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 aetiology of depression is associated with depletion in central levels of serotonin (5-HT). Hence, a major effect of antidepressant drugs is to increase synaptic 5-HT levels. Stressful conditions have also been shown to affect neuronal plasticity and 5-HT neurotransmission in the hippocampus. Neuronal plasticity, which is typically referred to as a structural adaptation of neurons to functional requirements, requires more dynamic forms of microtubules (cytoskeletal component). The alpha-tubulin, which is the major component of microtubules, can be postranslationally modified and both the tyrosinated (tyr-tub) and acetylated (acet-tub) forms are considered markers of more dynamic or more stable microtubules, respectively. The aim of the present work was to investigate the expression of tyr-tub and acet-tub in the hippocampus of rats submitted to either acute (6 h for 1 day) or sub-chronic (6 h for 4 days every day) restraint stress. In addition, ex vivo hippocampal 5-HT levels were monitored by differential pulse voltammetry to analyse the influence of both stress conditions upon 5-HT levels. Our results showed that the expression of tyr-tub in the hippocampus was significantly decreased to 70 +/- 7% following sub-chronic restraint stress (P < 0.01). In contrast, acute and sub-chronic restraint stress increased the hippocampal expression of acet-tub to 139 +/- 11% and 145 +/- 11% of control, respectively. Finally, 5-HT levels were significantly increased (P < 0.05) to 142 +/- 15% and 135 +/- 11% following acute and sub-chronic restraint stress, respectively. The stress-induced cytoskeletal changes observed in the present study suggest that the microtubular network is a potential new pathway that may increase our understanding of stress-related events.
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PMID:Cytoskeletal changes in the hippocampus following restraint stress: role of serotonin and microtubules. 1277 3

Neuronal injury following focal cerebral ischemia is widely attributed to the excitatory effects of glutamate. However, critical analysis of published data on glutamate toxicity in vitro and the comparison of this data with in vivo release of glutamate and the therapeutic effect of glutamate antagonists raises doubts about a neurotoxic mechanism. An alternative explanation for glutamate-mediated injury is energy failure due to peri-infarct spreading depression-like depolarizations. These depolarizations cause a sharp increase in metabolic activity and therefore produce a mismatch between blood flow and the oxygen requirements of the tissue. The generation of peri-infarct spreading depressions and the associated metabolic workload can be suppressed by glutamate antagonists. As a result, energy failure is also prevented, and the volume of ischemic infarct decreases. Interventions to improve ischemic resistance should therefore aim at improving the oxygen supply or reducing the metabolic workload, rather than interfering with the consequences of a putative excitotoxic injury cascade.
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PMID:[Glutamate hypothesis of stroke]. 1294 38

For human based space research it is of high importance to understand the influence of gravity on the properties of the central nervous system (CNS). Until now it is not much known about how neuronal tissue can sense gravity. The aim of this study was to find out weather and how the CNS, as a complex system, can percept and react to changes in gravity. Neuronal tissue and especially the CNS fulfils all the requirements for excitable media. Consequently, self-organisation, pattern formation and propagating excitation waves as typical events of excitable media have been observed in such tissue. The spreading depression (SD), an excitation depression wave is the most obvious and best described of these phenomena in the CNS. In our experiments we showed that the properties of the SD and therefore the CNS in its properties as an excitable medium reacts very sensitive to changes in gravity.
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PMID:Gravity sensing in the central nervous system. 1470 79

A neuroprotective role of astrocytes has been hypothesized, but the mechanism is debated and in vivo evidence is limited. To test this hypothesis, a sublethal stressor (spreading depression) and fluorocitrate (FC), a selective inhibitor of the astrocytic Krebs cycle, were used in urethane-anaesthetized adult rats. Neuronal damage was assessed 24 h after treatment with silver stain and immunoreactivity for a 72-kDa heat-shock protein. ATP levels and mitochondrial aconitase activity, a marker indicating exposure to reactive oxygen species, were measured after 4 and 24 h. Spreading depression alone did not affect ATP levels, mitochondrial aconitase activity, or induce neuronal injury in the cortex. Local or intraventricular injection of FC significantly decreased ATP levels and mitochondrial aconitase activity, but did not produce neuronal damage. In animals receiving injections of FC and then spreading depression, there was evidence of significant neuronal stress and damage. Isocitrate, which bypasses the metabolic inhibition produced by FC, prevented all of the changes seen after the combination of FC and spreading depression. One-hour pretreatment with dimethyl sulfoxide (a scavenger of hydroxyl radicals), deferoxamine (an iron chelator) or fructose-1,6-bisphosphate also blocked inactivation of mitochondrial aconitase, ATP depletion and the neuronal damage induced by FC and spreading depression. These experiments demonstrate that inhibition of the metabolism of astrocytes, with a decrease in ATP levels, will increase the susceptibility of neurons to the stress induced by spreading depression. The neuroprotective effects of dimethyl sulfoxide, deferoxamine and fructose-1,6-bisphosphate suggest that oxidative stress contributes to the neurotoxicity in this situation.
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PMID:Energy failure in astrocytes increases the vulnerability of neurons to spreading depression. 1512 98

We have identified truncating mutations in the human DLG3 (neuroendocrine dlg) gene in 4 of 329 families with moderate to severe X-linked mental retardation. DLG3 encodes synapse-associated protein 102 (SAP102), a member of the membrane-associated guanylate kinase protein family. Neuronal SAP102 is expressed during early brain development and is localized to the postsynaptic density of excitatory synapses. It is composed of three amino-terminal PDZ domains, an src homology domain, and a carboxyl-terminal guanylate kinase domain. The PDZ domains interact directly with the NR2 subunits of the NMDA glutamate receptor and with other proteins responsible for NMDA receptor localization, immobilization, and signaling. The mutations identified in this study all introduce premature stop codons within or before the third PDZ domain, and it is likely that this impairs the ability of SAP102 to interact with the NMDA receptor and/or other proteins involved in downstream NMDA receptor signaling pathways. NMDA receptors have been implicated in the induction of certain forms of synaptic plasticity, such as long-term potentiation and long-term depression, and these changes in synaptic efficacy have been proposed as neural mechanisms underlying memory and learning. The disruption of NMDA receptor targeting or signaling, as a result of the loss of SAP102, may lead to altered synaptic plasticity and may explain the intellectual impairment observed in individuals with DLG3 mutations.
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PMID:Mutations in the DLG3 gene cause nonsyndromic X-linked mental retardation. 1518 69

Neuronal calcium sensor-1 (NCS-1) is a member of EF-hand calcium-binding protein superfamily, which is considered to modulate synaptic transmission and plasticity. In this mini-review, we first summarize distribution of NCS-1 in the cerebellum. NCS-1 is mainly detected in postsynaptic sites, such as somata and dendrites of Purkinje cells, stellate/basket cells and granule cells. In addition, GABAergic inhibitory stellate/basket cell axon terminals also contain NCS-1. Secondly, we describe cerebellar compartmentation defined by NCS-1. The NCS-1 immunostaining displayed characteristic parasagittal-banding pattern in the Purkinje cell layer and molecular layer, whereas there were no apparent bands in the granule cell layer. The alternating positively and negatively NCS-1-labeled Purkinje cell clusters contributed to this cerebellar compartmentation. In contrast, stellate/basket cells were uniformly NCS-1-positive throughout the cerebellum. Interestingly, NCS-1 and zebrin II exhibited a similar parasagittal-banding pattern. But it is noteworthy that NCS-1-negative/zebrin II-positive Purkinje cell clusters were detected selectively in anterior lobule vermis and paraflocculus. These results suggest that NCS-1 defines a novel pattern of cerebellar cortical compartmentation. Lastly, we describe recent data suggesting some relationship between NCS-1 and cerebellar long-term depression-related molecules, and discuss the possible role of NCS-1 in the cerebellum.
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PMID:Expression and possible role of neuronal calcium sensor-1 in the cerebellum. 1523 74

Neuronal nicotinic acetylcholine receptors (nAChRs) are widely distributed within the brain where they contribute to the regulation of higher cognitive functions. The loss of the cholinergic function in Alzheimer's disease patients, along with the well-known memory enhancing effect of nicotine, emphasizes the role of cholinergic signalling in memory functions. The hippocampus, a key structure in learning and memory, is endowed with nAChRs localized at pre- and postsynaptic levels. In previous work on the immature hippocampus we have shown that, at low probability (P) synapses, activation of alpha7 nAChRs by nicotine or by endogenously released acetylcholine persistently enhanced glutamate release and converted 'presynaptically silent' synapses into functional ones. Here we show that in the same preparation, at high P synapses, nicotine induces long-term depression of AMPA- and NMDA-mediated synaptic currents. This effect was mediated by presynaptic alpha7- and beta2-containing receptors and was associated with an increase in the paired pulse ratio and in the coefficient of variation. High P synapses could be converted into low P and vice versa by changing the extracellular Ca2+/Mg2+ ratio. In these conditions nicotine was able to persistently potentiate or depress synaptic responses depending on the initial P-values. A bi-directional control of synaptic plasticity by nicotine would considerably enhance the computational properties of the network during a critical period of postnatal development thus contributing to sculpt the neuronal circuit.
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PMID:Persistent decrease in synaptic efficacy induced by nicotine at Schaffer collateral-CA1 synapses in the immature rat hippocampus. 1527 42

Neuronal plasticity is now known to be very important in the adult, both in the formation of new synaptic connections and of new neurones (neurogenesis) and of glial cells. However, old age and stress can inhibit this plasticity and lead to cerebral atrophy. The time course of changes in neuronal plasticity involves, in the first milliseconds to seconds, changes in synaptic strength (long term potentialisation, LTP, or long term depression, LTD), then, over minutes to hours, changes in the number of synaptic connections (linked to changes in neurotrophic factors), and over weeks to months, to changes in neuronal reconfiguration. These changes in brain systems are particularly targeted in psychiatric disorders to the areas which are sensitive to stress and play roles in memory and emotion (hippocampus, amygdala and prefrontal cortex). The discovery and development of drugs modifying neuronal plasticity and neurotrophins production has been a priority for Servier research for the last ten years; Servier has a clinically effective antidepressant, tianeptine (Stablon), with a favourable side effect profile, but which does not inhibit the uptake of serotonin, or other monoamines. However, this drug can reverse the deleterious effects of stress on neuronal plasticity, thereby acting on the causes of psychiatric disorders. Furthermore, a new research area is being investigated - facilitation of AMPA receptors, favouring the production of neurotrophic factors.
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PMID:[Synaptic plasticity and neuropathology: new approaches in drug discovery]. 1563 31

Neuronal synaptic connections can be potentiated or depressed by paired pre- and postsynaptic spikes, depending on the spike timing. We show that in cultured rat hippocampal neurons a calcium/calmodulin-dependent protein kinase II (CaMKII)-mediated potentiation process and a calcineurin-mediated depression process can be activated concomitantly by spike triplets or quadruplets. The integration of the two processes critically depends on their activation timing. Depression can cancel previously activated potentiation, whereas potentiation tends to override previously activated depression. The time window for potentiation to dominate is about 70 ms, beyond which the two processes cancel. These results indicate that the signaling machinery underlying spike timing-dependent plasticity (STDP) may be separated into functional modules that are sensitive to the spatiotemporal dynamics (rather than the amount) of calcium influx. The timing dependence of modular interaction provides a quantitative framework for understanding the temporal integration of STDP.
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PMID:Coactivation and timing-dependent integration of synaptic potentiation and depression. 1565 96

Although studies of epileptic human hippocampus suggest changes of synaptic and intrinsic excitability, few changes, save the appearance of spontaneous field/synaptic potentials, are known in epileptic neocortical tissue. However, invasive EEG and histological studies suggest that neocortical tissue, even in mesial temporal lobe epilepsy, can play an important role as an irritative zone or extrahippocampal focus. We hypothesized that intrinsic neuronal and synaptic excitability, as well as short-term plasticity, are altered in neocortical areas, particularly with elevated K+ levels as occur during seizures. We analyzed neuronal firing properties, synaptic responses, and paired-pulse plasticity in human neocortical slices from tissue resected during epilepsy surgery, both under normal and under pathological conditions, i.e., after elevating K+ (4/8 mM), with rat neocortical slices as controls. Neuronal firing properties were not different. We did find, however, alterations of synaptic responsiveness in epileptic tissue, i.e., an elevated network excitability with K+ elevations, and reduction of paired-pulse depression.
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PMID:Intrinsic excitability, synaptic potentials, and short-term plasticity in human epileptic neocortex. 1588 Mar 82


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