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PubMed2002

Regulation of A-kinase anchoring protein 79/150-cAMP-dependent protein kinase postsynaptic targeting by NMDA receptor activation of calcineurin and remodeling of dendritic actin.

At the postsynaptic membrane of glutamatergic synapses, the cAMP-dependent protein kinase (PKA), protein kinase C (PKC), and calcineurin (CaN) anchoring protein AKAP79/150 is recruited to NMDA and AMPA glutamate receptors by postsynaptic density (PSD)-95 family membrane-associated guanylate kinase (MAGUK) scaffold proteins. These signaling scaffold complexes may function to regulate receptor phosphorylation in synaptic plasticity. Thus, it is important to understand regulation of AKAP79/150 targeting to synapses and recruitment to PSD-MAGUK complexes. AKAP79 is targeted to the plasma membrane by an N-terminal basic domain that binds phosphatidylinositol-4,5-bisphosphate (PI-4,5-P(2)) and is regulated by PKC phosphorylation and calmodulin binding. Here we demonstrate that this same domain also binds F-actin in a calmodulin- and PKC-regulated manner, targets to membrane ruffles enriched in F-actin and PI-4,5-P(2) in COS7 cells, and localizes to dendritic spines with F-actin and PSD-MAGUKs in hippocampal neurons. Inhibition of actin polymerization disrupted AKAP79 targeting of PKA and CaN to ruffles in COS7 cells and endogenous AKAP79/150 dendritic spine localization with PKA, CaN, and PSD-MAGUKs in neurons. AKAP79/150 postsynaptic localization was rapidly regulated by NMDA receptors through CaN activation and F-actin remodeling, further suggesting that AKAP79/150 signaling scaffold targeting depends on actin dynamics. NMDA receptor activation also regulated dendritic spine localization of PKA and CaN and association of the AKAP79/150-PKA complex with PSD-MAGUKs. Because AMPA receptor PKA phosphorylation and synaptic localization are regulated by similar NMDA receptor-CaN signaling pathways linked to hippocampal long-term depression, this regulation of AKAP79/150 postsynaptic targeting might be important for synaptic plasticity.

A Kinase Anchor Proteins↗
PubMed2003

Validation of target volume and position in respiratory gated CT planning and treatment.

The capability of a commercial respiratory gating system based on video tracking of reflective markers to reduce motion-induced CT planning and treatment errors was evaluated. Spherical plastic shells (2.8-82 cm3), simulating the gross target volume (GTV), were placed in a water-filled body phantom that was moved sinusoidally along the longitudinal axis of the CT scanner and the accelerator for +/- 1 cm at 15-30 cycle/min. During gated CT imaging, the x-ray exposure was initiated by the gating system shortly before the end of expiration (so that the imaging time would be centered at the end of expiration); it was terminated by the scanner after completion of each slice. In nongated CT images, the target appeared distorted and often broken up. GTVs volume errors ranged 16%-110% in axial scans, and 7%-36% in spiral scans. In gated CT images, the spheres appeared 3 and 5 mm longer than their actual diameters (volume errors 2%-16%), at the respective respiration rates of 15 and 20 cycles/min. At 30 cycles/min the target appeared 1 cm longer, and volume error ranged 25%-53%. During treatment, gating kept the beam on for a duration equal to the CT acquisition time of 1 s/slice. The difference in positional errors between gated CT and portal films was 1 mm, regardless the size of residual motion errors. Because of the potential of suboptimal placement of the gating window between CT imaging and treatment, an extra 1.5-2.5 mm safety margin can be added regardless of the size of residual motion error. For respiratory rates > or = 30 cycles/min, the effectiveness of gating is limited by large residual motion in the 1 s CT acquisition time.

Humans↗
PubMed2003

Time-restricted role for dendritic activation of the mTOR-p70S6K pathway in the induction of late-phase long-term potentiation in the CA1.

Mammalian target of rapamycin (mTOR) is a key regulator of translational capacity. The mTOR inhibitor rapamycin can prevent forms of protein synthesis-dependent synaptic plasticity such as long-term facilitation in Aplysia and late-phase long-term potentiation (L-LTP) in the hippocampal CA1 region of rodents. In the latter model, two issues remain to be addressed: defining the L-LTP phase sensitive to rapamycin and identifying the site of rapamycin-sensitive protein synthesis. Here, we show that L-LTP is sensitive to application of rapamycin only during the induction paradigm, whereas rapamycin application after the establishment of L-LTP was ineffective. Second, we observed that Thr-389-phosphorylated p70 S6 kinase (p70S6K), the main active phosphoform of the mTOR effector p70S6K, was induced in an N-methyl-D-aspartate and phosphatidylinositol 3-kinase-dependent manner throughout the dendrites but not in the cell bodies of CA1 neurons in hippocampal slices after L-LTP induction. A similar dendrite-wide activation of p70S6K was induced in primary hippocampal neurons by depolarization with KCL or glutamate. In primary hippocampal neurons, the sites of dendritic activation of p70S6K appeared as discrete compartments along dendritic shafts like the hotspots for fast dendritic translation. Conversely, only a subset of dendritic spines also displayed activated p70S6K. Taken together, the present data suggest that the N-methyl-d-aspartate-, phosphatidylinositol 3-kinase-dependent dendritic activation of the mTOR-p70S6K pathway is necessary for the induction phase of protein synthesis-dependent synaptic plasticity. Newly synthesized proteins in dendritic shafts could be targeted selectively to activity-tagged synapses. Thus, coordinated activation of dendrite-wide translation and synaptic-specific activation is likely to be necessary for long-term synaptic plasticity.

Animals↗
PubMed1998

Physiologic basis for motor learning in the vestibulo-ocular reflex.

The vestibulo-ocular reflex has been used extensively for study of the neural mechanisms of learning that is dependent on an intact cerebellum. Anatomic, physiologic, behavioral, and computational approaches have revealed the neural circuits that are used to generate the vestibulo-ocular reflex and have identified two likely sites of plasticity within those circuits. One site of plasticity is in the vestibular inputs to floccular target neurons, which are located in the vestibular nuclei and receive monosynaptic inhibition from Purkinje cells in the floccular complex of the cerebellar cortex. The other site of plasticity is in the vestibular inputs to Purkinje cells in the floccular complex, possibly in the cerebellar cortex. After reviewing the evidence that supports these conclusions, I consider a number of observations showing that the dynamics of neural circuits or cellular mechanisms play important roles in learning in the vestibulo-ocular reflex.

Fixation, Ocular↗
PubMed1990

Robust synaptic plasticity of striatal cells following partial deafferentation.

Partial ablation of the cerebral cortical input to the neostriatum generates a rapid lasting effect on the size of remaining synaptic sites. The neocortex was lesioned in adult rats and the neostriatum was analyzed for effects on remaining spines of principal cells during the period from 2 to 40 days. There was an increase in the size of spine heads, boutons and synaptic contact sites. The spine heads became very complex and a corresponding bouton enlargement was accompanied by an increase in the number of synaptic vesicles. By two days, the average profile length of postsynaptic membrane densities (PSDs) had increased by 25% representing an equivalent 50% increase in synaptic contact area. The number of synaptic sites was reduced on each principal neuron of the lesioned group. Comparison of the number of sites per unit volume to their average contact area revealed a reciprocal relationship indicating a conservation in the total synaptic contact area on each neuron. This effect was consistent for all postsurgical days. The lack of a significant return of synaptic number by 40 days indicates that axonal sprouting is not a major factor in neuronal plasticity in the adult striatum. The rapid increase in the size of spines, boutons and synaptic sites at remaining connections suggests that dendrites are the first to initiate the plasticity response in adult neurons through postsynaptic attachments and their corresponding receptor structure. The underlying mechanism of this plasticity may be through a conservation of macromolecules forming postsynaptic membrane specializations on target neurons. Remaining axons appear to follow the dendritic response with a plasticity generating presynaptic appositional specializations to match the contact area of the postsynaptic site.

Animals↗
PubMed2004

Nonredundant roles for hippocampal and entorhinal cortical plasticity in spatial memory storage.

Recently, it has been demonstrated that targeted blockade of the extracellular signal-regulated kinase (ERK) cascade in either the entorhinal cortex (EC) or hippocampus (HIP) results in spatial memory deficits. However, it is unclear if ERK-mediated plasticity in these structures has redundant functions or unique roles. In this report, we contrast the role of long-term plasticity in these two structures with side-by-side comparisons of the effects of PD098059 infusion following water maze training. Analysis of performance during the long-term retention test indicates a role for plasticity in the EC in storing broad location information. In contrast, blocking plasticity in the HIP resulted in deficits in indices of precise location information and goal-directed navigational error. To distinguish between a navigational and location deficit, a "two-room" experimental design was employed. Training in the first room allowed animals to consolidate information regarding navigational strategies prior to training and drug infusion in the second room. Hippocampal-PD098059-infused animals demonstrated behavior suggestive of an expanded representation of the platform location and, thus, a loss of precise location information, suggesting that plasticity in these structures is involved in nonredundant, but complementary, processes necessary for spatial memory.

Animals↗
PubMed2005

Translational control of hippocampal synaptic plasticity and memory by the eIF2alpha kinase GCN2.

Studies on various forms of synaptic plasticity have shown a link between messenger RNA translation, learning and memory. Like memory, synaptic plasticity includes an early phase that depends on modification of pre-existing proteins, and a late phase that requires transcription and synthesis of new proteins. Activation of postsynaptic targets seems to trigger the transcription of plasticity-related genes. The new mRNAs are either translated in the soma or transported to synapses before translation. GCN2, a key protein kinase, regulates the initiation of translation. Here we report a unique feature of hippocampal slices from GCN2(-/-) mice: in CA1, a single 100-Hz train induces a strong and sustained long-term potentiation (late LTP or L-LTP), which is dependent on transcription and translation. In contrast, stimulation that elicits L-LTP in wild-type slices, such as four 100-Hz trains or forskolin, fails to evoke L-LTP in GCN2(-/-) slices. This aberrant synaptic plasticity is mirrored in the behaviour of GCN2(-/-) mice in the Morris water maze: after weak training, their spatial memory is enhanced, but it is impaired after more intense training. Activated GCN2 stimulates mRNA translation of ATF4, an antagonist of cyclic-AMP-response-element-binding protein (CREB). Thus, in the hippocampus of GCN2(-/-) mice, the expression of ATF4 is reduced and CREB activity is increased. Our study provides genetic, physiological, behavioural and molecular evidence that GCN2 regulates synaptic plasticity, as well as learning and memory, through modulation of the ATF4/CREB pathway.

Animals↗
PubMedDate not supplied

In vivo fatigue microcracks in human bone: material properties of the surrounding bone matrix.

Human bones sustain fatigue damage in the form of in vivo microcracks as a result of the normal everyday loading activities. These microcracks appear to preferentially accumulate in certain regions of bone and most notably in interstitial bone matrix areas. These are remnants of old bone tissue left unremodelled, which show a higher than average mineral content and consequently the occurrence of microcracks has been attributed to the possible brittleness brought about by such hypermineralisation. There is a need, therefore, for information on the in situ bone matrix properties in the vicinity of such in vivo microcracks to elucidate the possible causes of their appearance. The present study examined the elastic, strain rate (viscous) and plastic properties of bone matrix in selectively targeted areas by nanoindentation and in both quasistatic and dynamic mode. The results showed that in vivo crack areas are not as stiff as some well-known extremely mineralised and brittle bone examples (bulla, rostrum); the strain rate effects of crack regions were identical to those of other regions of human bone and agreed well with values collected for human bone in the past at the macroscale; while the plasticity index of the crack regions was also not statistically different from most bone examples (including human at random, bovine, bulla and rostrum) except antler, which showed lower plasticity and thus a greater fraction of elastic recovery in indentation energy. It is difficult, therefore, to explain the susceptibility of these interstitial regions to crack in terms of the mineral content and its after-effects on elasticity, viscosity and plasticity alone, but one need to attribute the cracks to the cumulative loading history of these areas, or raise the suggestion that these areas of bone matrix are in some measure 'aged' or material/quality defective.

Aged↗
PubMed1983

Suppression of lymphocyte proliferative responses: characterization of the suppressor and kinetics of suppression.

Culturing spleen cells for 2 or more days in the absence of mitogenic stimulation results in the generation of suppressor cells that can effectively inhibit the proliferative responses of freshly prepared spleen cells to mitogen or alloantigen stimulation. Suppression does not appear to be mediated by prostaglandins nor other soluble factors produced during the preculture period. The suppressor cell is described as a plastic-adherent Thy-1.2-, IgM-, FcR+ macrophage-like cell. Significant suppression of Con A responses can be detected at suppressor to target ratios as low as 1:100. The plastic-adherent suppressor is capable of terminating Con A-induced proliferation of spleen cells whether added at the onset of the Con A response or added as late as 48 hr after mitogenic stimulation. The suppressed spleen cell population displays an absence of large blast cells and a decrease in surface density of Thy-1.2 determinants.

Animals↗
PubMed2001

Variation of serotonergic gene expression: neurodevelopment and the complexity of response to psychopharmacologic drugs.

Individual differences in drug effects and treatment response are relatively enduring, continuously distributed, as well as substantially heritable, and are therefore likely to result from an interplay of multiple genomic variations with environmental influences. As the etiology and pathogenesis of behavioral and psychiatric disorders is genetically complex, so is the response to drug treatment. Psychopharmacologic drug response depends on the structure and functional expression of gene products, which may be direct drug targets or may indirectly modify the development and synaptic plasticity of neural networks critically involved in drug response. While formation and integration of these neural networks is dependent on the action of manifold proteins, converging lines of evidence indicate that genetically controlled variability in the expression of genes critical to the development and plasticity of distinct neurocircuits influences a wide spectrum of quantitative traits including treatment response. During brain development, neurotransmitter systems (e.g. serotonergic system), which are frequently targeted by psychotropic drugs, control neuronal specification, differentiation, and phenotype maintenance. The formation and maturation of these neurotransmitter systems, in turn, is directed by an intrinsic genetic program. Based on the notion that complex gene-gene and gene environment interactions in the regulation of brain plasticity are presumed to contribute to interindividual differences in drug response, the concept of developmental psychopharmacogenetics is emerging. This review appraises prototypical genomic variation with impact on gene expression and complementary studies of genetic and environmental effects on brain development and synaptic plasticity in the mouse model. Although special emphasis is given to molecular mechanisms of neurodevelopmental genetics, relevant conceptual and methodological issues pertinent to the dissection of the psychopharmacogenetic-neurodevelopmental interface are also considered.

Animals↗
PubMed2001

Innervation of cerebral blood vessels: morphology, plasticity, age-related, and Alzheimer's disease-related neurodegeneration.

The light microscopical and ultrastructural morphology of the innervation of the major cerebral arteries and pial vessels is described, including the origins of the different groups of nerve fibres and their characteristic neurotransmitter phenotype. Species and region specific variations are described and novel data regarding the parasympathetic innervation of cerebral vessels are presented. The dynamic nature, or plasticity, of cerebrovascular innervation is emphasized in describing changes affecting particular subpopulations of neurons during normal ageing and in Alzheimer's disease. The molecular controls on plasticity are discussed with particular reference to target-associated factors such as the neurotrophins and their neuronal receptors, as well as extracellular matrix related factors such as laminin. Hypotheses are presented regarding the principal extrinsic and intrinsic influences on plasticity of the cerebrovascular innervation.

Aging↗
PubMed2006

ARP, the cleavable C-terminal peptide of "readthrough" acetylcholinesterase, promotes neuronal development and plasticity.

The mammalian acetylcholinesterase (ACHE) gene gives rise to diverse enzymatically active proteins with three different carboxyl termini. In the brain, the normally rare readthrough AChE-R monomer accumulates under embryonic development and in adults following psychological stress, head injury, or exposure to AChEs. In the prenatal developing cortex, its unique C-terminal peptide ARP associates with radial glial fibers supporting neuronal migration. In contrast, the major synaptic AChE-S variant appears in the migrating neurons themselves. Moreover, antisense suppression of AChE-R attenuates neuronal migration, allowing increased proliferation of neuronal progenitors. In the adult brain, neuronal AChE-R is either secreted or accumulates intraneuronally, where it interacts through ARP with the scaffold protein RACK1 and activated PKC-betaII. This associates with increased PKC-betaII activity, which shuttles to submembranal clusters (e.g., in hyperactivated hippocampal neurons). Cleavage yields the AChE-R-specific C-terminal peptide, including immunopositive ARP. Importantly, intrahippocampal injection of synthetic ARP was followed by its efficient neuronal penetration and retrograde transport into cortical and basal nuclei neurons. Moreover, ARP-injected mice presented increased stress-induced contextual fear, inhibitable by antisense suppression of AChE-R mRNA. Together, our findings point at the cleavable ARP peptide as a key regulator of neuronal development and plasticity and suggest its use as a drug target and/or research and therapeutic tool.

Acetylcholine↗
PubMed1999

Expression and branch-specific export of mRNA are regulated by synapse formation and interaction with specific postsynaptic targets.

Mechanosensory neurons (SNs) of Aplysia form synapses in culture with some targets (L7), but not others (L11), even when a SN is plated with both targets. We examined whether branch-specific net export of mRNA encoding synapse-specific molecules might contribute to branch-specific synapse formation. Single-cell RT-PCR was used to assay levels of mRNA encoding the SN-specific neuropeptide (sensorin A) and other transcripts in cell bodies and neuritic processes of SNs cultured alone or with synaptic targets. Some mRNAs are exported to neurites, but not others. Sensorin A mRNA is detected only in SN cell bodies and neurites, and expression levels correlate with the strength of the synaptic connections formed with L7 after 4 d in culture. After 4 d, more sensorin A transcripts are detected in SN neurites contacting L7 than in SN neurites contacting L11. The differential expression at 4 d is found even when a single SN contacts both targets simultaneously. By contrast, no significant difference in expression is detected in SN neurites contacting L7 versus L11 after 1 d of coculture. The results suggest that interaction and synapse formation with a specific target lead to a time-dependent change in the branch-specific accumulation of sensorin A mRNA in SNs. Because local protein synthesis at synaptic sites might contribute to synaptic function or plasticity, the results suggest that branch-specific targeting of mRNA encoding synapse-related molecules may contribute to the formation of specific synapses.

Animals↗
PubMed2005

Increased AMPA GluR1 receptor subunit labeling on the plasma membrane of dendrites in the basolateral amygdala of rats self-administering morphine.

Glutamate-dependent synaptic plasticity is emerging as an important neural substrate of addiction. These drug-dependent neural adaptations may occur within brain systems that mediate reward, emotion, and cognitive function such as the amygdala complex. Modification of glutamate receptor targeting may be a key mechanism mediating neural plasticity; however, evidence for alteration of amygdala AMPA receptor localization in response to drug self-administration is lacking. High-resolution immunogold electron microscopic immunocytochemistry was used to compare surface and intracellular labeling of the calcium sensitive AMPA GluR1 receptor subunit in the basolateral (BLA) and central (CeA) nuclei of the amygdala in rats self-administering escalating doses of morphine or saline. Morphine self-administration was associated with regionally diverse effects on dendritic GluR1 targeting in the BLA and CeA. In the BLA of morphine self-administering animals, there was a significant increase in the proportion of immunogold particles for GluR1 on the plasma membrane of dendrites, particularly in association with extrasynaptic sites, which was most prominent in large (2-4 microm) profiles. In contrast, there were no significant differences in surface or intracellular immunogold labeling in the CeA between morphine self-administering and control animals. In both amygdala regions, GluR1 and the micro-opioid receptor, the major cellular target of morphine, were only infrequently colocalized. These results indicate that GluR1 targeting is a dynamic process that can be differentially affected in distinct amygdala regions in response to chronic self-administration of morphine. Homeostatic adaptations in the subcellular localization of calcium sensitive AMPA receptors within the BLA may be an important neural substrate for alterations in reward, autonomic function, and behavioral processes associated with opiate addiction.

Amygdala↗
PubMed2006

Presynaptic kainate receptor activation is a novel mechanism for target cell-specific short-term facilitation at Schaffer collateral synapses.

Target cell-specific differences in short-term plasticity have been attributed to differences in the initial release probability of synapses. Using GIN (GFP-expressing inhibitory neurons) transgenic mice that express enhanced green fluorescent protein (EGFP) in a subset of interneurons containing somatostatin, we show that Schaffer collateral synapses onto the EGFP-expressing somatostatin interneurons in CA1 have very large short-term facilitation, even larger facilitation than onto pyramidal cells, in contrast to the majority of interneurons that have little or no facilitation. Using a combination of electrophysiological recordings and mathematical modeling, we show that the large short-term facilitation is caused both by a very low initial release probability and by synaptic activation of presynaptic kainate receptors that increase release probability on subsequent stimuli. Thus, we have discovered a novel mechanism for target cell-specific short-term plasticity at Schaffer collateral synapses in which the activation of presynaptic kainate receptors by synaptically released glutamate contributes to large short-term facilitation, enabling selective enhancement of the inputs to a subset of interneurons.

Animals↗
PubMed1979

Retinohypothalamic tract development: alteration by suprachiasmatic lesions in the neonatal rat.

The suprachiasmatic nucleus (SCN), the terminal nucleus of the retinohypothalamic (RH) tract, was ablated electrolytically in 2-day-old rats. Since previous studies have demonstrated that the earliest retinal fibers arrive on postnatal day 3 to 4 (refs. 4, 17), the lesions were inflicted prior to the formation of retinal connections. At day 25, [3H]proline was injected into the eye and autoradiography performed to determine if developing RH fibers would exhibit plasticity and innervate any hypothalamic nucleus other than the SCN. No evidence was found for the formation of anomalous retinal connections after complete, bilateral SCN lesions. Incomplete lesions, however, result in some alteration in the distribution of retinal fibers to the SCN. If a part of the caudal three-quarters of the SCN remains, RH projections form in a pattern dependent upon the size and location of the intact SCN fragment. These results indicate a high degree of specificity in developing RH fibers for their normal target tissue and a minimal capacity for plasticity in contrast with the various forms of neuronal reorganization observed after early destruction of other components of the visual system.

Animals↗
PubMed2001

Analysis for organic residues from aids to polymerization used to make plastics intended for food contact.

Polymers intended for food contact use have been analysed for organic residues which could be attributed to a range of substances employed as polymerization aids (e.g. initiators and catalysts). A wide range of polymers was extracted with solvents and the extracts analysed by gas chromatography mass spectrometry (GC-MS). The overwhelming majority of substances identified were not derived from aids to polymerization but were oligomers, additives and adventitious contaminants. However, a small number of substances were identified as initiator residues. These included tetramethylsuccinonitrile (TMSN) which was observed in two polymers and it derived from recombination of two azobisisobutyronitrile (AIBN) initiator radicals. Methyl benzoate, benzoic acid, biphenyl and phenyl benzoate were detected in one poly(methyl methacrylate) sample and in two polyvinylchlorides and they are thought to be derived from benzoyl peroxide initiator. TMSN was subsequently targeted for analysis of poly-(methyl methacrylate) plastics using proton nuclear magnetic resonance spectrometry (1H-NMR) and GC-MS. NMR detected the presence of cyanoisopropyl radical residues in the plastic at 470-3400 mg/kg whereas GC-MS detected TMSN at only 65-540 mg/kg in the samples. It is concluded that the bulk of cyanoisopropyl residues detected by NMR were either polymer-bound or were the products of side-reactions of the initiator radical. The migration of TMSN itself into the food simulants 3% aqueous acetic acid, 15% aqueous ethanol, and olive oil, at 40 degrees C for 10 days, was measured using GC-MS. Migration was very low with < 1 microg/kg released from a finished article (a drinking straw) and < 5 microg/kg from resin pellets. The overall conclusions from this work are that organic residues from aids to polymerization are generally found at reassuringly low levels in plastics intended for food contact and their potential for migration to foods is correspondingly low.

Food Contamination↗
PubMed1999

Reg1ulatory role and molecular interactions of a cell-surface heparan sulfate proteoglycan (N-syndecan) in hippocampal long-term potentiation.

The cellular mechanisms responsible for synaptic plasticity involve interactions between neurons and the extracellular matrix. Heparan sulfates (HSs) constitute a group of glycosaminoglycans that accumulate in the beta-amyloid deposits in Alzheimer's disease and influence the development of neuron-target contacts by interacting with other cell surface and matrix molecules. However, the contribution of HSs to brain function is unknown. We found that HSs play a crucial role in long-term potentiation (LTP), a finding that is consistent with the idea that converging molecular mechanisms are used in the development of neuron-target contacts and in activity-induced synaptic plasticity in adults. Enzymatic cleavage of HS by heparitinase as well as addition of soluble heparin-type carbohydrates prevented expression of LTP in response to 100 Hz/1 sec stimulation of Schaffer collaterals in rat hippocampal slices. A prominent carrier protein for the type of glycans implicated in LTP regulation in the adult hippocampus was identified as N-syndecan (syndecan-3), a transmembrane proteoglycan that was expressed at the processes of the CA1 pyramidal neurons in an activity-dependent manner. Addition of soluble N-syndecan into the CA1 dendritic area prevented tetanus-induced LTP. A major substrate of src-type kinases, cortactin (p80/85), and the tyrosine kinase fyn copurified with N-syndecan from hippocampus. Moreover, association of both cortactin and fyn to N-syndecan was rapidly increased after induction of LTP. N-syndecan may thus act as an important regulator in the activity-dependent modulation of neuronal connectivity by transmitting signals between extracellular heparin-binding factors and the fyn signaling pathway.

Animals↗