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)

Previous work has shown that seizure-like activity can disrupt the induction of long-term potentiation (LTP). However, how seizure-like event disrupts the LTP induction remains unknown. To understand the cellular and molecular mechanisms underlying this process better, a set of studies was implemented in area CA1 of rat hippocampal slices using extracellular recording methods. We showed here that prior transient seizure-like activity generated by perfused slices with Mg(2+)-free artificial cerebrospinal fluid (ACSF) exhibited a persistent suppression of LTP induction. This effect lasted between 2 and 3 h after normal ACSF replacement and was specifically inhibited by N-methyl-D-aspartate (NMDA) receptor antagonist D-2-amino-5-phosphovaleric acid (D-APV) and L-type voltage-operated Ca(2+) channel (VOCC) blocker nimodipine, but not by non-NMDA receptor antagonist 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX). In addition, this suppressive effect was specifically blocked by the selective protein kinase C (PKC) inhibitor NPC-15437. However, neither Ca(2+)/calmodulin-dependent protein kinase II inhibitor KN-62 nor cAMP-dependent protein kinase inhibitor Rp-adenosine 3', 5'-cyclic monophosphothioate (Rp-cAMPS) affected this suppressive effect. This persistent suppression of LTP was not secondary to the long-lasting changes in NMDA receptor activation, because the isolated NMDA receptor-mediated responses did not show a long-term enhancement in response to a 30-min Mg(2+)-free ACSF application. Additionally, in prior Mg(2+)-free ACSF-treated slices, the entire frequency-response curve of LTP and long-term depression (LTD) is shifted systematically to favor LTD. These results suggest that the increase of Ca(2+) influx through NMDA channels and L-type VOCCs in turn triggering a PKC-dependent signaling cascade is a possible cellular basis underlying this seizure-like activity-induced inhibition of LTP.
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PMID:Transient removal of extracellular Mg(2+) elicits persistent suppression of LTP at hippocampal CA1 synapses via PKC activation. 1098 2

Transgenic and knockout mice are used extensively to elucidate the molecular mechanisms of hippocampal synaptic plasticity. However, genetic and phenotypic variations between inbred mouse strains that are used to construct genetic models may confound the interpretation of cellular neurophysiological data derived from these models. Using in vitro slice stimulation and recording methods, we compared the membrane biophysical, cellular electrophysiological, and synaptoplastic properties of hippocampal CA1 neurons in four specific strains of inbred mice: C57BL/6J, CBA/J, DBA/2J, and 129/SvEms/J. Hippocampal long-term potentiation (LTP) induced by theta-pattern stimulation, and by repeated multi-burst 100-Hz stimulation at various interburst intervals, was better maintained in area CA1 of slices from BL/6J mice than in slices from CBA and DBA mice. At an interburst interval of 20 s, maintenance of LTP was impaired in CBA and DBA slices, as compared with BL/6J slices. When the interburst interval was reduced to 3 s, induction of LTP was significantly enhanced in129/SvEms slices, but not in DBA and CBA slices. Long-term depression (LTD) was not significantly different between slices from these four strains. For the four strains examined, CA1 pyramidal neurons showed no significant differences in spike-frequency accommodation, membrane input resistance, and number of spikes elicited by current injection. Synaptically-evoked glutamatergic postsynaptic currents did not significantly differ among CA1 pyramidal neurons in these four strains. Since the observed LTP deficits resembled those previously seen in transgenic mice with reduced hippocampal cAMP-dependent protein kinase (PKA) activity, we searched for possible strain-dependent differences in cAMP-dependent synaptic facilitation induced by forskolin (an activator of adenylate cyclase) and IBMX (a phosphodiesterase inhibitor). We found that forskolin/IBMX-induced synaptic facilitation was deficient in area CA1 of DBA/2J and CBA/J slices, but not in BL/6J and 129/SvEms/J slices. These defects in cAMP-induced synaptic facilitation may underlie the deficits in memory, observed in CBA/J and DBA/2J mice, that have been previously reported. We conclude that hippocampal LTP is influenced by genetic background and by the temporal characteristics of the stimulation protocol. The plasticity of hippocampal synapses in some inbred mouse strains may be "tuned" to particular temporal patterns of synaptic activity. From a broader perspective, our data support the notion that strain-dependent variation in genetic background is an important factor that can influence the synaptoplastic phenotypes observed in studies that use genetically modified mice to explore the molecular bases of synaptic plasticity.
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PMID:Differential maintenance and frequency-dependent tuning of LTP at hippocampal synapses of specific strains of inbred mice. 1106 91

Chronic activity blockade increases synaptic levels of NMDA receptor immunoreactivity in hippocampal neurons. We show here that blockade-induced synaptic NMDA receptors are functional and mediate enhanced excitotoxicity in response to synaptically released glutamate. Activity blockade increased the cell surface association of NMDA receptors. Blockade-induced synaptic targeting of NMDA receptors did not require protein synthesis but required phosphorylation and specifically cAMP-dependent protein kinase (PKA). Furthermore, activation of PKA was sufficient to induce synaptic targeting of NMDA receptors regardless of receptor activity status. These results implicate PKA activity downstream of receptor blockade as a mediator of enhanced synaptic transport or stabilization of NMDA receptors. Synaptic clustering of NR1-green fluorescent protein was observed in living neurons in response to NMDA receptor and cAMP phosphodiesterase antagonists and occurred gradually over the course of a day. This pathway represents a cellular mechanism for synaptic homeostasis and is likely to function in metaplasticity, long-term regulation of the ability of a synapse to undergo potentiation or depression.
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PMID:cAMP-dependent protein kinase mediates activity-regulated synaptic targeting of NMDA receptors. 1143 83

A persistent question concerning mechanisms underlying long-term, activity-dependent synaptic plasticity is whether the sites of alterations are presynaptic, postsynaptic, or both. Recently, we discovered a chemical method of inducing long-term depression (LTD) of synaptic strength at Schaffer collateral-CA1 synapses by simultaneously elevating [cGMP] and inhibiting cAMP-dependent protein kinase (PKA). Chemical LTD (CLTD) is activity-independent, occluded by stimulus-evoked LTD, and requires access of pharmacologic agents to presynaptic terminals. In the present study, we used fluorescence and two-photon imaging of presynaptic terminals with the fluorescent dye N-(3-triethylammoniumpropyl)-4-(4-(dibutylamino)styryl) pyridinium dibromide (FM1-43) to determine directly if inducing CLTD is associated with a long-term reduction in transmitter release. In presynaptic Schaffer collateral-CA1 terminals of control hippocampal slices loaded with FM1-43, electrical stimulation (10 Hz/2 min) elicited a frequency-dependent destaining that peaked at 20% reduction in fluorescence. In contrast, when we first induced CLTD by a 30 min treatment of slices with the type V phosphodiesterase inhibitor zaprinast (20 microm) plus the PKA inhibitor N-[2-(p-bromocinnamylamino)ethyl]-5-isoquinolinesulfonamide (H-89; 10 microm), then washed for 60 min, the destaining of FM1-43 fluorescence evoked by the same stimulation was reduced to 4%. Treatment and washout of slices with either drug singly had a significantly smaller effect on stimulus-evoked FM1-43 destaining. Only CLTD was associated with virtually complete suppression of stimulus-evoked FM1-43 release, the first direct evidence for at least one form of LTD being mediated by persistent reduction of presynaptic transmitter release.
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PMID:FM1-43 imaging reveals cGMP-dependent long-term depression of presynaptic transmitter release. 1156 78

In a previous study, we showed that type 1 cannabinoid (CB(1)) receptor activation substantially depresses the corticostriatal glutamatergic transmission onto striatal neurons in the brain slice preparation. We now report that the adenylyl cyclase activator forskolin and cAMP analog (S)-p-8-(4-chlorophenythil) adenosine-3',5'-monophosphorothioate (Sp-8-CPT-cAMPS) strongly suppressed the synaptic depression induced by cannabimimetic aminoalkylindole, WIN 55,212-2. Application of the cAMP-dependent protein kinase (PKA) inhibitor KT5720 alone had no consistent effect on basal synaptic transmission but the synaptic enhancement elicited by forskolin was blocked. In addition, pretreatment of striatal slices with either KT5720 or another PKA inhibitor, H89, completely abolished the attenuation by forskolin on WIN 55,212-2-induced synaptic depression. The effect of forskolin on CB(1) receptor function was still observed in a low Ca(2+) bathing solution, suggesting that the forskolin's action is not attributable to its ability to saturate the presynaptic transmitter release processes. The possibility that forskolin acted by increasing CB(1) receptor phosphorylation was confirmed by demonstrating that the serine-phosphorylated component with CB(1) receptors was significantly increased after forskolin treatment. This forskolin effect was markedly attenuated in the presence of KT5720. Moreover, the activation of beta-adrenergic receptors by isoproterenol mimics forskolin to elicit a PKA-dependent inhibition of CB(1) receptor function. Together, these observations indicate that the presynaptic inhibitory action of CB(1) receptors at corticostriatal synapses could be negatively regulated by cAMP/PKA-mediated receptor phosphorylation. This effect of PKA may play a functional role in fine-tuning glutamatergic transmission at corticostriatal synapses.
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PMID:Activation of cAMP-dependent protein kinase suppresses the presynaptic cannabinoid inhibition of glutamatergic transmission at corticostriatal synapses. 1185 38

Second messengers regulate synaptic plasticity by influencing the balance between kinase and phosphatase activity. One target of this balance is the phosphorylation state of the AMPA receptor glutamate receptor 1 (GluR1) subunit. Hippocampal long-term depression (LTD) is a calcium-dependent downregulation of synaptic AMPA receptor currents associated with dephosphorylation of Ser845, a cAMP-dependent protein kinase (PKA) site on GluR1. Recruitment of kinases and phosphatases to the AMPA receptor might enable modulation of AMPA receptor function. The neuronal A-kinase anchoring protein AKAP79/150 interacts with PKA and the calcium-dependent protein phosphatase PP2B and is linked to the AMPA receptor GluR1 subunit by synapse-associated protein 97 (SAP97), a membrane-associated guanylate kinase family protein. Here we demonstrate that AKAP79 not only promotes basal phosphorylation of Ser845 but also confers a calcium- and PP2B-mediated downregulation to GluR1 receptor currents. This AKAP79-dependent downregulation is contingent on the local presence of PKA, Ser845 of GluR1, and a PDZ (postsynaptic density 95/Discs large/zona occludens 1)-domain interaction between GluR1 and SAP97, all of which support basal phosphorylation of the receptor. These findings suggest that the AKAP79 signaling complex is sufficient to couple intracellular calcium levels to the PKA phosphorylation state of GluR1. Thus, the integration of intracellular signals relevant for LTD may be transduced to GluR1 by the AKAP79 signaling complex.
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PMID:Regulation of GluR1 by the A-kinase anchoring protein 79 (AKAP79) signaling complex shares properties with long-term depression. 1194 7

At the postsynaptic membrane of glutamatergic synapses, the cAMP-dependent protein kinase (PKA), protein kinase C (PKC), and calcineurin (CaN) anchoring protein AKAP79/150 is recruited to NMDA and AMPA glutamate receptors by postsynaptic density (PSD)-95 family membrane-associated guanylate kinase (MAGUK) scaffold proteins. These signaling scaffold complexes may function to regulate receptor phosphorylation in synaptic plasticity. Thus, it is important to understand regulation of AKAP79/150 targeting to synapses and recruitment to PSD-MAGUK complexes. AKAP79 is targeted to the plasma membrane by an N-terminal basic domain that binds phosphatidylinositol-4,5-bisphosphate (PI-4,5-P(2)) and is regulated by PKC phosphorylation and calmodulin binding. Here we demonstrate that this same domain also binds F-actin in a calmodulin- and PKC-regulated manner, targets to membrane ruffles enriched in F-actin and PI-4,5-P(2) in COS7 cells, and localizes to dendritic spines with F-actin and PSD-MAGUKs in hippocampal neurons. Inhibition of actin polymerization disrupted AKAP79 targeting of PKA and CaN to ruffles in COS7 cells and endogenous AKAP79/150 dendritic spine localization with PKA, CaN, and PSD-MAGUKs in neurons. AKAP79/150 postsynaptic localization was rapidly regulated by NMDA receptors through CaN activation and F-actin remodeling, further suggesting that AKAP79/150 signaling scaffold targeting depends on actin dynamics. NMDA receptor activation also regulated dendritic spine localization of PKA and CaN and association of the AKAP79/150-PKA complex with PSD-MAGUKs. Because AMPA receptor PKA phosphorylation and synaptic localization are regulated by similar NMDA receptor-CaN signaling pathways linked to hippocampal long-term depression, this regulation of AKAP79/150 postsynaptic targeting might be important for synaptic plasticity.
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PMID:Regulation of A-kinase anchoring protein 79/150-cAMP-dependent protein kinase postsynaptic targeting by NMDA receptor activation of calcineurin and remodeling of dendritic actin. 1217

cAMP-dependent protein kinase (PKA) and protein kinase C (PKC) are two major modulators of synaptic transmission in the CNS but little is known about how they affect synaptic transmission in the human CNS. In this study, we used forskolin, a PKA activator, and phorbol ester, a PKC activator, to examine the effects of these kinases on synaptic transmission in granule cells of the dentate gyrus in human hippocampal slices using whole-cell recording methods. We found that both forskolin and phorbol ester increased the frequency of spontaneous and miniature excitatory postsynaptic currents (sEPSCs and mEPSCs) but left the amplitude unaffected. Inactive forskolin and phorbol ester had no effect on sEPSCs in human dentate granule cells. Prior application of forskolin occluded the effects of phorbol ester on mEPSC frequency. Tetanic stimulation applied to the perforant path induced short-term depression in dentate gyrus granule cells. Both forskolin and phorbol ester significantly enhanced this short-term depression. Taken together, these results demonstrate that PKA and PKC are involved in up-regulation of excitatory synaptic transmission in human dentate granule cells, primarily by presynaptic mechanisms. In addition, the occlusion experiments suggest that the two kinases may share a common signal pathway.
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PMID:PKA and PKC enhance excitatory synaptic transmission in human dentate gyrus. 1261 80

Elevated glucocorticoid levels are associated with many diseases, including age-related depression, hypertension, Alzheimer's disease, and acquired immunodeficiency syndrome. Cortisol-lowering agents could provide useful complementary therapy for these disorders. We examined the effect of procaine and procaine in a pharmaceutical formulation on adrenal cortical steroid formation. Procaine inhibited dibutyryl cyclic AMP (dbcAMP)-induced corticosteroid synthesis by murine Y1 and human H295R adrenal cells in a dose-dependent manner without affecting basal steroid formation. Treatment of rats with the procaine-based formulation reduced circulating corticosterone levels. This steroidogenesis-inhibiting activity of procaine was not observed in Leydig cells, suggesting that the effect was specific to adrenocortical cells. In search of the mechanism underlying this inhibitory effect on cAMP-induced corticosteroidogenesis, procaine was found to affect neither the cAMP-dependent protein kinase activity nor key proteins involved in cholesterol transport into mitochondria, cytochrome P450 side chain cleavage enzyme expression, and enzymatic activities associated with cholesterol metabolism to final steroid products. However, procaine reduced in a dose-dependent manner the 3-hydroxy-3-methylglutaryl-coenzyme A reductase (HMG-CoA) activity and the dbcAMP-induced HMG-CoA reductase mRNA levels by affecting mRNA stability. These data suggest that the inhibitory effect of procaine on cAMP-induced corticosteroid formation is due to the reduced synthesis of cholesterol. This modulatory effect of procaine on HMG-CoA reductase mRNA expression was also seen in dbcAMP-stimulated Hepa1-6 mouse liver hepatoma cells. Taken together, these results suggest that procaine may provide a pharmacological means for the control of hormone-induced HMG-CoA reductase mRNA expression and hypercortisolemia.
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PMID:Inhibition of adrenal cortical steroid formation by procaine is mediated by reduction of the cAMP-induced 3-hydroxy-3-methylglutaryl-coenzyme A reductase messenger ribonucleic acid levels. 1456 37

Psychiatric or depressed patients show alterations in both olfactory projection areas and mucosa. In rodents, ablation of olfactory bulbs causes a depression-like syndrome, useful to test antidepressant agents. We studied in mice the behavioral symptoms and neuroanatomical correlates after mucosal damage or ablation of the olfactory bulb. Our results are based on a battery of tests exploiting anxious, aggressive, and depressive behavior, on morphological and immunohistochemical analysis. We found similar results in both sensory-damaged and bulbectomized animals, with a behavioral dissociation concerning different forms of aggression. These findings do not support a simple downregulation of social interactions in damaged mice. The most prominent modifications in the brains of sensory damaged and bulbectomized mice are detected in the subventricular zone (SVZ), the source area of neural stem cells, and in the content of cAMP-dependent protein kinase within the amygdala, suggesting a central role of this structure in the functional modulation of behavior.
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PMID:Animal models of depression: olfactory lesions affect amygdala, subventricular zone, and aggression. 1519 95


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