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)

Pharmacological studies have suggested that long-term potentiation (LTP) and long-term depression (LTD) and depotentiation, three forms of synaptic plasticity in the hippocampus, require the activity of the phosphatase calcineurin. At least two different isoforms of calcineurin are found in the central nervous system. To investigate whether all of these forms of synaptic plasticity require the same isoforms of calcineurin, we have examined LTD, depotentiation, and LTP in mice lacking the predominant calcineurin isoform in the central nervous system, Aalpha-/- mice. Depotentiation was abolished completely whereas neither LTD nor LTP were affected. These studies provide genetic evidence that the Aalpha isoform of calcineurin is important for the reversal of LTP in the hippocampus and indicate that depotentiation and LTD operate through somewhat different molecular mechanisms.
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PMID:A selective role of calcineurin aalpha in synaptic depotentiation in hippocampus. 1020 Mar 17

In the central nervous system, release of Ca2+ from intracellular stores contributes to numerous functions, including neurotransmitter release and long-term potentiation and depression. We have investigated the developmental profile and the regulation of inositol 1,4,5-trisphosphate receptor (IP3R) and ryanodine receptor (RyR) in primary cultures of cerebellar granule cells. The expression of both receptor types increases during development. Whereas the expression of type 1 IP3R appears to be regulated by Ca2+ influx through L type channels or N-methyl-D-aspartate (NMDA) receptors, RyR levels increase independently of Ca2+. The main target of Ca2+-influx-regulating IP3R expression is the Ca2+ calmodulin-dependent protein phosphatase calcineurin, because pharmacological blockade of this protein abolishes IP3R expression. Although calcineurin has been shown to regulate the phosphorylation state of the IP3R, the effect described here is at the transcriptional level because IP3R mRNA changes in parallel with protein levels. Thus, calcineurin plays a dual role in IP3R-mediated Ca2+ signaling: it regulates IP3R function by dephosphorylation in the short-term time scale and IP3R expression over more extended periods.
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PMID:Calcineurin controls inositol 1,4,5-trisphosphate type 1 receptor expression in neurons. 1031 64

Using slices of the dorsal lateral geniculate nucleus, it has been shown that, in the presence of excitatory and inhibitory amino acid antagonists, brief periods of hypoxia (3-4 min of 95% N(2)/5% CO(2)) induce in thalamocortical neurons an increase in instantaneous input conductance (G(N)) accompanied by an inward shift in baseline holding current (I(BH)). These effects have been suggested to be mediated, at least in part, by a positive shift in the voltage-dependence of the hyperpolarization-activated, mixed Na(+)/K(+) current (I(h)) and a change in its activation kinetics which transforms it into an almost instantaneously activated current. In this study, using the whole-cell patch-clamp technique, the contribution of an increased Ca(2+)-dependent transmitter release to the hypoxic response of thalamocortical neurons was further investigated using (i) blockers of calcineurin, a Ca(2+)/calmodulin-activated phosphatase that selectively regulates Ca(2+)-dependent release, and (ii) antagonists of neurotransmitters that are known to modulate I(h). Thalamocortical neurons (n = 23) recorded with electrodes filled with calcineurin autoinhibitory fragment (30-250 microM), a membrane impermeable blocker of calcinuerin, showed no difference either in resting, or in the hypoxia-induced changes in, G(N), I(BH) and I(h), when compared to thalamocortical cells patched with electrodes that did not contain calcineurin autoinhibitory fragment. In contrast, in 18 of these neurons recorded with calcineurin autoinhibitory fragment-filled electrodes, bath application either of cyclosporin-A (20 microM) or tacrolimus (50-100 microM), two membrane permeable blockers of calcineurin, abolished the effects of hypoxia on G(N), I(BH), and I(h). Separate application of noradrenaline, serotonin, histamine and nitric oxide antagonists produced only a small depression of the hypoxic response, while concomitant bath application of these antagonists decreased the hypoxia-induced changes in G(N) and I(BH) by 55 and 42%, respectively (n = 12). Concomitant bath application of 8-bromo-adenosine-3'5'-cyclicmonophosphate and 8-bromo-guanosine-3'5'-cyclicmonophosphate (both 1mM), which are known to mediate the action of these transmitters on I(h), increased G(N) (40%), decreased I(h) time-constant of activation (30%) and significantly occluded (50%) the hypoxia-induced effect on G(N) and I(BH). Thalamocortical neurons (n = 6) patched with electrodes filled with 8-bromo-adenosine-3'5'-cyclicmonophosphate and 8-bromo-guanosine-3'5'-cyclicmonophosphate (both 1 mM) showed a larger G(N) than the one recorded with the standard internal solution, and a significant depression of the hypoxia-induced changes in G(N) and I(BH). These results indicate that during acute thalamic hypoxia an increased release of noradrenaline, serotonin, histamine and nitric oxide is responsible for transforming I(h) into an instantaneously activating current via cyclic AMP- and cyclic GMP-mediated mechanisms.
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PMID:Release of monoamines and nitric oxide is involved in the modulation of hyperpolarization-activated inward current during acute thalamic hypoxia. 1071 36

Neurotransmitter receptor function can be influenced by the phosphorylation state of the receptor or of associated proteins. Here we show that kainate receptors expressed in cultured hippocampal neurons can be modulated by Ca(2+)/calmodulin-dependent phosphatase (calcineurin) and Ca(2+)/calmodulin-dependent kinase (CaMK). Ca(2+) influx through NMDA receptor or voltage-sensitive calcium channels resulted in a transient depression of the kainate receptor current. This calcium-induced depression of the kainate receptor current depended on the activation of the phosphatase calcineurin. The amplitude of the kainate receptor currents returned to the baseline level in approximately 9 sec (tau = 3.6 sec), and the recovery of the current amplitude depended on CaMK activity. The effect on kainate receptor currents was dependent on the frequency of NMDA receptor activation. Although low-frequency (0.1 Hz) NMDA application induced depression followed by recovery of the kainate receptor currents, higher frequency (1 Hz) NMDA applications induced a more prolonged depression. Kainate receptors have been shown to modulate synaptic transmission by both presynaptic and postsynaptic mechanisms. Our results suggest that synaptic activity mediated by NMDA receptors, or other routes of Ca(2+) influx, may, in turn, modulate the function of kainate receptors.
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PMID:NMDA-Dependent modulation of hippocampal kainate receptors by calcineurin and Ca(2+)/calmodulin-dependent protein kinase. 1075 27

Coincident pre- and postsynaptic activity generates long-term potentiation (LTP), a possible cellular model of learning and memory. LTP has two components: (1) an increase in the excitatory postsynaptic potential (EPSP), and (2) an increase in the ability of the EPSP to generate a spike (E-S coupling of LTP). We have used pharmacological and genetic approaches to address the molecular nature of E-S coupling in CA1 pyramidal neurons. Blockade of the Ca2+-sensitive phosphatase, calcineurin, prevents induction of E-S coupling without interfering with LTP of the EPSP. Calcineurin produces its effect on E-S coupling by inducing a long-lasting depression (LTD) of the GABA(A)-mediated inhibitory postsynaptic potentials (IPSPs). This LTD of the IPSP was prevented by blockade of NMDA receptors. Thus, the tetanus that elicits NMDA-dependent LTP mediates a coordinately regulated double function. It produces LTP of the EPSP and, concomitantly, LTD of the IPSP that leads to enhancement of E-S coupling.
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PMID:Calcineurin-mediated LTD of GABAergic inhibition underlies the increased excitability of CA1 neurons associated with LTP. 1079 4

The inhibitory GABA(A) receptor is a key element in determining the pattern of nerve cell electrical activity. Thus, modulation of its function is of paramount impact in shaping neuronal functional activity under physiological and pathological conditions. This applies to cerebellar granule neurons as to all the other neurons in the brain. The culture of cerebellar granules from newborn rats is a convenient means by which to approach these cells for electrophysiological studies provided that they maintain, as far as GABA(A) receptors are concerned, the same characteristics as in situ. Thus, the regulation of GABA(A) receptor activity in these neurons has been studied by the patch-clamp technique, both in the whole-cell and outside-out configuration. An obvious first level of control of such receptors' activity is their desensitization under continued agonist application, with biphasic kinetics. The data do not allow one to conclude whether one is dealing with two different populations of receptors or with a single population with two desensitization phases; although the presence of two GABA(A) receptor populations is suggested by a host of observations. The granule cell GABA(A) receptors are modulated by changes in extracellular pH with lower pH resulting in an enhanced receptor activity. They display, under the conditions of whole-cell recording, a run-down phenomenon which is most probably due to a tyrosine phosphatase activity which is in turn under control by a protein serine kinase. Thus, in situ tyrosine phosphorylation is a key element in determining the efficiency of GABA mediated inhibition. Activation of protein kinase A or protein kinase G (PKG) down-regulates GABA(A) receptors' activity. This last event is involved in the depression of those receptors' activity by L-arginine via the production of nitric oxide. In addition, the activity of calmodulin-activated adenylate cyclase I is controlled by GABA(B) receptors. Dendritic GABA(A) receptor activity is partially blocked by previous activation of N-methyl-D-aspartate (NMDA) receptors via calcineurin mediated dephosphorylation/activation of protein tyrosine phosphatase and concomitant production of nitric oxide and PKG activation. The site phosphorylated by PKG is evidently not available for calcineurin-mediated serine dephosphorylation, due to calcineurin-specific membrane localization in respect of the GABA(A) receptor. Overall, a complex network of biochemical signals appear to keep granule cells GABA(A) receptors under a fine balance between up- and down-regulatory mechanisms. The overall data appear also to indicate the presence of two GABA(A) receptor populations: a dendritic one which can be modulated by Ca++ entering via NMDA receptors and a cell body one. The two populations are probably different in terms of desensitization kinetics and benzodiazepine sensitivity.
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PMID:GABA(A) receptor modulation in rat cerebellum granule cells. 1095 91

The endocytosis of AMPA receptors is thought to be important in the expression of long-term depression (LTD) triggered by NMDA receptor activation. Although signaling pathways necessary for LTD induction have been identified, those responsible for the regulated internalization of AMPA receptors are unknown. Here we show that activation of NMDA receptors alone can trigger AMPA receptor endocytosis through calcium influx and activation of the calcium-dependent protein phosphatase calcineurin. A distinct signaling mechanism mediates the AMPA receptor endocytosis stimulated by insulin. These results demonstrate that although multiple signaling pathways can induce AMPA receptor internalization, NMDA receptor activation enhances AMPA receptor endocytosis via a signaling mechanism required for the induction of LTD.
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PMID:Regulation of AMPA receptor endocytosis by a signaling mechanism shared with LTD. 1110 Jan 50

Calcineurin is ubiquitously distributed phosphatase in the central nervous system. It has various functions, such as modulating channel properties, suppressing transmitter release, and activating transcript factors. Recently the critical role of calcineurin on synaptic plasticity, especially long-term depression, was reported, although the precise mechanism underlying LTD induction is still being debated. Calcineurin, activated by the Ca2+ influx mainly through the NMDA channel and calmodulin, dephosphorylates inhibitor-1, which suppresses PP1 activity. Thus the activation of calcineurin enhances PP1, resulting in facilitating the process leading to LTD induction. The activation of calcineurin modifies the threshold of LTP induction. A recent interesting finding is the gating mechanism from the early phase of LTP to the late phase of LTP by calcineurin activity, a process regulated by cAMP. We have reported a new type of LTD, which is suppressed by calcineurin that is dependent on group 2 mGluR receptor activity. According to the result using whole cell study with a patch pipette, including FK-506, an antagonist of calcineurin, the induction site of this LTD is presynaptic, which defers from conventional LTD. We have also discussed the involvement of murine protein tyrosine phosphatase (MPTP) in LTD induction in the hippocampal CA1 region by using an MPTP delta knockout mouse.
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PMID:[The role of calcineurin on the induction of synaptic plasticity]. 1132 44

NMDAR-dependent long-term depression involves the activation of protein phosphatase 1 (PP1) and 2B (calcineurin) and the subsequent dephosphorylation of synaptic proteins. In this issue of Neuron, Morishita et al. (2001) provide evidence that precise targeting of PP1 to synaptic substrates is critical for the expression of LTD.
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PMID:Protein phosphatase 1 and LTD: synapses are the architects of depression. 1175 43

We investigated metabotropic glutamate receptor (mGluR)-dependent long-term depression (LTD) in hippocampal CA1 pyramidal neurons of 6- to 8-d-old [postnatal days 6-8 (P6-P8)] and 21- to 25-d-old (P21-P25) rats. In P6-P8 rats, induction of LTD depended on the activity of group II mGluRs. In P21-P25 rats, however, this LTD disappeared, and instead, NMDA receptor (NMDAR)-dependent LTD appeared. A bath containing a specific calcineurin (CaN) inhibitor restored the group II mGluR-dependent LTD in the neurons of the P21-P25 rats. Although postsynaptic injection of CaN inhibitors suppressed NMDAR-dependent LTD, it did not affect induction of group II mGluR-dependent LTD. These results demonstrate that CaN plays different roles in the induction of two forms of LTD: presynaptic CaN inhibits group II mGluR-dependent LTD, whereas postsynaptic CaN facilitates NMDAR-dependent LTD. These findings are the first demonstration in vitro of group II mGluR-dependent LTD that is negatively regulated by CaN via an age-dependent mechanism.
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PMID:Calcineurin plays different roles in group II metabotropic glutamate receptor- and NMDA receptor-dependent long-term depression. 1207 99


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