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At least 1,099 records · Page 61Linked to original sources
PubMed2002

Reversible inhibition of CREB/ATF transcription factors in region CA1 of the dorsal hippocampus disrupts hippocampus-dependent spatial memory.

CREB is critical for long-lasting synaptic and behavioral plasticity in invertebrates. Its role in the mammalian hippocampus is less clear. We have interfered with CREB family transcription factors in region CA1 of the dorsal hippocampus. This impairs learning in the Morris water maze, which specifically requires the dorsal hippocampus, but not context conditioning, which does not. The deficit is specific to long-term memory, as shown in an object recognition task. Several forms of late-phase LTP are normal, but forskolin-induced and dopamine-regulated potentiation are disrupted. These experiments represent the first targeting of the dorsal hippocampus in genetically modified mice and confirm a role for CREB in hippocampus-dependent learning. Nevertheless, they suggest that some experimental forms of plasticity bypass the requirement for CREB.

Activating Transcription Factor 1↗
PubMed2000

mGluR1 in cerebellar Purkinje cells essential for long-term depression, synapse elimination, and motor coordination.

Targeted deletion of metabotropic glutamate receptor-subtype 1 (mGluR1) gene can cause defects in development and function in the cerebellum. We introduced the mGluR1alpha transgene into mGluR1-null mutant [mGluR1 (-/-)] mice with a Purkinje cell (PC)-specific promoter. mGluR1-rescue mice showed normal cerebellar long-term depression and regression of multiple climbing fiber innervation, events significantly impaired in mGluR1 (-/-) mice. The impaired motor coordination was rescued by this transgene, in a dose-dependent manner. We propose that mGluR1 in PCs is a key molecule for normal synapse formation, synaptic plasticity, and motor control in the cerebellum.

Animals↗
PubMed2001

Kinase-independent requirement of EphB2 receptors in hippocampal synaptic plasticity.

During development, Eph receptors mediate the repulsive axon guidance function of ephrins, a family of membrane attached ligands with their own receptor-like signaling potential. In cultured glutamatergic neurons, EphB2 receptors were recently shown to associate with NMDA receptors at synaptic sites and were suggested to play a role in synaptogenesis. Here we show that Eph receptor stimulation in cultured neurons modulates signaling pathways implicated in synaptic plasticity, suggesting cross-talk with NMDA receptor-activated pathways. Mice lacking EphB2 have normal hippocampal synapse morphology, but display defects in synaptic plasticity. In EphB2(-/-) hippocampal slices, protein synthesis-dependent long-term potentiation (LTP) was impaired, and two forms of synaptic depression were completely extinguished. Interestingly, targeted expression of a carboxy-terminally truncated form of EphB2 rescued the EphB2 null phenotype, indicating that EphB2 kinase signaling is not required for these EphB2-mediated functions.

Age Factors↗
PubMed2006

Barrel map development relies on protein kinase A regulatory subunit II beta-mediated cAMP signaling.

The cellular and molecular mechanisms mediating the activity-dependent development of brain circuitry are still incompletely understood. Here, we examine the role of cAMP-dependent protein kinase [protein kinase A (PKA)] signaling in cortical development and plasticity, focusing on its role in thalamocortical synapse and barrel map development. We provide direct evidence that PKA activity mediates barrel map formation using knock-out mice that lack type IIbeta regulatory subunits of PKA (PKARIIbeta). We show that PKARIIbeta-mediated PKA function is required for proper dendritogenesis and the organization of cortical layer IV neurons into barrels, but not for the development and plasticity of thalamocortical afferent clustering into a barrel pattern. We localize PKARIIbeta function to postsynaptic processes in barrel cortex and show that postsynaptic PKA targets, but not presynaptic PKA targets, have decreased phosphorylation in pkar2b knock-out (PKARIIbeta(-/-)) mice. We also show that long-term potentiation at TC synapses and the associated developmental increase in AMPA receptor function at these synapses, which normally occurs as barrels form, is absent in PKARIIbeta(-/-) mice. Together, these experiments support an activity-dependent model for barrel map development in which the selective addition and elimination of thalamocortical synapses based on Hebbian mechanisms for synapse formation is mediated by a cAMP/PKA-dependent pathway that relies on PKARIIbeta function.

Animals↗
PubMed2006

Cellular plasticity cascades: genes-to-behavior pathways in animal models of bipolar disorder.

BACKGROUND: Despite extensive research, the molecular/cellular underpinnings of bipolar disorder (BD) remain to be fully elucidated. Recent data has demonstrated that mood stabilizers exert major effects on signaling that regulate cellular plasticity; however, a direct extrapolation to mechanisms of disease demands proof that manipulation of candidate genes, proteins, or pathways result in relevant behavioral changes. METHODS: We critique and evaluate the behavioral changes induced by manipulation of cellular plasticity cascades implicated in BD. RESULTS: Not surprisingly, the behavioral data suggest that several important signaling molecules might play important roles in mediating facets of the complex symptomatology of BD. Notably, the protein kinase C and extracellular signal-regulated kinase cascades might play important roles in the antimanic effects of mood stabilizers, whereas glycogen synthase kinase (GSK)-3 might mediate facets of lithium's antimanic/antidepressant actions. Glucocorticoid receptor (GR) modulation also seems to be capable to inducing affective-like changes observed in mood disorders. And Bcl-2, amino-3-hydroxy-5-methylisoxazole-4-propionic acid receptors, and inositol homeostasis represent important pharmacological targets for mood stabilizers, but additional behavioral research is needed to more fully delineate their behavioral effects. CONCLUSIONS: Behavioral data support the notion that regulation of cellular plasticity is involved in affective-like behavioral changes observed in BD. These findings are leading to the development of novel therapeutics for this devastating illness.

Animals↗
PubMed1997

Postnatal changes in the laminar and subcellular distribution of NMDA-R1 subunits in the cat visual cortex as revealed by immuno-electron microscopy.

Although it is recognized that nearly all synapses in the cerebral cortex form postnatally, little is known about the emergence of molecules necessary to render these synapses functional. This study visualized the emergence of synaptically localized NMDA receptors by immuno-electron microscopic labeling of the receptor's obligatory subunit, NMDA-R1, in the developing cat visual cortex. Prior to eye-opening (postnatal day 2-10), NMDA-R1 immunoreactivity is already present within dendritic and growth cones, even though these profiles are devoid of synaptic specializations. This indicates that synthesis and incorporation of NMDA-R1 into plasma membranes are independent of form vision. During the next 2-3 weeks, i.e., preceding the onset of the critical period for ocular dominance plasticity (around the fourth week), NMDA-R1 immunoreactivity changes from a diffuse distribution within dendrites to a more discrete aggregation over postsynaptic densities of axo-spinous junctions. Such clustering of NMDA-R1 at synapses may be a prerequisite for stabilization and strengthening of synapses activated by visual stimulation during the critical period. Furthermore, only during the first several weeks, intensely NMDA-R1-immunoreactive neurons are present in the infragranular layers and the white matter. Enrichment of NMDA-R1 in the deep-layer neurons may reflect the neurons' supportive role in the development of cortical circuitry, serving as transient synaptic targets for geniculate and cortico-cortical afferents while these afferents 'wait' in the infragranular for their ultimate, life-long target neurons to become receptive in the upper layers.

Animals↗
PubMed2005

Critical period mechanisms in developing visual cortex.

Binocular vision is shaped by experience during a critical period of early postnatal life. Loss of visual acuity following monocular deprivation is mediated by a shift of spiking output from the primary visual cortex. Both synaptic and network explanations have been offered for this heightened brain plasticity. Direct experimental control over its timing, duration, and closure has now been achieved through a consideration of balanced local circuit excitation-inhibition. Notably, canonical models of homosynaptic plasticity at excitatory synapses alone (LTP/LTD) fail to produce predictable manipulations of the critical period in vivo. Instead, a late functional maturation of intracortical inhibition is the driving force, with one subtype in particular standing out. Parvalbumin-positive large basket cells that innervate target cell bodies with synapses containing the alpha1-subunit of GABA(A) receptors appear to be critical. With age, these cells are preferentially enwrapped in peri-neuronal nets of extracellular matrix molecules, whose disruption by chondroitinase treatment reactivates ocular dominance plasticity in adulthood. In fact, critical period plasticity is best viewed as a continuum of local circuit computations ending in structural consolidation of inputs. Monocular deprivation induces an increase of endogenous proteolytic (tPA-plasmin) activity and consequently motility of spines followed by their pruning, then re-growth. These early morphological events faithfully reflect competition only during the critical period and lie downstream of excitatory-inhibitory balance on a timescale (of days) consistent with the physiological loss of deprived-eye responses in vivo. Ultimately, thalamic afferents retract or expand accordingly to hardwire the rapid functional changes in connectivity. Competition detected by local inhibitory circuits then implemented at an extracellular locus by proteases represents a novel, cellular understanding of the critical period mechanism. It is hoped that this paradigm shift will lead to novel therapies and training strategies for rehabilitation, recovery from injury, and lifelong learning in adulthood.

Animals↗
PubMed2026

Precision Medicine in Pancreatic Cancer: Targeting KRAS and Beyond.

For the past decades, chemotherapy constituted the therapeutic foundation in advanced or metastatic pancreatic cancer. Despite significant advances in the molecular understanding, translation into tangible patient benefit has remained modest. Until recently, mutant KRAS, the dominant oncogenic driver, was considered undruggable, and only a small subgroup of patients potentially benefited from targeted therapies. With the emergence of KRAS inhibitors, most patients with pancreatic cancer in theory qualify for targeted therapeutics. Final results from the RASolute 302 trial showed clinically meaningful activity of RAS inhibition in patients with metastatic pancreatic cancer and paved the way for approval. Ongoing preclinical and coclinical studies have documented both intrinsic and acquired mechanisms of resistance to KRAS inhibition. Given the cellular plasticity seen in pancreatic cancer, the identification and anticipation of resistance mechanisms will be critical to exploit emerging therapeutic vulnerabilities through novel combination strategies. In view of the increasing number of trials and the growing body of evidence for targeted therapies, pancreatic cancer is entering a transitional phase in which precision oncology strategies must be redefined beyond rare molecular subgroups. In this review, we will briefly revisit targeted therapeutic approaches in pancreatic cancer to then discuss the clinical implications of genomic and transcriptomic heterogeneity in KRAS-mutant and KRAS wild-type disease. We will outline how our expanding biological insights into pancreatic cancer could inform combination and sequential therapeutic approaches.

Humans↗
PubMed1982

Plasticity in human blindsight.

A subject with an unually large cortical scotoma, leaving a 9 degrees hemifield of vision in each eye, showed improvement with practice in pointing to an oscillating target positioned within the scotoma. The practice effect transferred to low-contrast targets and to stationary ones, though oscillating targets were always located more accurately. Following practice, the subject reported improved confidence in visual orientation. Results are interpreted in the context of the contrast between the functions of two visual systems (subcortical and cortical) present in normal humans.

Brain Diseases↗
PubMed2005

Increased anxiety-like behaviors and mitochondrial dysfunction in mice with targeted mutation of the Bcl-2 gene: further support for the involvement of mitochondrial function in anxiety disorders.

There is growing evidence that anxiety disorders are associated with impairments of cellular plasticity and resilience. Paralleling these advances in our understanding of the neurobiologic underpinnings of anxiety disorders is the growing appreciation of the diverse functions that mitochondria play in regulating integrated CNS function. The emerging data suggest that mitochondrial Ca2+ sequestration has a key role in modulating the tone of synaptic plasticity in a variety of neuroanatomical regions, including those implicated in the pathophysiology of anxiety disorders. Furthermore, activation of peripheral mitochondrial benzodiazepine receptors resulted in reduced anxiety in rats. One of the major modulators of mitochondrial function is Bcl-2 proteins imbedded in the inner mitochondrial membrane. Bcl-2 overexpression increases mitochondria Ca2+ uptake capacity and resistance to Ca2+-inhibition of respiration and upregulation of Bcl-2 increases maximal uptake capacity of mitochondria. We have, therefore, explored the significance of Bcl-2 in the association between mitochondrial function and affective disorders testing Bcl-2 heterozygote mice in models of affective and anxiety disorders. Mutant mice have reduced mitochondrial Bcl-2 levels, and although they have no gross behavioral abnormalities, they demonstrate a significant increase of anxiety-like behaviors. Bcl-2 heterozygote mice spent less time in the center of an open field, spent less time outside an enclosure in the "emergence test", were less likely to explore the transparent part of a black/white box or the open arms of an elevated plus maze compared with WT controls. Mutant mice did not differ from WT in measures of locomotion or in the forced swim test for depression-like behavior suggesting a specific effect on anxiety-like behaviors. Our study, therefore demonstrates that Bcl-2 may be a key factor in anxiety disorders and that its effects may possibly originate from its role in the mitochondria.

Animals↗
PubMed2005

Distribution of synaptic zinc in the macaque monkey amygdala.

We have mapped the macaque amygdala for the distribution of synaptic zinc (Zn), a co-factor of glutamate implicated in plasticity, as well as in several excitotoxic and other pathophysiological conditions. In brief, we found that the amygdala is Zn enriched in all nuclear groups (i.e., basolateral and cortical groups, as well as central and medial nuclei) but with marked differences in density. By comparing parallel tissue series histologically reacted for Zn and parvalbumin (PV), we further found that regions high in Zn are typically low in PV neuropil. In the basolateral group, there is a particularly distinct dorsoventral gradation such that Zn levels are most dense ventrally, i.e., in the paralaminar nucleus, the ventral division of the lateral nucleus, and the parvicellular divisions of both the basal nucleus and the accessory basal nucleus. PV levels are least dense in these same regions. For the central and medial nuclei, there is a slight mediolateral gradient, with Zn levels being higher medially. PV is low overall in these nuclei. Electron microscopic results confirmed that Zn is contained in synaptic boutons. These form asymmetrical, presumably excitatory, synapses, and the postsynaptic targets are mainly spines of projection neurons. The inhomogeneous distribution of Zn in the monkey amygdala may be related to different types or degrees of plasticity among the amygdaloid subnuclei. The complementary distribution with PV parallels that of several other substances and is interesting in the context of subnuclear vulnerability for human neuronal disease, such as seizure and Alzheimer's disease.

Amygdala↗
PubMed2004

Identification of PSD-95 as a regulator of dopamine-mediated synaptic and behavioral plasticity.

To identify the molecular mechanisms underlying psychostimulant-elicited plasticity in the brain reward system, we undertook a phenotype-driven approach using genome-wide microarray profiling of striatal transcripts from three genetic and one pharmacological mouse models of psychostimulant or dopamine supersensitivity. A small set of co-affected genes was identified. One of these genes encoding the synaptic scaffolding protein PSD-95 is downregulated in the striatum of all three mutants and in chronically, but not acutely, cocaine-treated mice. At the synaptic level, enhanced long-term potentiation (LTP) of the frontocortico-accumbal glutamatergic synapses correlates with PSD-95 reduction in every case. Finally, targeted deletion of PSD-95 in an independent line of mice enhances LTP, augments the acute locomotor-stimulating effects of cocaine, but leads to no further behavioral plasticity in response to chronic cocaine. Our findings uncover a previously unappreciated role of PSD-95 in psychostimulant action and identify a molecular and cellular mechanism shared between drug-related plasticity and learning.

Animals↗
PubMed2001

Bakers' yeast, a model for fungal biofilm formation.

Biofilms are formed by the aggregation of microorganisms into multicellular structures that adhere to surfaces. Here we show that bakers' yeast Saccharomyces cerevisiae can initiate biofilm formation. When grown in low-glucose medium, the yeast cells adhered avidly to a number of plastic surfaces. On semi-solid (0.3% agar) medium they formed "mats": complex multicellular structures composed of yeast-form cells. Both attachment to plastic and mat formation require Flo11p, a member of a large family of fungal cell surface glycoproteins involved in adherence. The ability to study biofilm formation in a tractable genetic system may facilitate the identification of new targets for antifungal therapy.

Agar↗
PubMed1997

A new twist in an old story: the role for crosstalk of neuronal and trophic activity.

A number of recent findings suggest a reciprocal interaction between neurotransmitters and neurotrophins functioning at the level of the synapse, which may be relevant not only for plasticity changes in the mature nervous system, but also for the development of synaptic connectivity and for survival or maturation of neurons prior to target contact. Thus, neurotrophin-induced attenuation of frequency-dependent depletion of releasable synaptic vesicle pools of neurotransmitter at synapses may participate in Hebbian and non-Hebbian forms of LTP, as a characteristic of mature synaptic contacts. Subsequent to nerve/target contact, neurotrophins also appear to mediate contact-induced enhancement of neurotransmitter release; this may participate in a developmental improvement of synapse efficacy, stabilization of synaptic contacts, and maturation of "conductive" functional synapses. Coincident with a transmitter-induced elevation of cytosolic Ca2+ levels within growth cones, a local neurotrophin-mediated increase in released neurotransmitter occurring subsequent to stabilization of a distinct synaptic contact may then participate in the refinement of synapses with retention of those neurites affected by neurotrophins and withdrawal of those neurites not affected by neurotrophins. Finally, prior to nerve/target contact, Ca2+ channel-generated spontaneous neuronal activity as well as co-expression of neurotrophins and their receptors may play a role in maturational changes.

Animals↗
PubMedDate not supplied

Absorption, disposition and metabolism of di-isononyl phthalate (DINP) in F-344 rats.

Di-isononyl phthalate (DINP; CAS no. 68515-48-0) is a general-purpose plasticizer for polyvinyl chloride. It produced liver and kidney effects when given to rodents at high oral doses, but there were no target organ effects in primates treated under similar conditions. To assist in understanding the basis for these species differences, the pharmacokinetic properties of DINP were evaluated in rodents following both oral and dermal administration. These studies demonstrated that the pharmacokinetic properties of DINP are similar to those of other high-molecular-weight phthalates. When orally administered to rodents, DINP is rapidly metabolized in the gastrointestinal tract to the corresponding monoester, absorbed and excreted, primarily in the urine. Shortly after administration, DINP is found primarily in liver and kidneys, but it does not persist or accumulate in any organ or tissue. It is very poorly absorbed from the skin, but once absorbed it behaves in the same way as the orally administered material. The results of these rodent studies contrast with data from studies involving humans or other primates, which indicate low absorption at low oral doses and much more limited total absorption at high doses. It appears that many, if not all, of the effects of DINP in rodent studies are associated with internal doses that would be difficult, if not impossible, to achieve in humans under any circumstances. Thus, the results of rodent studies may not be very useful in assessing the potential risks to humans from high-molecular-weight phthalates.

Administration, Cutaneous↗
PubMed2005

Hox genes and their candidate downstream targets in the developing central nervous system.

1. Homeobox (Hox) genes were originally discovered in the fruit fly Drosophila, where they function through a conserved homeodomain as transcriptional regulators to control embryonic morphogenesis. Since then over 1000 homeodomain proteins have been identified in several species. In vertebrates, 39 Hox genes have been identified as homologs of the original Drosophila complex, and like their Drosophila counterparts they are organized within chromosomal clusters. Vertebrate Hox genes have also been shown to play a critical role in embryonic development as transcriptional regulators. 2. Both the Drosophila and vertebrate Hox genes have been shown to interact with various cofactors, such as the TALE homeodomain proteins, in recognition of consensus sequences within regulatory elements of their target genes. These protein-protein interactions are believed to contribute to enhancing the specificity of target gene recognition in a cell-type or tissue- dependent manner. The regulatory activity of a particular Hox protein on a specific regulatory element is highly variable and dependent on its interacting partners within the transcriptional complex. 3. In vertebrates, Hox genes display spatially restricted patterns of expression within the developing CNS, both along the anterioposterior and dorsoventral axis of the embryo. Their restricted gene expression is suggestive of a regulatory role in patterning of the CNS, as well as in cell specification. Determining the precise function of individual Hox genes in CNS morphogenesis through classical mutational analyses is complicated due to functional redundancy between Hox genes. 4. Understanding the precise mechanisms through which Hox genes mediate embryonic morphogenesis requires the identification of their downstream target genes. Although Hox genes have been implicated in the regulation of several pathways, few target genes have been shown to be under their direct regulatory control. Development of methodologies used for the isolation of target genes and for the analysis of putative targets will be beneficial in establishing the genetic pathways controlled by Hox factors. 5. Within the developing CNS various cell adhesion molecules and signaling molecules have been identified as candidate downstream target genes of Hox proteins. These targets play a role in processes such as cell migration and differentiation, and are implicated in contributing to neuronal processes such as plasticity and/or specification. Hence, Hox genes not only play a role in patterning of the CNS during early development, but may also contribute to cell specification and identity.

Animals↗
PubMed2004

Altered response to mirtazapine on gene expression profile of lymphocytes from Alzheimer's patients.

Antidepressants are widely used in the treatment of mood disorders associated with dementia, however little information is available on their effect at the molecular level. We have demonstrated that gene expression profiles of lymphocytes from patients with Alzheimer dementia differ from that seen with controls, with alpha(2)-adrenoceptor being the most highly repressed transcript. To address this issue in light of antidepressant treatment, we used lymphocytes derived from Alzheimer patients and control individuals to assess the impact of mirtazapine, the novel antidepressant with alpha(2)-adrenoceptor antagonistic activities, on gene expression using a cDNA microarray representing 3200 distinct human genes. Sequences that are differentially regulated after treatment with mirtazapine were identified and categorized based on similarities in biological functions. This analysis revealed that selected biological processes, including protein metabolism, cytoskeleton integrity, immune response, cellular plasticity, and neurotransmission, are involved in early phases of administration of this antidepressant. In addition, although it was possible to identify common targets, the expression profiles of Alzheimer lymphocytes differed mainly in their magnitude from those seen with controls. These results confirm the usefulness of the gene array approach for studying Alzheimer-specific changes in the periphery and suggest that the expression of genes of Alzheimer lymphocytes is modulated differently by mirtazapine, which correlates with the pathology.

Aged↗
PubMed2004

Density, but not shape, of hippocampal dendritic spines varies after a seizure-inducing acute dose of monosodium glutamate in rats.

Dendritic spines are the main postsynaptic neuronal targets of excitatory inputs in cortical neurons, and both spine density and shape possess a well known adaptive synaptic-stimulation-dependent plastic capacity. Eighteen Sprague-Dawley adult male rats were used. Monosodium glutamate-treated rats (4 g/kg of body weight, i.p.) showed tonic and clonic epileptic seizures, as well as less dendritic spines in the apical arborization of their hippocampal CA1 pyramidal cells, compared to both control groups. No changes were seen in the proportional density of thin, stubby, mushroom-shaped, wide, or ramified spines between groups. Excessive glutamate-mediated excitatory activity on receptors could have led dendritic spines to shrink until they disappeared, while the spine-type proportion may be kept balanced as an adaptive response.

Animals↗