Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0011570 (depression)
 172,036 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The genetically selected long attack latency (LAL) and short attack latency (SAL) mice differ in a wide variety of behavioural traits and display differences in the serotonergic system and the hypothalamus-pituitary-adrenocortical (HPA)-axis. Serial analysis of gene expression (SAGE) was used to generate a hippocampal expression profile of almost 30 000 genes in LAL and SAL mice. Using SAGE, we found differential expression of 191 genes. Among these were genes involved in growth, signal transduction, and cell metabolism. The SAGE study was supported by GeneChip analysis (Affymetrix). Strikingly, both SAGE and GeneChips showed a higher expression of numerous cytoskeleton genes, such as cofilin and several tubulin isotypes in LAL mice. LAL mice also showed a higher expression of several calmodulin-related genes and genes encoding components of a MAPK cascade, namely raf-related oncogene and ERK2. The findings were confirmed by in situ hybridization. Our results of differential expression of cytoskeleton and signal transduction genes therefore suggest differential regulation of the raf/ERK pathway that may be related to structural differences in the hippocampus of LAL and SAL mice. As stress-related disorders, such as depression, are also linked to differential regulation of the HPA-axis and the serotonergic system and are associated with altered hippocampal morphology, differential regulation of these genes may be involved in the pathogenesis of these diseases.
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PMID:Serial analysis of gene expression predicts structural differences in hippocampus of long attack latency and short attack latency mice. 1254 75

Activity-induced modification of neuronal connections is essential for the development of the nervous system and may also underlie learning and memory functions of mature brain. Previous studies have shown an increase in dendritic spine density and/or enlargement of spines after the induction of long-term potentiation (LTP). Using two-photon time-lapse imaging of dendritic spines in acute hippocampal slices from neonatal rats, we found that the induction of long-term depression (LTD) by low-frequency stimulation is accompanied by a marked shrinkage of spines, which can be reversed by subsequent high-frequency stimulation that induces LTP. The spine shrinkage requires activation of NMDA receptors and calcineurin, similar to that for LTD. However, spine shrinkage is mediated by cofilin, but not by protein phosphatase 1 (PP1), which is essential for LTD, suggesting that different downstream pathways are involved in spine shrinkage and LTD. This activity-induced spine shrinkage may contribute to activity-dependent elimination of synaptic connections.
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PMID:Shrinkage of dendritic spines associated with long-term depression of hippocampal synapses. 1557 7

Although long-term depression (LTD) of AMPA receptor-mediated postsynaptic currents (AMPAR EPSCs) has been extensively examined, little is known about the mechanisms responsible for LTD of NMDA receptor (NMDAR)-mediated EPSCs. Here we show differences in the intracellular signaling cascades that mediate LTD of AMPAR EPSCs versus NMDAR EPSCs in rat hippocampus. Both forms of LTD were blocked by inhibitors of protein phosphatase 1, but only LTD of AMPAR EPSCs was affected by inhibition of calcineurin. Notably, in contrast to LTD of AMPAR EPSCs, LTD of NMDAR EPSCs was unaffected by endocytosis inhibitors. A role for calcium-dependent actin depolymerization in LTD of NMDAR EPSCs was supported by the findings that the actin stabilizer phalloidin and a cofilin inhibitory peptide each blocked LTD of NMDAR EPSCs but not AMPAR EPSCs. These results suggest that the same pattern of afferent activity elicits depression of AMPAR- and NMDAR-mediated synaptic responses by means of distinct triggering and expression mechanisms.
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PMID:Distinct triggering and expression mechanisms underlie LTD of AMPA and NMDA synaptic responses. 1602 9

Synaptic consolidation refers to the development and stabilization of protein synthesis-dependent modifications of synaptic strength as observed during long-term potentiation (LTP) and long-term depression (LTD). Activity-dependent changes in synaptic strength are thought to underlie memory storage and other adaptive responses of the nervous systems of importance in mood stability, reward behavior, and pain control. This chapter focuses on the mechanisms and functions of synaptic consolidation in the dentate gyrus, a critical structure not only in hippocampal memory function, but also in regulation of stress responses and cognitive aspects of depression. Recent evidence suggests that synaptic consolidation at excitatory medial perforant path-granule cell synapses requires brain-derived neurotrophic factor (BDNF) signaling and induction of the immediate early gene activity-regulated cytoskeleton-associated protein (Arc). Arc mRNA is strongly induced and transported to dendritic processes following high-frequency stimulation (HFS) that induces LTP in the rat dentate gyrus in vivo. Sustained synthesis of Arc during a surprisingly protracted time-window is required for hyperphosphorylation of actin depolymerizing factor/cofilin and local expansion of the actin cytoskeleton in vivo. Furthermore, this process of Arc-dependent synaptic consolidation is activated in response to brief infusion of BDNF. Microarray expression profiling has revealed a panel of BDNF-regulated genes that may cooperate with Arc during synaptic consolidation. In addition to regulating gene expression, BDNF signaling modulates the fine localization and biochemical activation of the translation machinery. By modulating the spatial and temporal translation of newly induced (Arc) and constitutively-expressed mRNA in dendrites, BDNF may effectively control the window of synaptic consolidation. Dysregulation of BDNF synthesis and Arc function, specifically within the dentate gyrus, is linked to behavioral symptoms and cognitive deficits in animal models of depression and Alzheimer's disease. Therapeutics strategies targeting synaptic consolidation hold promise for the future.
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PMID:Control of synaptic consolidation in the dentate gyrus: mechanisms, functions, and therapeutic implications. 1776 33

In a manner unique among activity-regulated immediate early genes (IEGs), mRNA encoded by Arc (also known as Arg3.1) undergoes rapid transport to dendrites and local synaptic translation. Despite this intrinsic appeal, relatively little is known about the neuronal and behavioral functions of Arc or its molecular mechanisms of action. Here, we attempt to distill recent advances on Arc spanning its transcriptional and translational regulation, the functions of the Arc protein in multiple forms of neuronal plasticity [long-term potentiation (LTP), long-term depression (LTD), and homeostatic plasticity], and its broader role in neural networks of behaving animals. Worley and colleagues have shown that Arc interacts with endophilin and dynamin, creating a postsynaptic trafficking endosome that selectively modifies the expression of AMPA-type glutamate receptors at the excitatory synapses. Both LTD and homeostatic plasticity in the hippocampus are critically dependent on Arc-mediated endocytosis of AMPA receptors. LTD evoked by activation of metabotropic glutamate receptors depends on rapid Arc translation controlled by elongation factor 2. Bramham and colleagues have shown that sustained translation of newly induced Arc mRNA is necessary for cofilin phosphorylation and stable expansion of the F-actin cytoskeleton underlying LTP consolidation in the dentate gyrus of live rats. In addition to regulating F-actin, Arc synthesis maintains the activity of key translation factors during LTP consolidation. This process of Arc-dependent consolidation is activated by the secretory neurotrophin, BDNF. Moore and colleagues have shown that Arc mRNA is a natural target for nonsense-mediated mRNA decay (NMD) by virtue of its two conserved 3'-UTR introns. NMD and other related translation-dependent mRNA decay mechanisms may serve as critical brakes on protein expression that contribute to the fine spatial-temporal control of Arc synthesis. In studies in behaving rats, Guzowski and colleagues have shown that location-specific firing of CA3 and CA1 hippocampal neurons in the presence of theta rhythm provides the necessary stimuli for activation of Arc transcription. The impact of Arc transcription in memory processes may depend on the specific context of coexpressed IEGs, in addition to posttranscriptional regulation of Arc by neuromodulatory inputs from the amygdala and other brain regions. In sum, Arc is emerging as a versatile, finely tuned system capable of coupling changes in neuronal activity patterns to diverse forms of synaptic plasticity, thereby optimizing information storage in active networks.
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PMID:The immediate early gene arc/arg3.1: regulation, mechanisms, and function. 1900 37

SynGAP, a prominent Ras/Rap GTPase-activating protein in the postsynaptic density, regulates the timing of spine formation and trafficking of glutamate receptors in cultured neurons. However, the molecular mechanisms by which it does this are unknown. Here, we show that synGAP is a key regulator of spine morphology in adult mice. Heterozygous deletion of synGAP was sufficient to cause an excess of mushroom spines in adult brains, indicating that synGAP is involved in steady-state regulation of actin in mature spines. Both Ras- and Rac-GTP levels were elevated in forebrains from adult synGAP(+/-) mice. Rac is a well known regulator of actin polymerization and spine morphology. The steady-state level of phosphorylation of cofilin was also elevated in synGAP(+/-) mice. Cofilin, an F-actin severing protein that is inactivated by phosphorylation, is a downstream target of a pathway regulated by Rac. We show that transient regulation of cofilin by treatment with NMDA is also disrupted in synGAP mutant neurons. Treatment of wild-type neurons with 25 mum NMDA triggered transient dephosphorylation and activation of cofilin within 15 s. In contrast, neurons cultured from mice with a homozygous or heterozygous deletion of synGAP lacked the transient regulation by the NMDA receptor. Depression of EPSPs induced by a similar treatment of hippocampal slices with NMDA was disrupted in slices from synGAP(+/-) mice. Our data show that synGAP mediates a rate-limiting step in steady-state regulation of spine morphology and in transient NMDA-receptor-dependent regulation of the spine cytoskeleton.
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PMID:SynGAP regulates steady-state and activity-dependent phosphorylation of cofilin. 1907 40

Auditory hair cell function requires proper assembly and regulation of the nonmuscle gamma isoactin-rich cytoskeleton, and six point mutations in this isoactin cause a type of delayed onset autosomal dominant nonsyndromic progressive hearing loss, DFNA20/26. The molecular basis underlying this actin-dependent hearing loss is unknown. To address this problem, the mutations have been introduced into yeast actin, and their effects on actin function were assessed in vivo and in vitro. Because we previously showed that polymerization was unaffected in five of the six mutants, we have focused on proteins that regulate actin, in particular cofilin, which severs F-actin and sequesters actin monomers. The mutations do not affect the interaction of cofilin with G-actin. However, T89I and V370A mutant F-actins are much more susceptible to cofilin disassembly than WT filaments in vitro. Conversely, P332A filaments demonstrate enhanced resistance. Wild type actin solutions containing T89I, K118M, or P332A mutant actins at mole fractions similar to those found in the hair cell respond in vitro toward cofilin in a manner proportional to the level of the mutant present. Finally, depression of cofilin action in vivo by elimination of the cofilin-activating protein, Aip1p, rescues the inability to grow on glycerol caused by K118M, T278I, P332A, and V370A. These results suggest that a filament instability caused by these mutations can be balanced by decreasing a system in vivo that promotes increased filament turnover. Such mutant-dependent filament destabilization could easily result in hair cell malfunction leading to the late-onset hearing loss observed in these patients.
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PMID:Allele-specific effects of human deafness gamma-actin mutations (DFNA20/26) on the actin/cofilin interaction. 1941 63

Neuronal plasticity is an important process for learning, memory and complex behaviour. Rapid remodelling of the actin cytoskeleton in the postsynaptic compartment is thought to have an important function for synaptic plasticity. However, the actin-binding proteins involved and the molecular mechanisms that in vivo link actin dynamics to postsynaptic physiology are not well understood. Here, we show that the actin filament depolymerizing protein n-cofilin is controlling dendritic spine morphology and postsynaptic parameters such as late long-term potentiation and long-term depression. Loss of n-cofilin-mediated synaptic actin dynamics in the forebrain specifically leads to impairment of all types of associative learning, whereas exploratory learning is not affected. We provide evidence for a novel function of n-cofilin function in synaptic plasticity and in the control of extrasynaptic excitatory AMPA receptors diffusion. These results suggest a critical function of actin dynamics in associative learning and postsynaptic receptor availability.
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PMID:Learning, AMPA receptor mobility and synaptic plasticity depend on n-cofilin-mediated actin dynamics. 2051 33

Estrogen, in addition to its genomic effects, triggers rapid synaptic changes in hippocampus and cortex. Here we summarize evidence that the acute actions of the steroid arise from actin signaling cascades centrally involved in long-term potentiation (LTP). A 10-min infusion of E2 reversibly increased fast EPSPs and promoted theta burst-induced LTP within adult hippocampal slices. The latter effect reflected a lowered threshold and an elevated ceiling for the potentiation effect. E2's actions on transmission and plasticity were completely blocked by latrunculin, a toxin that prevents actin polymerization. E2 also caused a reversible increase in spine concentrations of filamentous (F-) actin and markedly enhanced polymerization caused by theta burst stimulation (TBS). Estrogen activated the small GTPase RhoA, but not the related GTPase Rac, and phosphorylated (inactivated) synaptic cofilin, an actin severing protein targeted by RhoA. An inhibitor of RhoA kinase (ROCK) thoroughly suppressed the synaptic effects of E2. Collectively, these results indicate that E2 engages a RhoA >ROCK> cofilin> actin pathway also used by brain-derived neurotrophic factor and adenosine, and therefore belongs to a family of 'synaptic modulators' that regulate plasticity. Finally, we describe evidence that the acute signaling cascade is critical to the depression of LTP produced by ovariectomy.
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PMID:Estrogen's Place in the Family of Synaptic Modulators. 2041 49

The GluA2 (GluR2) subunit is critical for the regulation of AMPA receptor properties and synaptic plasticity, but the underlying mechanisms remain unclear. Here, we demonstrate that GluA2 regulates metabotropic glutamate receptor-dependent long-term depression (mGluR-LTD) through a previously unknown mechanism involving N-cadherin-dependent and cofilin-mediated actin reorganization. We show that GluA2 is indispensable for mGluR-LTD in the hippocampus, and surprisingly this action of GluA2 is mediated by its extracellular domain interaction with N-cadherin. Accordingly, we show that the function of N-cadherin is regulated by and required for mGluR-LTD. Furthermore, we show that the regulatory effect of GluA2/N-cadherin is mediated through activation of Rho GTPase Rac1 and its downstream actin regulator cofilin, and, importantly, the requirement for GluA2/N-cadherin can be overcome by manipulating cofilin. These results provide compelling evidence that the extracellular domain of GluA2 regulates long-lasting synaptic plasticity through a signaling mechanism that is distinct from those used by the other domains of the receptor subunit.
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PMID:GluA2 (GluR2) regulates metabotropic glutamate receptor-dependent long-term depression through N-cadherin-dependent and cofilin-mediated actin reorganization. 2124 5


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