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Query: UMLS:C0011570 (depression)
 172,036 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The barrel cortex has yielded a wealth of information about cortical plasticity in recent years. Barrel cortex is one of the few cortical areas studied so far where plasticity can be examined from birth through to adulthood. This review looks at plasticity mechanisms in three periods of life: early post-natal development, adolescence and adulthood. Separate consideration is given to depression and potentiation mechanisms. Plasticity can be induced in barrel cortex by whisker deprivation. Single whisker experience leads to expansion of the area of cortex responding to the spared whisker. In early post-natal life, plasticity occurs in thalamocortical pathways, while later in adolescence, intracortical pathways become more important. Ablation of the spared whisker's barrel prevents expression of plasticity in the cortex. A row of lesions between the spared and an adjacent barrel prevents expression of plasticity in the adjacent barrel. This evidence, together with latency of response data and an analysis of pathways capable of inducing long-term potentiation (LTP) within barrel cortex, leads to the view that horizontal and/or diagonal pathways between barrels are responsible for plasticity expression. The mouse has become the most commonly mutated mammalian species and has a well-developed barrel cortex. Therefore, mutations can be used to study the role of particular molecules in experience-dependent plasticity of barrel cortex. Through this work, it has become clear that the major post-synaptic density protein, alpha-CaMKII, and its T286 autophosphorylation site are essential for experience-dependent plasticity. This points to a major role for excitatory transmission in cortical plasticity and raises the possibility that LTP like mechanisms are involved. Furthermore, transgenic mice carrying a reporter gene for CRE have provided evidence that CRE-mediated gene expression is also involved in barrel cortex plasticity. This view is supported by studies on alpha/delta CREB knockouts, and provides a starting point for studying the role of gene expression in experience-dependent cortical plasticity.
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PMID:Anatomical pathways and molecular mechanisms for plasticity in the barrel cortex. 1203 5

Recent studies show that AMPA receptor (-R) trafficking is important in synaptic plasticity. However, the signaling controlling this trafficking is poorly understood. Small GTPases have diverse neuronal functions and their perturbation is responsible for several mental disorders. Here, we examine the small GTPases Ras and Rap in the postsynaptic signaling underlying synaptic plasticity. We show that Ras relays the NMDA-R and CaMKII signaling that drives synaptic delivery of AMPA-Rs during long-term potentiation. In contrast, Rap mediates NMDA-R-dependent removal of synaptic AMPA-Rs that occurs during long-term depression. Ras and Rap exert their effects on AMPA-Rs that contain different subunit composition. Thus, Ras and Rap, whose activity can be controlled by postsynaptic enzymes, serve as independent regulators for potentiating and depressing central synapses.
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PMID:Ras and Rap control AMPA receptor trafficking during synaptic plasticity. 1220 34

Glutamate produces a hyperpolarizing postsynaptic potential in ON bipolar cells by binding to the metabotropic receptor mGluR6 and subsequently closing a cation-selective channel. It has been proposed that Ca(2+) influx through the cation channel triggers a depression of the synaptic potential. Here we report that this Ca(2+)-mediated depression requires activation of calcineurin, a Ca(2+)/calmodulin-regulated phosphatase. We measured glutamate-evoked currents (I(glu)) with whole cell recordings of ON bipolar cells in light-adapted retinal slices. Depression of I(glu) by Ca(2+) was prevented by inhibitors of calcineurin or by tightly buffering Ca(2+) with bis-(o-aminophenoxy)-N,N,N',N'-tetraacetic acid (BAPTA). However, when cells were dialyzed with BAPTA and a Ca(2+)-independent form of calcineurin (CaN420), depression of I(glu) was restored. Similarly, CaN420 induced depression of I(glu) during continuous glutamate application, a protocol that ordinarily prevents depression. Analysis of changes in the amplitude of the cation-selective current (I(cat)) of cells that were dialyzed with high Ca(2+) (1 microM), or with BAPTA and CaN420, indicates that Ca(2+) depresses I(glu) by reducing I(cat) and that calcineurin acts via the same mechanism. Ca(2+)-mediated depression of I(glu) was not found to involve CaMKII, as inhibitors of CaMKII did not prevent this depression nor did they affect the sensitivity of the response to small changes in the concentration of mGluR6 agonist. Our data suggest that Ca(2+) and calcineurin may play an adaptive role at the synapse between photoreceptor and ON bipolar cells, closing postsynaptic cation channels that are opened by a drop in synaptic glutamate levels during prolonged photoreceptor illumination.
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PMID:Regulation of the retinal bipolar cell mGluR6 pathway by calcineurin. 1220 31

The effects of neonatal dexamethasone (DEX) treatment on spatial learning and hippocampal synaptic plasticity were investigated in adult rats. Spatial learning in reference and working memory versions of the Morris maze was impaired in DEX-treated rats. In hippocampal slices of DEX rats, long-term depression was facilitated and potentiation was impaired. Paired-pulse facilitation was normal, suggesting a postsynaptic defect as cause of the learning and plasticity deficits. Western blot analysis of hippocampal postsynaptic densities (PSD) revealed a reduction in NR2B subunit protein, whereas the abundance of the other major N-methyl-D-aspartate (NMDA) receptor subunits (NR1, NR2A), AMPA receptor subunits (GluR2/3), scaffolding proteins, and Ca2+/calmodulin-dependent protein kinase II (alphaCaMKII) were unaltered. This selective reduction in NR2B likely resulted from altered receptor assembly rather than subunit expression, because the abundance of NR2B in the homogenate and crude synaptosomal fractions was unaltered. In addition, the activity of alphaCaMKII, an NMDA receptor complex associated protein kinase, was increased in PSD of DEX rats. The results indicate that neonatal treatment with DEX causes alterations in composition and function of the hippocampal NMDA receptor complex that persist into adulthood. These alterations likely explain the deficits in hippocampal synaptic plasticity and spatial learning induced by neonatal DEX treatment.
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PMID:Long-lasting effects of neonatal dexamethasone treatment on spatial learning and hippocampal synaptic plasticity: involvement of the NMDA receptor complex. 1262 41

Voltage-sensitive Ca2+ channels (VSCCs) constitute a major source of calcium ions in dendritic spines, but their function is unknown. Here we show that R-type VSCCs in spines of rat CA1 pyramidal neurons are depressed for at least 30 min after brief trains of back-propagating action potentials. Populations of channels in single spines are depressed stochastically and synchronously, independent of channels in the parent dendrite and other spines, implying that depression is the result of signaling restricted to individual spines. Induction of VSCC depression blocks theta-burst-induced long-term potentiation (LTP), indicating that postsynaptic action potentials can modulate synaptic plasticity by tuning VSCCs. Induction of depression requires [Ca2+] elevations and activation of L-type VSCCs, which activate Ca2+/calmodulin-dependent kinase II (CaMKII) and a cyclic adenosine monophosphate (cAMP)-dependent pathway. Given that L-type VSCCs do not contribute measurably to Ca2+ influx in spines, they must activate downstream effectors either directly through voltage-dependent conformational changes or via [Ca2+] microdomains.
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PMID:Plasticity of calcium channels in dendritic spines. 1293 22

NCAM, a neural cell adhesion molecule of the immunoglobulin superfamily, is involved in neuronal migration and differentiation, axon outgrowth and fasciculation, and synaptic plasticity. To dissociate the functional roles of NCAM in the adult brain from developmental abnormalities, we generated a mutant in which the NCAM gene is inactivated by cre-recombinase under the control of the calcium-calmodulin-dependent kinase II promoter, resulting in reduction of NCAM expression predominantly in the hippocampus. This mutant (NCAMff+) did not show the overt morphological and behavioral abnormalities previously observed in constitutive NCAM-deficient (NCAM-/-) mice. However, similar to the NCAM-/- mouse, a reduction in long-term potentiation (LTP) in the CA1 region of the hippocampus was revealed. Long-term depression was also abolished in NCAMff+ mice. The deficit in LTP could be rescued by elevation of extracellular Ca2+ concentrations from 1.5 or 2.0 to 2.5 mm, suggesting an involvement of NCAM in regulation of Ca2+-dependent signaling during LTP. Contrary to the NCAM-/- mouse, LTP in the CA3 region was normal, consistent with normal mossy fiber lamination in NCAMff+ as opposed to abnormal lamination in NCAM-/- mice. NCAMff+ mutants did not show general deficits in short- and long-term memory in global landmark navigation in the water maze but were delayed in the acquisition of precise spatial orientation, a deficit that could be overcome by training. Thus, mice conditionally deficient in hippocampal NCAM expression in the adult share certain abnormalities characteristic of NCAM-/- mice, highlighting the role of NCAM in the regulation of synaptic plasticity in the CA1 region.
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PMID:Conditional ablation of the neural cell adhesion molecule reduces precision of spatial learning, long-term potentiation, and depression in the CA1 subfield of mouse hippocampus. 1497 28

The acute hippocampal slice preparation has been widely used to study the cellular mechanisms underlying activity-dependent forms of synaptic plasticity such as long-term potentiation (LTP) and long-term depression (LTD). Although protein phosphorylation has a key role in LTP and LTD, little is known about how protein phosphorylation might be altered in hippocampal slices maintained in vitro. To begin to address this issue, we examined the effects of slicing and in vitro maintenance on phosphorylation of six proteins involved in LTP and/or LTD. We found that AMPA receptor (AMPAR) glutamate receptor 1 (GluR1) subunits are persistently dephosphorylated in slices maintained in vitro for up to 8 h. alpha calcium/calmodulin-dependent kinase II (alphaCamKII) was also strongly dephosphorylated during the first 3 h in vitro but thereafter recovered to near control levels. In contrast, phosphorylation of the extracellular signal-regulated kinase ERK2, the ERK kinase MEK, proline-rich tyrosine kinase 2 (Pyk2), and Src family kinases was significantly, but transiently, increased. Electrophysiological experiments revealed that the induction of LTD by low-frequency synaptic stimulation was sensitive to time in vitro. These findings indicate that phosphorylation of proteins involved in N-methyl-D-aspartate (NMDA) receptor-dependent forms of synaptic plasticity is altered in hippocampal slices and suggest that some of these changes can significantly influence the induction of LTD.
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PMID:Phosphorylation of proteins involved in activity-dependent forms of synaptic plasticity is altered in hippocampal slices maintained in vitro. 1558 11

Cardioprotection by intermittent high-altitude (IHA) hypoxia against ischemia-reperfusion (I/R) injury is associated with Ca(2+) overload reduction. Phospholamban (PLB) phosphorylation relieves cardiac sarcoplasmic reticulum (SR) Ca(2+)-pump ATPase, a critical regulator in intracellular Ca(2+) cycling, from inhibition. To test the hypothesis that IHA hypoxia increases PLB phosphorylation and that such an effect plays a role in cardioprotection, we compared the time-dependent changes in the PLB phosphorylation at Ser(16) (PKA site) and Thr(17) (CaMKII site) in perfused normoxic rat hearts with those in IHA hypoxic rat hearts submitted to 30-min ischemia (I30) followed by 30-min reperfusion (R30). IHA hypoxia improved postischemic contractile recovery, reduced the maximum extent of ischemic contracture, and attenuated I/R-induced depression in Ca(2+)-pump ATPase activity. Although the PLB protein levels remained constant during I/R in both groups, Ser(16) phosphorylation increased at I30 and 1 min of reperfusion (R1) but decreased at R30 in normoxic hearts. IHA hypoxia upregulated the increase further at I30 and R1. Thr(17) phosphorylation decreased at I30, R1, and R30 in normoxic hearts, but IHA hypoxia attenuated the depression at R1 and R30. Moreover, PKA inhibitor H89 abolished IHA hypoxia-induced increase in Ser(16) phosphorylation, Ca(2+)-pump ATPase activity, and the recovery of cardiac performance after ischemia. CaMKII inhibitor KN-93 also abolished the beneficial effects of IHA hypoxia on Thr(17) phosphorylation, Ca(2+)-pump ATPase activity, and the postischemic contractile recovery. These findings indicate that IHA hypoxia mitigates I/R-induced depression in SR Ca(2+)-pump ATPase activity by upregulating dual-site PLB phosphorylation, which may consequently contribute to IHA hypoxia-induced cardioprotection against I/R injury.
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PMID:Role of dual-site phospholamban phosphorylation in intermittent hypoxia-induced cardioprotection against ischemia-reperfusion injury. 1563 15

Synaptic plasticity involves protein phosphorylation cascades that alter the density of AMPA-type glutamate receptors at excitatory synapses; however, the crucial phosphorylated substrates remain uncertain. Here, we show that the AMPA receptor-associated protein stargazin is quantitatively phosphorylated and that stargazin phosphorylation promotes synaptic trafficking of AMPA receptors. Synaptic NMDA receptor activity can induce both stargazin phosphorylation, via activation of CaMKII and PKC, and stargazin dephosphorylation, by activation of PP1 downstream of PP2B. At hippocampal synapses, long-term potentiation and long-term depression require stargazin phosphorylation and dephosphorylation, respectively. These results establish stargazin as a critical substrate in the bidirectional control of synaptic strength, which is thought to underlie aspects of learning and memory.
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PMID:Bidirectional synaptic plasticity regulated by phosphorylation of stargazin-like TARPs. 1566 78

Neurokinin 1 (NK-1) receptor knockout mice showed behavioral responses similar to animals chronically treated with antidepressants. The aim of this study was to analyse, in NK-1 receptor knockout, the molecular modifications of signaling pathways involved in the pathophysiology of depression and antidepressant mechanism. We found, in total cell cytosol from the prefrontal/frontal cortex, hippocampus and striatum, a marked up-regulation of Ca(2+)-independent enzymatic activity and Thr(286) autophosphorylation of Ca(2+)/calmodulin-dependent protein kinase (CaMK) II. Similar changes in CaMKII regulation were previously observed in rats chronically treated with antidepressants. In striatum, up-regulation of the activity and phosphorylation of CaMKII was also found in the homogenate and synaptosomes. No major changes were observed in the Ca(2+)-dependent kinase activity, with the exception of homogenate from the prefrontal/frontal cortex. We also analysed the expression and phosphorylation of presynaptic proteins, which modulate synaptic vesicle trafficking and exocytosis, and found a marked decrease in synapsin I total expression and basal phosphorylation of Ser(603) (the phosphorylation site for CaMKII) in the prefrontal/frontal cortex. Accordingly, the Ca(2+)/calmodulin-dependent posthoc endogenous phosphorylation of synapsin I in the same area was increased. The knockout of NK-1 receptor had no consequences on the expression or phosphorylation levels of the transcription factor cAMP-responsive element-binding protein and its regulating kinase CaMKIV. However, phosphorylation of ERK1/2-mitogen-activated protein kinases was reduced in the hippocampus and striatum, again resembling an effect previously observed in antidepressant-treated rats. These results show similarities between NK-1 knockouts and animals chronically treated with antidepressants and support the putative antidepressant activity of NK-1 receptor antagonists.
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PMID:Changes in signaling pathways regulating neuroplasticity induced by neurokinin 1 receptor knockout. 1581 46


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