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In hypoxic-ischemic encephalopathy, the neural progenitors (NPs) of the developing brain fail to replenish the oligodendrocyte progenitor cells lost during hypoxic-ischemic injury (HII). In this study, we aim to examine the influence of HII on the vulnerability of human NPs derived from human embryonic stem cells with regard to cell survival and oxidative stress, followed by assessment of cellular deregulation through measuring glutathione levels, basal calcium, glutamate release, and intracellular calcium ([Ca

Studies on brain plasticity have undertaken different roads, tackling a wide range of biological processes: from small synaptic changes affecting the contacts among neurons at the very tip of their processes, to birth, differentiation, and integration of new neurons (adult neurogenesis). Stem cell-driven adult neurogenesis is an exception in the substantially static mammalian brain, yet, it has dominated the research in neurodevelopmental biology during the last thirty years. Studies of comparative neuroplasticity have revealed that neurogenic processes are reduced in large-brained mammals, including humans. On the other hand, large-brained mammals, with respect to rodents, host large populations of special “immature” neurons that are generated prenatally but express immature markers in adulthood. The history of these “immature” neurons started from studies on adhesion molecules carried out at the beginning of the nineties. The identity of these neurons as “stand by” cells “frozen” in a state of immaturity remained un-detected for long time, because of their ill-defined features and because clouded by research ef-forts focused on adult neurogenesis. In this review article, the history of these cells will be reconstructed, and a series of nuances and confounding factors that have hindered the distinction between newly generated and “immature” neurons will be addressed.

Plasticity, and in particular, neurogenesis, is a promising target to treat and prevent a wide variety of diseases (e.g., epilepsy, stroke, dementia). There are different types of plasticity, which vary with age, brain region, and species. These observations stress the importance of defining plasticity along temporal and spatial dimensions. We review recent studies focused on brain plasticity across the lifespan and in different species. One main theme to emerge from this work is that plasticity declines with age but that we have yet to map these different forms of plasticity across species. As part of this effort, we discuss our recent progress aimed to identify corresponding ages across species, and how this information can be used to map temporal variation in plasticity from model systems to humans.

Neuroplastic alterations are the key processes involved in adaptation and rehabilitation after all neurological injuries and pathologies. Being the central contributor to the developmental and adult neuroplasticity, the polysialylated form of Neural Cell Adhesion Molecule (PSA-NCAM) may prove to be a potential target to facilitate repair/regeneration after CNS injury and disease. Over the years, several experimental approaches have been developed to exploit the therapeutic potential of PSA-NCAM. Broadly, the studies focused on cell-transplantation strategies to alter PSA-NCAM properties at the injury site, injection of peptide based as well as synthetic PSA mimetics directly into the injury site or the application of PSA containing hydrogels and scaffolds as biomaterials. A comprehensive understanding of the PSA-based experimental approaches, as well as their pros and cons, is urgently required for successful implementation of this molecule in therapeutics. The current review, therefore, has been designed to give the readers a thorough account of all the diverse roles of PSA in the adult nervous system and the recent progress that has been made in developing PSA-based therapeutic approaches for neuroregeneration.

BACKGROUND: Glioblastoma (GBM) is the most common and aggressive primary brain tumour in adults. Despite the current clinical management of surgical resection, followed by radiation and chemotherapy, the median survival time is still a dismal 15 months. This may be due to treatment-resistant GBM stem cells (GSCs) that survive and migrate, resulting in tumour recurrence. Therefore, elucidating the mechanisms of GSC migration and studying ways of limiting this process will be beneficial in the treatment of GBM. A key molecule of interest is polysialylated neural cell adhesion molecule (PSA-NCAM). During normal development and adult neurogenesis, its presence on the cell surface reduces interactions with the extracellular matrix and aids in cellular migration. However, it has also been associated with malignant brain tumours and with negative patient prognosis. METHODS: We investigated PSA-NCAM’s role in tumour recurrence by immunohistologically evaluating over 160 surgically resected brain tumour specimens for PSA-NCAM expression and correlating this with patient outcomes. We also utilized GSCs isolated from the same patient specimens to investigate the role of PSA-NCAM in tumour cell migration. RESULTS: Univariate and Cox proportional hazard analysis showed that PSA-NCAM expression was a strong predictor of rapid tumour progression, even more so than the cell proliferation marker Ki67, which is often used to assess tumour grade. In addition, high-content image analysis revealed that PSA-NCAM was highly expressed by migrating patient-derived GSCs in vitro, and drugs that limited their migration also decreased PSA-NCAM expression. This led to investigations that aimed to elucidate the effects of PSA-NCAM removal on GSC migration. SUMMARY: Our work highlights the potential role of PSA-NCAM in GSC migration and tumour progression. This opens up avenues to pharmacologically and genetically manipulate PSA-NCAM to reduce GBM cell migration and curb tumour recurrence.

Immaturity of neurons in normoganglionic colon in Hirschsprung disease (HD), anorectal malformation (AM), idiopathic constipation (IC), and normal controls (C) was assessed using polysialyated neural cell adhesion molecule.Polysialyated neural cell adhesion molecule immunoreactivity in 3 sections of normoganglionic colon from HD (n = 48), AM (n = 25), IC (n = 36), and C (n = 18) were scored semiquantitatively according to age; 1 day to 11 months (G1), 1 to 4 years (G2), and 5 years and older (G3).Neurons in all specimens appeared mature irrespective of age on hematoxylin-eosin stain. Polysialyated neural cell adhesion molecule was positive (immaturity) in all specimens during G1 (1.34 in HD, 1.60 in AM, 0.89 in IC, and 1.59 in C) and decreased significantly with age in C (0.34* for G2, 0.25* for G3; *P.01), decreased after 4 years old in IC (0.93 for G2, 0.10(#) for G3; (#)P.05), decreased gradually in AM (1.10 for G2, 0.75( section sign) for G3; ( section sign)P.05), but remained strongly positive in HD (1.34 for G1, 1.26 for G2, and 1.21 for G3; P = not significant), which after 4 years was significantly higher than C (P.05).Postoperative colonic dysmotility may be because of persistence of immature neurons in HD and impaired maturation of neurons in AM and IC.

The Ncx/Hox11L.1 gene is required for adequate development of enteric neurons in mice and Ncx/Hox11L.1 deficient (Ncx-/-) mice are used as a model for human intestinal neuronal dysplasia (IND) because of similar histopathology (hyperganglionosis), however, some 50% of Ncx-/- mice develop megacolon with a caliber change in the proximal colon, and die when 21-35 days old. We used polysialylated neural cell adhesion molecule (PSA-NCAM) to examine the maturity of enteric neurons in Ncx-/- mice to further understand the etiology of IND.PSA-NCAM immunoreactivity was measured in specimens taken 1 cm proximal to the ileocecal valve (ileum), 1 cm distal to the ileocecal valve (proximal colon), and 1 cm proximal to the anus (distal colon) from 63 mice (Ncx-/-: n = 14, Ncx+/-: n = 30, and Ncx+/+: n = 19) on days 14 (D14), 21 (D21), and 27 or later (D27).PSA-NCAM was positive (indicating immaturity) in proximal colon (submucosal and myenteric plexuses) from 8/14 (57%) Ncx-/- mice (2/4 on D14, 4/6 on D21, and 2/4 onD27) and from 5/30 (17%) Ncx+/- mice (0/2 in D14, 2/13 in D21, and 3/15 inD27). PSA-NCAM was negative (indicating maturity) in all other specimens. The incidence of PSA-NCAM positive neurons in Ncx-/- appeared to be correlated with the mortality rate seen in IND mice.Our data suggest that colonic dysmotility and pathology seen in Ncx-/- mice may be due to persistence of immature neurons in the proximal colon, which could also be the case in human IND and warrants further investigation.

The present study investigates whether the anti-schizophrenic drug risperidone may evoke changes in the expression of NCAM/PSA-NCAM proteins, an indispensable element in the remodeling of synaptic arrangements, in the medial prefrontal cortex (mPFC). Rats were treated with risperidone (0.2 mg/kg, i.p.) either once or repeatedly (once a day, for 21 days). The expression of NCAM and PSA-NCAM proteins was analyzed via western blot and immunohistochemistry at intervals of 3 h and 3, 6, and 9 days after the single or the last risperidone dose. Repeated (but not acute) administration of risperidone was found to increase the expression of NCAM-180, NCAM-140 and PSA-NCAM proteins at 3 or 6 days after treatment. PSA-NCAM immunoreactivity was found in cell bodies, perisomatic-like sites, and in the neuropil of the mPFC. Neither single nor repeated risperidone administration changed the number of PSA-NCAM neurons in the mPFC. In contrast, the repeated risperidone treatment increased the number of PSA-NCAM perisomatic-like sites and the length density of PSA-NCAM positive neuropil at 3 days after the last injection. The data obtained indicate that risperidone, given repeatedly, may promote the remodeling of the structure of presumably GABA-ergic interneurons and that it may evoke the rearrangement of the synaptic contact in the mPFC.

Exposure to particles of high energy and charge can disrupt the neuronal systems as well as the motor and cognitive behaviors mediated by these systems in a similar fashion to that seen during the aging process. In the hippocampus, adult neurogenesis is affected both by aging and irradiation with ionizing particles. Likewise, the maturation of newly formed cells in this region as measured by PSA-NCAM expression is also altered by the aging process. The present study was designed to investigate the effects of 2.5 Gy of 1 GeV/n 56Fe particles on neurogenesis using the nuclear proliferation marker 5-bromodeoxyuridine (BrdU and PSA-NCAM expression in the dentate gyrus of rats exposed to whole-body irradiation or simply placed in the chamber without being irradiated. All subjects (n=10) were sacrificed 28 days after the last BrdU injection (50 mg/kg X 3 days) and their brains were processed for immunohistochemistry. Results illustrate a decrease in the number of BrdU-positive cells as well as different distribution of these cells in the dentate gyrus of irradiated animals. Additionally, irradiated subjects show decreased levels of PSA-NCAM expression. These changes are consistent with those found in aged subjects indicating that heavy-particle irradiation is an adequate model for the study of aging.

Dendritic and synapse remodeling are forms of structural plasticity that play a critical role in normal hippocampal function. Neural cell adhesion molecule (NCAM) and its polysialylated form (PSA-NCAM) participate in neurite outgrowth and synapse formation and plasticity. However, it remains unclear whether they contribute to dendritic retraction and synaptic disassembly. Cultured hippocampal neurons exposed to glutamate (5 µM) showed a reduced MAP-2 (+) area in the absence of neuronal death 24 h after the insult. Concomitantly, synapse loss, revealed by decreased synaptophysin and post-synaptic density-95 cluster number and area, together with changes in NCAM and PSA-NCAM levels were found. Dendritic atrophy and PSA-NCAM reduction proved NMDA-receptor dependent. Live-imaging experiments evidenced dendritic atrophy 4 h after the insult; this effect was preceded by smaller NCAM clusters (1 h) and decreased surface and total PSA-NCAM levels (3 h). Simultaneously, total NCAM cluster number and area remained unchanged. The subsequent synapse disassembly (6 h) was accompanied by reductions in total NCAM cluster number and area. A PSA mimetic peptide prevented both the dendritic atrophy and the subsequent synaptic changes (6 h) but had no effect on the earliest synaptic remodeling (3 h). Thus, NCAM-synaptic reorganization and PSA-NCAM level decrease precede glutamate-induced dendritic atrophy, whereas the NCAM level reduction is a delayed event related to synapse loss. Consequently, distinctive stages in PSA-NCAM/NCAM balance seem to accompany glutamate-induced dendritic atrophy and synapse loss. Fil: Podestá, María Fernabda. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Investigaciones Farmacológicas. Universidad de Buenos Aires. Facultad de Farmacia y Bioquímica. Instituto de Investigaciones Farmacológicas; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Biología Celular y Neurociencia "Prof. Eduardo de Robertis". Universidad de Buenos Aires. Facultad de Medicina. Instituto de Biología Celular y Neurociencia ; Argentina. Universidad de Buenos Aires. Facultad de Farmacia y Bioquímica. Departamento de Farmacología. Cátedra de Farmacología; Argentina Fil: Yam, Patricia. McGill University. Montreal Neurological Institute and Hospital; Canadá Fil: Codagnone, Martín Gabriel. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Investigaciones Farmacológicas. Universidad de Buenos Aires. Facultad de Farmacia y Bioquímica. Instituto de Investigaciones Farmacológicas; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Biología Celular y Neurociencia "Prof. Eduardo de Robertis". Universidad de Buenos Aires. Facultad de Medicina. Instituto de Biología Celular y Neurociencia ; Argentina. Universidad de Buenos Aires. Facultad de Farmacia y Bioquímica. Departamento de Farmacología. Cátedra de Farmacología; Argentina Fil: Uccelli, Nonthué Alejandra. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Investigaciones Farmacológicas. Universidad de Buenos Aires. Facultad de Farmacia y Bioquímica. Instituto de Investigaciones Farmacológicas; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Biología Celular y Neurociencia "Prof. Eduardo de Robertis". Universidad de Buenos Aires. Facultad de Medicina. Instituto de Biología Celular y Neurociencia ; Argentina. Universidad de Buenos Aires. Facultad de Farmacia y Bioquímica. Departamento de Farmacología. Cátedra de Farmacología; Argentina Fil: Colman, David. McGill University. Montreal Neurological Institute and Hospital; Canadá Fil: Reines, Analia Gabriela. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Investigaciones Farmacológicas. Universidad de Buenos Aires. Facultad de Farmacia y Bioquímica. Instituto de Investigaciones Farmacológicas; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Biología Celular y Neurociencia "Prof. Eduardo de Robertis". Universidad de Buenos Aires. Facultad de Medicina. Instituto de Biología Celular y Neurociencia ; Argentina. Universidad de Buenos Aires. Facultad de Farmacia y Bioquímica. Departamento de Farmacología. Cátedra de Farmacología; Argentina

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Polysialic acid (PSA) is a highly hydrated polymer whose presence at the cell surface can reduce cell interactions, and thereby increase tissue and cellular plasticity. Given its ability to create a permissive environment for cell migration and axonal growth, the potential of engineered overexpression of PSA to promote tissue repair has been explored in the adult CNS. Several promising results have been obtained that suggest that PSA engineering may become a valuable therapeutic tool.

NCAM is an abundant cell adhesion molecule known to be important during development. Together with its posttranslational modification consisting of the addition of the polysaccharide polysialic acid (PSA), NCAM has been classically implicated in the regulation - among other developmental functions - of neurite outgrowth and stabilization of synaptic connections. A large body of work has also demonstrated that NCAM is required in the adult brain for different behavioral functions. In this review, we focus on those studies that have shown a role of NCAM and PSA-NCAM in the regulation of emotional responses and in the learning and memory processes.

Increasing evidence indicates that adhesion molecules are critically involved in the regulation of mechanisms of synaptic plasticity including synapse formation, and also synaptic remodeling associated with changes in synaptic strength. Among these, the Neural Cell Adhesion Molecule (NCAM) and its polysialylated form PSA-NCAM are important candidates. Here, we review recent results that point to a possible role of these two molecules in regulating the structural properties of excitatory synapses - namely, the composition and stability of the postsynaptic density - thereby accounting for their contribution to mechanisms of synaptogenesis and activity-dependent synaptic plasticity.

Polysialic acid (PSA) is a highly hydrated polymer whose presence at the cell surface can reduce cell interactions, and thereby increase tissue and cellular plasticity. Given its ability to create a permissive environment for cell migration and axonal growth, the potential of engineered overexpression of PSA to promote tissue repair has been explored in the adult CNS. Several promising results have been obtained that suggest that PSA engineering may become a valuable therapeutic tool.

Titelblatt und Inhaltsverzeichnis Einleitung Material und Methoden Ergebnisse Diskussion Abbildungsverzeichnis Literaturverzeichnis Danksagung Lebenslauf Erklärung, Während der Entwicklung haben die Nervenzellen des Gehirns die bemerkenswerte Fähigkeit, gegenseitige Verbindungen auszubilden, ein Entwicklungsvorgang, der präzises axonales Auswachsen, Wegfindung und korrekte Synapsenbildung voraussetzt. Im Gegensatz dazu, ist die Fähigkeit, neuronale Kontakte nach Läsion wieder herzustellen im ZNS sehr begrenzt. Zunächst untersuchten wir in vitro die späte embryonale und postnatale Entwicklung der hippocampalen Formation mit ihren Projektionen, in für das Homeobox-Gen Emx2-defizienten Mäusen. Da die Emx2-Knockout-Tiere perinatal versterben, haben wir organotypische Schnittkulturen hergestellt. In Schnitten von Knockout-Tieren war die Zytoarchitektur des prospektiven Gyrus dentatus gestört, reiften die Körnerzellen nicht aus und bildeten auch keinen Moosfasertrakt. Diese Befunde zeigen, dass Emx2 essentiell für die endgültige Differenzierung der Körnerzellen und ihrer korrekten Ausbildung der intrinsischen hippocampalen Projektionen ist. Im nächsten Versuchsaufbau konnten wir unter Verwendung der organotypischen Kokultur und anhand von in vivo Experimenten weiterhin in unseren Untersuchungen belegen, dass in den Vorgängen des Auswachsens, der Wegfindung und der synaptischen Zielfindung während der Entwicklung und nach Läsion, die Entität der Polysialinsäure (Polysialic Acid = PSA) involviert ist. Diese stellt eine einzigartige während der Entwicklung regulierte posttranslationale Modifikation des Neuralen Zelladhäsionsmolekül (Neural Cell Adhesion Molecule) NCAM dar. Durch die Verwendung eines chemisch veränderten Sialinsäurevorläufers, konnten wir die Polysialylierung von NCAM zu definierten Entwicklungs- und postläsionalen Zeitpunkten hemmen. Der PSA- Mangel bewirkte nicht nur eine fehlerhafte Moosfaserverteilung in der CA3- Pyramidenzellband, sondern auch das aberrante Eindringen von Moosfasern in die CA1-Region in vivo und förderte das axonalen Auswachsens in vitro. Des Weiteren war die Reinnervation der Moosfasern nach Läsion durch die Inhibition der PSA-Synthese in vitro signifikant erhöht. Basierend auf diesen Ergebnissen schlussfolgern wir, dass PSA notwendig für die axonale Zielfindung während der Ausbildung neuraler Schaltkreise ist und andererseits die Regeneration nach Läsion stört. Dieses Fazit impliziert umgekehrt einen positiven Effekt der pharmakologischen Modifikation von NCAM auf die Regeneration nach axonaler Schädigung, die sich in weiterführenden Experimenten als viel versprechend, in Hinblick auf einen möglichen therapeutischen Nutzen, herausstellen könnte. Um das Phänomen des axonalen Auswachsens besser untersuchen zu können, variierten wir das bereits etablierte Modell der organotypischen Kokultur. In dieser Arbeit nutzten wir die Axonales Auswachsen in der Hippocampusformation 58 organotypische Kokultur mit neugeborener wildtyp und β-Aktin-GFP transgener Maus. Dies erlaubte es uns, die Axone in situ zu markieren und die gesamte Projektion zu verfolgen. In Kokulturen von entorhinalem Cortex und Hippocampus terminierten die GFP-markierten entorhinalen Axone und die kommissuralen Axone in den korrekten hippocampalen Schichten. Ausgehend von diesen Befunden, konnten wir demonstrieren, dass dieser Chimären-Kokultur- Ansatz dazu geeignet ist, die Gesamtheit sich entwickelnder Projektionen darzustellen und die Möglichkeit bietet, direkt das axonale Ansteuern und Auswachsen lebender Neuronen zu beobachten., During development, nerve cells within the brain have the remarkable ability to form mutual interconnections, a process that relies on precisely orchestrated steps of axonal outgrowth, pathfinding, and correct synaptic targeting. In contrast, reestablishing neuronal circuits after lesion in the CNS is extremely limited. First we analysed the late embryonic and postnatal development of the hippocampal formation and its axonal projections in mice lacking the homeobox gene Emx2 expression in vitro. Since the Emx2 mutants die perinatally we used slice cultures of Emx2 mutant hippocampus to circumvent this problem. In mutant cultured hippocampus the presumptive dentate gyrus failed to develop its normal cytoarchitecture and mature dentate granule cells, including the lack of their mossy fiber projection. These data indicate that Emx2 is essential for the terminal differentiation of granule cells and the correct formation of intrinsic hippocampal connections. In another set-up, using the model of the organotypic slice culture as well as in vivo experiments in our investigations we were able to provide confirmation, that the processes of outgrowth, pathfinding, and synaptic targeting during development and following lesion involve the polysialic acid (PSA) moiety, which is a unique, developmentally regulated posttranslational modification of the neural cell adhesion molecule (NCAM). Using a chemically modified sialic acid precursor, we inhibited NCAM polysialylation at selected developmental and postlesional time points. PSA deficiency resulted not only in an abnormal mossy fiber pattern in the CA3 pyramidal layer but also in aberrant invasion of mossy fibers into the CA1 region in vivo and promotion of axonal outgrowth in vitro. Furthermore, the reinnervation by mossy fibers after lesion was significantly enhanced when inhibiting PSA formation in vitro. Based on our data, we conclude that PSA is necessary for correct axonal targeting during neuronal circuit formation, but inhibits regeneration after lesion. Conversely, these results imply that pharmacological modification of NCAM could be beneficial for regeneration following axonal damage, and further experiments may be promising with regard to a potential therapeutical use of this approach. And finally to better investigate the phenomenon of axonal outgrowth, we modified the wellestablished organotypic slice culture approach. Here we used organotypic slice co-cultures from neonate wild-type mice and ß -actin-gfp transgenic mice, which allowed us to prelabel the vital axons and to monitor the complete axonal projection. In co-cultures from entorhinal cortex and hippocampus, gfp-labeled entorhinal axons and commissural projections terminate in their correct hippocampal layers. From our data, we demonstrate that this chimaeric co-culture Axonales Auswachsen in der Hippocampusformation 60 approach is appropriate in tracing entire developing projections and may serve as a tool in directly observing the navigation and axonal elongation of living neurons.

Recent data indicating that addictive substances are able to alter brain plasticity and its morphology inclined us to determine whether acute and chronic cocaine administration could modify the expression of a polysialylated form of the neuronal cell adhesion molecule (PSA-NCAM) in the dentate gyrus of the rat hippocampus. Alterations in the PSA-NCAM expression are known to effect a variety of neuroanatomical rearrangements in the brain structure. Cocaine was administered acutely (15 mg/kg, i.p.) or repeatedly (15 mg/kg, i.p. once a day for five consecutive days). The number of PSA-NCAM immunopositive cells was determined at six time points after cocaine treatment: 6 h and 1, 2, 4, 6, and 10 days (both in acute and repeated treatment). It was found that a single injection of cocaine induced a time-dependent decrease in the number of PSA-NCAM cells in the dentate gyrus. The decrease was observed on day 1 after cocaine treatment and lasted for at least 6 days. In contrast, an increase in the number of PSA-NCAM-positive cells in the dentate gyrus was observed 2 and 4 days after the last dose of repeated cocaine. It is concluded that cocaine can evoke long-lasting changes in the PSA-NCAM protein expression in the dentate gyrus and that the direction of cocaine-induced PSA-NCAM changes depends on the regimen of cocaine administration. It is postulated that cocaine may have impact on hippocampal plasticity and subsequent processes that are controlled by plastic changes in the hippocampal structure.

Since its first description the polysialylated form of NCAM (PSA-NCAM) is thought to be a major regulator of cell-cell interactions in the nervous system. Over the past few years many crucial questions have been answered concerning PSA biosynthesis and function. Among these are the identification and cloning of the key enzymes that are responsible for its synthesis and the fact that expression of PSA is not restricted to developmental stages but maintained in the adult nervous system. In the adult, PSA has been shown to be not only a marker of structural plasticity but seems to be a major player in these processes. Originally suggested to be a purely anti-adhesive factor, modulating cell-cell interactions in general and by this allowing plasticity, there is now increasing evidence that this might not be the whole story. Instead, it appears possible that PSA-NCAM interacts with secreted signaling molecules and by this fulfills a more instructive function in brain plasticity.