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PubMed2006

The X11/Mint family of adaptor proteins.

The X11 protein family are multidomain proteins composed of a conserved PTB domain and two C-terminal PDZ domains. They are involved in formation of multiprotein complexes and two of the family members, X11alpha and X11beta, are expressed primarily in neurones. Not much is known about the principal function of X11s, but through interactions with other neuronal proteins, they are believed to be involved in regulating neuronal signaling, trafficking and plasticity. Furthermore, they have been shown to modulate processing of APP and accumulation of Abeta, making them potential therapeutic targets for Alzheimer's disease. This article reviews the known interactions of the different X11s and their involvement in Alzheimer's disease.

Adaptor Proteins, Signal Transducing↗
PubMed2003

Proteins interactions implicated in AMPA receptor trafficking: a clear destination and an improving route map.

The mechanisms that regulate alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid receptor (AMPAR), synthesis, transport, targeting and surface expression are of fundamental importance to understand the molecular basis of fast excitatory neurotransmission and synaptic plasticity in the mammalian CNS. An area of intense current interest is how AMPARs are directed to the correct locations in the neuron as and when required. This is a multi-layered problem, which involves complex spatio-temporal coordination of multiple protein interactions. Considerable progress has been achieved in identifying a number of proteins that bind directly to AMPAR subunits and the functional consequences of blocking some of these interactions have been determined. This review highlights recent developments in the field.

Animals↗
PubMed2003

The transient depression of hippocampal CA1 LTP induced by chronic intermittent ethanol exposure is associated with an inhibition of the MAP kinase pathway.

Using electrophysiological and biochemical approaches, we investigated the effects of chronic, intermittent ethanol (CIE) treatment on activation of the mitogen activated protein kinase (MAPK), also known as extracellular signal regulated protein kinase 1 and 2. In hippocampal slices taken from control rats, brief high-frequency stimulation to Schaffer collateral fibers induced a large post-tetanic potentiation (PTP) in the CA1 region that decayed to stable long-term potentiation (LTP) of field extracellular postsynaptic potentials. Western blot analyses showed that phosphorylation of MAPK was increased during PTP and returned to baseline levels during LTP. In slices from the rats removed immediately from CIE treatment, PTP and MAPK activation during the PTP was significantly less than that observed in control slices and LTP was absent. In slices from rats subjected to 1 day withdrawal from CIE treatment, both the reduction in MAPK phosphorylation during PTP and the impairment of PTP and LTP were still evident. Recovery of PTP and partial recovery of LTP was observed in slices obtained from 5-day withdrawn rats. However, MAPK activation during PTP was still attenuated significantly. Interestingly, MAPK activation was enhanced significantly during LTP in 5-day withdrawn rats as well as the sensitivity to MAPK inhibitor PD 098059. In addition to these changes in HFS-induced MAPK activation, we also observed a significant reduction in the basal phosphorylation of MAPK in slices removed from rats immediately after CIE treatment. These results implicate the MAPK signal transduction pathway as a potential cellular target of ethanol. Alterations in MAPKs could play an important role in the alcohol-induced changes in synaptic plasticity associated with the effects of alcohol abuse on learning and memory processes.

Alcoholism↗
PubMed2000

Contrasting localizations of MALS/LIN-7 PDZ proteins in brain and molecular compensation in knockout mice.

Proteins containing PDZ (postsynaptic density-95, discs large, zonula occludens) domains play a general role in recruiting receptors and enzymes to specific synaptic sites. In Caenorhabditis elegans, a complex of three PDZ proteins, LIN-2/7/10, mediates basolateral targeting of a receptor tyrosine kinase. Homologs of these LIN proteins have also been identified in higher organisms, and here we analyze the MALS/Veli (mammalian LIN-7/vertebrate homolog of LIN-7) proteins in brain. Immunohistochemical staining and in situ hybridization show that MALS occur differentially in discrete populations of neurons throughout the brain. Most neurons express only one MALS protein, although some cells contain two or even all three MALS isoforms. At the subcellular level, MALS proteins are found in both dendritic and axonal locations, suggesting that they may regulate processes at both pre- and postsynaptic sites. Targeted disruption of MALS-1 and MALS-2 does not yield a detectable phenotype, and hippocampal synaptic function and plasticity are intact in the MALS-1/2 double knockouts. Interestingly, MALS-3 protein is dramatically induced in the MALS-1/2 double knockouts, implying that dynamic changes in protein expression may play an important regulatory role for this family of synaptic PDZ proteins.

Animals↗
PubMed2002

Protein kinase MARK/PAR-1 is required for neurite outgrowth and establishment of neuronal polarity.

Protein kinases of the microtubule affinity-regulating kinase (MARK) family were originally discovered because of their ability to phosphorylate certain sites in tau protein (KXGS motifs in the repeat domain). This type of phosphorylation is enhanced in abnormal tau from Alzheimer brain tissue and causes the detachment of tau from microtubules. MARK-related kinases (PAR-1 and KIN1) occur in various organisms and are involved in establishing and maintaining cell polarity. Herein, we report the ability of MARK2 to affect the differentiation and outgrowth of cell processes from neuroblastoma and other cell models. MARK2 phosphorylates tau protein at the KXGS motifs; this results in the detachment of tau from microtubules and their destabilization. The formation of neurites in N2a cells is blocked if MARK2 is inactivated, either by transfecting a dominant negative mutant, or by MARK2 inhibitors such as hymenialdisine. Alternatively, neurites are blocked if the target KXGS motifs on tau are rendered nonphosphorylatable by point mutations. The results suggest that MARK2 contributes to the plasticity of microtubules needed for neuronal polarity and the growth of neurites.

Amino Acid Motifs↗
PubMed2005

Development of a tissue array for primary melanoma with long-term follow-up: discovering melanoma cell adhesion molecule as an important prognostic marker.

Refining current prognostic capability is essential for improving the management of melanoma. This study was undertaken to develop a tumor array for the rapid assessment of novel prognostic markers in a series of specimens from melanoma patients with 7- to 10-year follow-up. A melanoma database of 120 patients with archival specimens was created after histopathological review of original specimens. A tissue array was developed allowing 480 biopsy samples from the 120 primary melanoma specimens to be embedded into a single paraffin block. This was sectioned and stained for the adhesion marker melanoma cell adhesion molecule (MCAM); after further review, 76 of the 120 specimens were suitable for further analysis. The slides were assessed by two independent observers without previous knowledge of the clinical outcome for staining positivity and stain intensity. Assessment of association between MCAM and clinicopathological features was carried out using chi-squared analysis, and univariate and Cox multivariate analyses were performed on the data. There was a high correlation between MCAM intensity and both Clark's level and Breslow thickness (Spearman correlation p < 0.001 for both). The data revealed that MACM was a highly specific prognostic marker for survival in univariate analysis (chi2 = 18, p < 0.0001). Subgroup analysis by stratification of the staining intensity revealed a sequentially worsening survival with increasing staining intensity (chi2 = 22.33, p < 0.0001). Multivariate analysis of survival showed MCAM to be an independent prognostic marker more accurate than all other clinicopathological parameters (p < 0.0001), including the Breslow depth. Further analysis within only intermediate-thickness tumors showed MCAM intensity added further refinement to outcome prediction (chi2 = 22.33, p < 0.0001). The tissue array provided a rapid method of analyzing up to 480 specimens within a single paraffin block. This will benefit many areas of plastic surgery research. The identification of adhesion markers revealed a valuable prognostic marker for predicting outcome and a potential target for therapeutic manipulation.

Adult↗
PubMed2002

Design and manufacture of spectrally selective reflecting coatings for the use with laser display projection screens.

To provide screens for laser projection that improve contrast, a spectrally selective reflecting filter was designed by using genetic algorithms to overcome the problem of unknown starting values. Colormetrics rather than fixed targets were used for evaluation. Various selective filters were deposited upon glass as well as upon solid and flexible plastic substrates by reactive mid-frequency magnetron sputtering. For process control, in situ spectroscopic ellipsometry was applied.

Journal Article↗
PubMed2005

G-protein-coupled receptor modulation of striatal CaV1.3 L-type Ca2+ channels is dependent on a Shank-binding domain.

Voltage-gated L-type Ca2+ channels are key determinants of synaptic integration and plasticity, dendritic electrogenesis, and activity-dependent gene expression in neurons. Fulfilling these functions requires appropriate channel gating, perisynaptic targeting, and linkage to intracellular signaling cascades controlled by G-protein-coupled receptors (GPCRs). Surprisingly, little is known about how these requirements are met in neurons. The studies described here shed new light on how this is accomplished. We show that D2 dopaminergic and M1 muscarinic receptors selectively modulate a biophysically distinctive subtype of L-type Ca2+ channels (CaV1.3) in striatal medium spiny neurons. The splice variant of these channels expressed in medium spiny neurons contains cytoplasmic Src homology 3 and PDZ (postsynaptic density-95 (PSD-95)/Discs large/zona occludens-1) domains that bind the synaptic scaffolding protein Shank. Medium spiny neurons coexpressed CaV1.3-interacting Shank isoforms that colocalized with PSD-95 and CaV1.3a channels in puncta resembling spines on which glutamatergic corticostriatal synapses are formed. The modulation of CaV1.3 channels by D2 and M1 receptors was disrupted by intracellular dialysis of a peptide designed to compete for the CaV1.3 PDZ domain but not with one targeting a related PDZ domain. The modulation also was disrupted by application of peptides targeting the Shank interaction with Homer. Upstate transitions in medium spiny neurons driven by activation of glutamatergic receptors were suppressed by genetic deletion of CaV1.3 channels or by activation of D2 dopaminergic receptors. Together, these results suggest that Shank promotes the assembly of a signaling complex at corticostriatal synapses that enables key GPCRs to regulate L-type Ca2+ channels and the integration of glutamatergic synaptic events.

3-Pyridinecarboxylic acid, 1,4-dihydro-2,6-dimethy↗
PubMed2005

Interdependence of oestrogen and insulin-like growth factor-I in the brain: potential for analysing neuroprotective mechanisms.

The actions of oestradiol in the brain involve interaction with growth factors, such as insulin-like growth factor-I (IGF-I). Many cells in the brain co-express receptors for oestradiol and IGF-I and both factors interact to regulate neural function. The relationship of oestrogen receptor alpha with IGF-I receptor through the mitogen-activated protein kinase and the phosphoinositide 3-kinase signalling pathways may represent the point of convergence used by these two factors to cooperatively modulate neuritic growth, synaptic plasticity, neuroendocrine events, reproductive behaviour and neuronal survival. In addition, Akt and glycogen synthase kinase 3beta are key molecular targets to explain the interaction of oestrogen and IGF-I receptor signalling in the promotion of neuroprotection.

Brain↗
PubMed2002

Regional and cellular mapping of cAMP response element-mediated transcription during naltrexone-precipitated morphine withdrawal.

Chronic opiate exposure is associated with upregulation of the cAMP signaling pathway and the transcription factor cAMP response element-binding protein in the locus ceruleus (LC) and certain other brain areas. To determine whether these adaptations ultimately affect transcription mediated by the cAMP response element (CRE), we induced morphine dependence in CRE-LacZ transgenic mice and performed a regional and cellular mapping of beta-galactosidase (beta-gal) expression during naltrexone-precipitated withdrawal. Consistent with our model of opiate dependence, beta-gal expression increased in the LC, but decreased in the lateral ventral tegmental area (VTA) and dorsal raphe nucleus (DRN). In addition, withdrawal increased beta-gal expression in the continuum of the extended amygdala and nucleus accumbens, macrostructures associated with the coupling of emotional stimuli to motor and autonomic responses. At the cellular level, in the central nucleus of the amygdala, beta-gal was found in cells both with and without mu opioid receptors as well as in corticotropin-releasing factor-expressing cells. In nucleus accumbens, beta-gal was expressed in several major subpopulations of neurons. In LC, beta-gal expression was induced predominantly in tyrosine hydroxylase-expressing cells, whereas in the VTA and DRN the majority of cells expressing beta-gal were nonmonoaminergic. These results show that molecular adaptations to chronic morphine alter CRE-mediated transcription during opiate withdrawal in physiologically salient regions involved in arousal, reward, mood, and affective responses. We propose that CRE-mediated transcription serves as a functional marker for neuronal plasticity during withdrawal. CRE-mediated transcription may itself contribute to re-establishing homeostasis in the organism through target gene regulation in these regions.

Amygdala↗
PubMed2004

Subregional changes in discharge rate, pattern, and drug sensitivity of putative GABAergic nigral neurons in the kindling model of epilepsy.

The substantia nigra pars reticulata (SNr) is thought to act as a seizure-gating mechanism in kindling and other epilepsy models. We investigated whether the kindling process induces site-specific (anterior-posterior) and seizure-outlasting alterations in the activity of putative GABAergic SNr neurons and in their response to pharmacological manipulation. Female Wistar rats were kindled via the basolateral amygdala by daily stimulation. In vivo extracellular single unit recordings of SNr neurons were performed in kindled rats 1 day after a generalized seizure in order to examine activity changes that outlast the kindled seizures. Sham-kindled and naive rats served as controls. We found a significant and seizure-outlasting increase of discharge rates within the posterior but not within the anterior SNr of kindled rats when compared to controls. Furthermore, kindling resulted in seizure-outlasting burst-like firing pattern of SNr neurons. The antiepileptic drug valproic acid (VPA; 100 mg/kg i.v.) significantly reduced SNr discharge rates in all animal groups. Interestingly, neurons located in the anterior SNr of kindled rats were significantly less depressed by VPA compared to the reduction obtained in naive controls. The present data disclose kindling induced functional plasticity within basal ganglia regions. The findings are relevant for a better understanding of the mechanisms underlying the seizure-gating function of the SNr and might provide new targets for rational therapeutic manipulations, which aim to establish a remote control of epileptic seizures.

Action Potentials↗
PubMed1975

Cytotoxic activity of lymphocytes. V. Role of soluble toxin in macrophage-inhibited cultures of tumor cells.

Macrophage cell-mediated cytolysis (M-CMC) of tumor cells may be measured by culturing target cells on macrophage monolayers and determining target cell survival by either Rb or H-thymidine incorporation. Using these techniques, one can demonstrate cytotoxicity of nonimmune human and rat macrophages to a variety of tumor cell lines. Toxicity becomes maximal 8 to 16 hr after attaching macrophages to plastic surfaces and disappears after 36 to 48 hr. Addition of Escherichia coli endotoxin at 48 hr restores macrophage toxicity. Culture of macrophages on plastic surfaces also results in the release, nonspecifically, of a soluble cytotoxin whose kinetics of release, disappearance, and reappearance after endotoxin all parallel the M-CMC. The amount of toxin released into cultures containing target cells is markedly reduced, suggesting that it is the mediator of the M-CMC and that it is utilized or absorbed during target destruction. Sephadex G-100 chromatography and treatment with heterologous anti-lymphotoxin can distinguish this toxin from lymphotoxin.

Adsorption↗
PubMed2005

Experience-dependent behavioral plasticity is disturbed following traumatic injury to the immature brain.

Traumatic brain injury (TBI) is most prevalent in children and young adults. The long-term effects of pediatric TBI include cognitive and behavioral impairments; however, over time, it is difficult to distinguish individual variability in intellect and behavior from sequelae of early injury. Postnatal day (PND) 19 rats underwent lateral fluid percussion (FP) injury, followed by rearing in either standard (STD) or enriched environment (EE) conditions. The hypothesis was that the traditional enhancement of cognitive functioning following EE rearing would be attenuated when this rearing is preceded by TBI at PND19. Thirty days after injury, Morris water maze (MWM) acquisition and subsequent probe trial retention were used to assess the behavioral effects of injury on experience-dependent plasticity induced by housing in EE at two different time windows. MWM acquisition demonstrated improvements following early EE rearing in both sham and injured animals; however, the degree of improvement was greater for uninjured animals. When EE rearing was delayed for 2 weeks after injury, the injury effect was absent and the effect of rearing even stronger. Memory testing in the early EE groups using a delayed probe trial showed an effect of injury and housing, with the sham EE animals benefiting the most. After the delayed EE, sham EE animals again showed more probe target hits, while FPEE animals did not, demonstrating an enduring memory deficit. These data confirm that early TBI has effects on experience-dependent plasticity resulting in long-term neurobehavioral deficits. In addition, the ability to benefit from environmental stimulation following TBI is dependent upon time after injury.

Adaptation, Psychological↗
PubMed2000

Regulation of long-term potentiation by H-Ras through NMDA receptor phosphorylation.

The proto-oncogene ras plays a critical role in cell proliferation and differentiation. However, ras genes are abundantly expressed in the adult CNS, although neuronal cells normally do not proliferate. Recently, several lines of evidence implicated the involvement of Ras signaling pathway in synaptic plasticity. To explore the role of the Ras proteins in the CNS, we generated knock-out mice lacking the H-ras gene and then used them to study the roles of Ras in synaptic transmission and plasticity. An investigation of protein phosphorylation and synaptic transmission in H-ras null mutant mice has shown that the NMDA receptor is a final target molecule of the Ras protein pathway in the CNS. In the H-ras null mutant hippocampus, the tyrosine phosphorylation of NR2A (epsilon1) and NR2B (epsilon2) subunits of NMDA receptors is increased, and, correspondingly, NMDA synaptic responses are selectively enhanced. In addition, long-term potentiation is markedly enhanced in mutant mice, most likely because of a selective enhancement of NMDA synaptic responses. Therefore, although Ras proteins have been implicated in cell proliferation and differentiation, the regulation of activity-dependent synaptic plasticity in the adult animals by downregulation of the phosphorylation of the NMDA receptor may be another major and pivotal role for H-Ras protein.

Animals↗
PubMed1996

Gonadal and adrenal steroids regulate neurochemical and structural plasticity of the hippocampus via cellular mechanisms involving NMDA receptors.

1. The hippocampus is an important brain structure for working and spatial memory in animals and humans, and it is also a vulnerable as well as plastic brain structure as far as sensitivity to epilepsy, ischemia, head trauma, stress, and aging. 2. The hippocampus is also a target brain area for the actions of hormones of the steroid/thyroid hormone family, which traditionally have been thought to work by regulating gene expression. "Genomic" actions of steroid hormones involve intracellular receptors, whereas "nongenomic" effects of steroids involve putative cell surface receptors. Although this distinction is valid, it does not go far enough in addressing the variety of mechanisms that steroid hormones use to produce their effects on cells. This is because cell surface receptors may signal changes in gene expression, while genomic actions sometimes affect neuronal excitability, often doing so quite rapidly. 3. Moreover, steroid hormones and neurotransmitters may operate together to produce effects, and sometimes these effects involve collaborations between groups of neurons. For example, a number of steroid actions in the hippocampus involve the coparticipation of excitatory amino acids. These interactions are evident for the regulation of synaptogenesis by estradiol in the CA1 pyramidal neurons of hippocampus and for the induction of dendritic atrophy of CA3 neurons by repeated stress as well as by glucocorticoid injections. In addition, neurogenesis in the adult and developing dentate gyrus is "contained" by adrenal steroids as well as by excitatory amino acids. In each of these three examples, NMDA receptors are involved. 4. These results not only point to a high degree of interdependency between certain neurotransmitters and the actions of steroid hormones, but also emphasize the degree to which structural plasticity is an important aspect of steroid hormone action in the adult as well as developing nervous system.

Adrenal Glands↗
PubMed1998

Perturbed dentate gyrus function in serotonin 5-HT2C receptor mutant mice.

Serotonin systems have been implicated in the regulation of hippocampal function. Serotonin 5-HT2C receptors are widely expressed throughout the hippocampal formation, and these receptors have been proposed to modulate synaptic plasticity in the visual cortex. To assess the contribution of 5-HT2C receptors to the serotonergic regulation of hippocampal function, mice with a targeted 5-HT2C-receptor gene mutation were examined. An examination of long-term potentiation at each of four principal regions of the hippocampal formation revealed a selective impairment restricted to medial perforant path-dentate gyrus synapses of mutant mice. This deficit was accompanied by abnormal performance in behavioral assays associated with dentate gyrus function. 5-HT2C receptor mutants exhibited abnormal performance in the Morris water maze assay of spatial learning and reduced aversion to a novel environment. These deficits were selective and were not associated with a generalized learning deficit or with an impairment in the discrimination of spatial context. These results indicate that a genetic perturbation of serotonin receptor function can modulate dentate gyrus plasticity and that plasticity in this structure may contribute to neural mechanisms underlying hippocampus-dependent behaviors.

Animals↗
PubMed2005

Quail-duck chimeras reveal spatiotemporal plasticity in molecular and histogenic programs of cranial feather development.

The avian feather complex represents a vivid example of how a developmental module composed of highly integrated molecular and histogenic programs can become rapidly elaborated during the course of evolution. Mechanisms that facilitate this evolutionary diversification may involve the maintenance of plasticity in developmental processes that underlie feather morphogenesis. Feathers arise as discrete buds of mesenchyme and epithelium, which are two embryonic tissues that respectively form dermis and epidermis of the integument. Epithelial-mesenchymal signaling interactions generate feather buds that are neatly arrayed in space and time. The dermis provides spatiotemporal patterning information to the epidermis but precise cellular and molecular mechanisms for generating species-specific differences in feather pattern remain obscure. In the present study, we exploit the quail-duck chimeric system to test the extent to which the dermis regulates the expression of genes required for feather development. Quail and duck have distinct feather patterns and divergent growth rates, and we exchange pre-migratory neural crest cells destined to form the craniofacial dermis between them. We find that donor dermis induces host epidermis to form feather buds according to the spatial pattern and timetable of the donor species by altering the expression of members and targets of the Bone Morphogenetic Protein, Sonic Hedgehog and Delta/Notch pathways. Overall, we demonstrate that there is a great deal of spatiotemporal plasticity inherent in the molecular and histogenic programs of feather development, a property that may have played a generative and regulatory role throughout the evolution of birds.

Animals↗
PubMed1999

Depletion in serotonin decreases neurogenesis in the dentate gyrus and the subventricular zone of adult rats.

During adulthood, neuronal precursor cells persist in two discrete regions, the subventricular zone and the hippocampal subgranular zone, as recently demonstrated in primates. To date, a few factors such as adrenal steroids and trophic factors are known to regulate adult neurogenesis. Since neuronal activity may also influence cellular development and plasticity in brain, we investigated the effects of serotonin depletion on cell proliferation occurring in these regions. Indeed, in addition to its role as a neurotransmitter, 5-hydroxytryptamine (serotonin) is considered as a developmental regulatory signal. Prenatal depletion in 5-hydroxytryptamine delays the onset of neurogenesis in 5-hydroxytryptamine target regions and 5-hydroxytryptamine promotes the differentiation of cortical and hippocampal neurons. Although in the adult brain, a few studies have suggested that 5-hydroxytryptamine may play a role in neuronal plasticity by maintaining the synaptic connections in the cortex and hippocampus, no information is actually available concerning the influence of 5-hydroxytryptamine on adult neurogenesis. If further work confirms that new neurons can be produced in the adult human brain as is the case for a variety of species, it is particularly relevant to determine the influence of 5-hydroxytryptamine on neurogenesis in the hippocampal formation, a part of the brain largely implicated in learning and memory processes. Indeed, lack of 5-hydroxytryptamine in the hippocampus has been associated with cognitive disorders, such as depression, schizophrenia and Alzheimer's disease. In the present study, we demonstrated that both inhibition of 5-hydroxytryptamine synthesis and selective lesions of 5-hydroxytryptamine neurons are associated with decreases in the number of newly generated cells in the dentate gyrus, as well as in the subventricular zone.

5,7-Dihydroxytryptamine↗