinated action of a variety of attractive and repulsive signals from the embryonic environment. Netrins form a family of extracellular proteins that regulate the migration of neurons and axonal growth cones. These proteins are bifunctional signals that are chemoattractive for some neurons and chemorepellent for others. Netrins mainly interact with the specific receptors DCC and UNC-5 family. To date, several Netrins have been described in mouse and humans: Netrin-1, -3/NTL2, -4/beta and G-Netrins. Netrin-1 is the most studied member of the family. It is involved in the development many projections of the nervous system. When Netrin-1 interacts with its specific receptors, a cascade of local cytoplasmic events is triggered. Several signal transduction pathways and effector molecules have been implicated in the response to Netrin-1: small Rho-GTPases, MAP-Kinases, second messengers and the Microtubule Associated Protein 1B (MAP1B).

Animals↗

PubMed2005

Role of class 3 semaphorins in the development and maturation of the septohippocampal pathway.

In examining the role of Class 3 secreted semaphorins in the prenatal and postnatal development of the septohippocampal pathway, we found that embryonic (E14-E16) septal axons were repelled by the cingulate cortex and the striatum. We also found that the hippocampus exerts chemorepulsion on dorsolateral septal fibers, but not on fibers arising in the medial septum/diagonal band complex, which is the source of septohippocampal axons. These data indicate that endogenous chemorepellents prevent the growth of septal axons in nonappropriate brain areas and direct septohippocampal fibers to the target hippocampus. The embryonic septum expressed np-1 and np-2 mRNAs, and the striatum and cerebral cortex expressed sema 3A and sema 3F. Experiments with recombinant semaphorins showed that Sema 3A and 3F, but not Sema 3C or 3E, induce chemorepulsion of septal axons. Sema 3A and 3F also induce growth cone collapse of septal axons. This indicates that these factors are endogenous cues for the early guidance of septohippocampal fibers, including cholinergic and gamma-aminobutyric acid (GABA)ergic axons, during the embryonic stages. During postnatal stages, when target cell selection and synaptogenesis take place, np-1 and np-2 were expressed by septohippocampal neurons at all ages tested. In the target hippocampus, pyramidal and granule cells expressed sema 3E and sema 3A, whereas most interneurons expressed sema 3C, but few expressed sema 3E or 3A. Combined tracing and expression studies showed that GABAergic septohippocampal fibers terminated preferentially onto sema 3C-positive interneurons. In contrast, cholinergic septohippocampal fibers terminated onto sema 3E and sema 3A-expressing pyramidal and granule cells. The data suggest that Class 3 secreted semaphorins are involved in postnatal development. Moreover, because GABAergic and cholinergic axons terminate onto neurons expressing distinct, but overlapping, patterns of semaphorin expression, semaphorin functions may be regulated by different signaling mechanisms at postnatal stages.

Acetylcholine↗