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

Serotonergic systems have been implicated in the pathogenesis of major depression in humans as well as in learned helplessness (LH), an animal model of depression. To understand the significance of neuronal responses in depression and LH that are mediated by serotonin (5-hydroxytryptamine, 5HT) receptors, we used intracerebroventricular injections to introduce a unique antisense oligonucleotide (ASO) to the 5HT2A receptor and determined its effect on LH behavior in Sprague-Dawley rats as determined by an escape-avoidance strategy. Of the rats injected with the 5HT2A receptor ASO, 8/16 rats met criteria for LH. By contrast, only 1/15 of the control group injected with 5HT2A sense oligonucleotide (SO) met criteria for LH. Quantitative receptor autoradiography revealed significant differences in 5HT2A receptor density between ASO and control sense oligonucleotides (SO), in close proximity to the injection site. Significant decreases in 5HT2A receptor density caused by oligonucleotide blockade were found in the CA3 hippocampal region. These data support the view that central 5HT, mediated by the 5HT2A receptor, participates in regulating behaviors that are affected by inescapable stress, and that the induction of behavioral depression may be specifically regulated via serotonergic pathways that terminate in this hippocampal subfield.
 ...
PMID:Modulation of learned helplessness by 5-hydroxytryptamine2A receptor antisense oligodeoxynucleotides. 887 16

A rise in Ca2+ concentration at postsynaptic sites provides an initial step in inducing both the long-term potentiation (LTP) and long-term depression (LTD) in the CA1 region of the hippocampus. LTP induction requires the activation of Ca(2+)-sensitive protein kinases following the rise in Ca2+. By contrast, the activity of protein phosphatase(s) appears to be critical to induce LTD. Here we demonstrate that inhibition of the synthesis of calcineurin A alpha and A beta, catalytic subunits of Ca2+/calmodulin- (CaM) dependent protein phosphatase, reduces the threshold of induction for commissural-CA1 LTP in anesthetized rats. In rats administered antisense oligodeoxynucleotides (ODNs) against calcineurin A alpha and A beta intraventricularly for 7 days, a brief tetanic stimulation to the CA3 region, which in the control case was below threshold for the induction of LTP, now produced a long-lasting increase in both the EPSP slope and the amplitude of population spike recorded from the commissural-CA1 pathway. Western blot analysis of calcineurin showed that the threshold reduction was accompanied by a selective decrease in the protein levels in the hippocampus. Thus our study provides direct evidence that calcineurin per se has an antagonizing role in LTP induction. Complementary experiments with the selective calcineurin inhibitor, FK506, also showed the reduction of LTP threshold in a dose-dependent manner. These results, together with previous studies, support the hypothesis that the quantitative phosphorylation level of critical intracellular proteins determines whether the synaptic efficacy will increase or decrease after the activity-dependent rise in postsynaptic Ca2+.
 ...
PMID:A facilitatory effect on the induction of long-term potentiation in vivo by chronic administration of antisense oligodeoxynucleotides against catalytic subunits of calcineurin. 888 51

The whole cell configuration of the patch clamp technique was used to study the mechanisms of induction of long term depression (LTD) occurring at the mossy fibre-CA3 synapse between postnatal (P) day 6 and P13. In control conditions, when two pulses were delivered to the mossy fibres with an interval of 50 ms a potentiation of the EPSC evoked by the second pulse associated with a reduction in the number of failures was observed. Tetanization of the mossy fibres induced LTD of the responses to the first and second stimulus without affecting the paired pulse facilitation. Loading the postsynaptic cell with BAPTA prevented the induction of LTD but did not modify the paired pulse facilitation, suggesting that LTD induction occurs at the postsynaptic site.
 ...
PMID:Postsynaptic induction of mossy fibre long term depression in developing rat hippocampus. 890 77

Extracellular and intracellular recordings and measurements of extracellular K+ concentration ([K+]o) were performed in the adult rat hippocampus in an in vitro slice preparation. Excitatory amino acid receptor antagonists, as well as the K(+)-channel blockers 4-aminopyridine (4AP, 50 microM) and/or tetraethylammonium (TEA, 5 mM), were added to the bath. Synchronous, negative-going field potentials were recorded in the CA3 stratum radiatum during application of 4AP and excitatory amino acid receptor antagonists. Each of these events was associated with an intracellular long-lasting depolarization and a concomitant rise in [K+]o that attained peak values of 4.3 +/- 0.1 mM (mean +/- S.E.M., n = 6 slices) and lasted 29 +/- 3 s. These field potentials were still recorded in CA3 stratum radiatum after addition of TEA. Under these conditions, prolonged field potentials (40.2 +/- 4.5 s, n = 18) characterized by a prominent positive component; discharge of population spikes also occurred. [K+]o increases associated with these prolonged field-potential discharges had a considerable variability in magnitude (peak value = 3.8-14.1 mM, 6.1 +/- 0.7 mM, n = 5) and duration (14-210 s; 48 +/- 13 s, n = 5). In 8% of the cases spreading depression-like episodes were observed. [K+]o increases during spreading depression-like episodes attained peak values of 11-27 mM (22.8 +/- 0.2 mM, n = 2) and had a duration of 160-396 s (244 +/- 29 s, n = 2). All types of synchronous activity were abolished by the GABAA-receptor antagonist bicuculline methiodide (10 microM) (n = 11). A similar effect was obtained by applying Ca(2+)-free/high-Mg2+ medium (n = 5). Simultaneous field-potential recordings in CA3, CA1, dentate area and subiculum demonstrated that negative-going potentials and prolonged field-potential discharges occurred in all areas in a synchronous fashion. Spreading depression-like episodes were more frequently recorded in the CA1 than in the CA3 area and were not seen in the subiculum or dentate area. These experiments indicate that a glutamatergic-independent, synchronous GABA-mediated potential which is elicited by 4AP in the adult rat hippocampus continues to occur in the presence of TEA. In addition, concomitant application of these K(+)-channel blockers induces a novel type of prolonged field-potential discharge as well as spreading depression-like episodes. Since all synchronous potentials (including spreading depression-like episodes) were abolished by bicuculline methiodide, we conclude that their occurrence is presumably dependent upon the post-synaptic activation of GABAA receptors located on neuronal and glial elements. As excitatory synaptic transmission was nominally blocked under our experimental conditions, we also propose that rises in [K+]o and consequent redistribution processes are per se sufficient to make all types of synchronous activity propagate.
 ...
PMID:Synchronization of rat hippocampal neurons in the absence of excitatory amino acid-mediated transmission. 891 57

1. The black widow spider venom component, alpha-latrotoxin (alpha-LTx) (< 0.5 nM), increased the frequency of miniature excitatory postsynaptic currents (mEPSCs) in hippocampal CA3 pyramidal cells 14-fold, without changing their amplitude. 2. This action of alpha-LTx was not affected by application of Ca(2+)-free/ethylene glycol-bis(b-aminoethyl ether)-N,N,N',N'-tetraacetic acid-containing saline, 100 microM Cd2+, or 50 microM Gd3+. The increase in mEPSC frequency was thus not due to an influx of Ca2+ into the axon terminal via voltage-dependent Ca2+ channels or alpha-LTx-induced pores. 3. alpha-LTx did not increase spontaneous release when synaptic transmission had been impaired by botulinum toxin/F. 4. alpha-LTx reduced the amplitude of EPSCs, elicited with stimulation of mossy fibers, without affecting paired-pulse facilitation. 5. The Ca2+ ionophore ionomycin (2-2.5 microM) also enhanced the frequency of mEPSCs, but unlike alpha-LTx, potentiated evoked EPSCs and reduced paired-pulse facilitation. Application of N-methyl-D-aspartate elicited a high frequency of Ca(2+)-dependent, tetrodotoxin-sensitive spontaneous EPSCs, but did not affect evoked EPSC amplitude. Agents that stimulate vesicular release by increasing presynaptic Ca2+ influx thus do not mimic the alpha-LTx-induced depression of evoked EPSCs. 6. We conclude that entry of Ca2+ into presynaptic axon terminals is not responsible for the effects of low concentrations of alpha-LTx on either spontaneous or evoked transmitter release in the hippocampus. 7. Potential presynaptic mechanisms that could mediate the opposing actions of alpha-LTx on spontaneous and evoked transmitter release in the hippocampus (i.e., alpha-LTx-induced ionic pores, depletion of synaptic vesicles, actions on exocytotic proteins) are discussed.
 ...
PMID:Calcium-independent actions of alpha-latrotoxin on spontaneous and evoked synaptic transmission in the hippocampus. 893 Feb 62

The metabotropic glutamate receptors (mGluRs) can be classified into three families based on amino acid sequence homology, signal transduction mechanisms and pharmacological properties. Generally, class I mGluRs mediate an excitation of neurons while activation of class II and III mGluRs results in a depression of synaptic transmission. In this study we have analyzed the expression pattern of mGluRs in human hippocampus using a panel of polyclonal antibodies specific for mGluR1b, mGluR2/3, mGluR4a, and mGluR5. Immunoreactivity for mGluR1b and mGluR5, i.e., the subtypes representing class I mGluRs, was found in all hippocampal neurons. The mGluR1b antiserum stained perikarya and proximal dendrites, whereas immunoreactivity for mGluR5 was also detectable in the distal dendritic compartments. Immunoreactivity for mGluR2/3, members of class II mGluRs, was present in all principle neurons in the dentate gyrus as well as in the CA4, CA3 and CA2 regions. Pyramidal cells of the CA1 region exhibited only weak labeling for mGluR2/3. Glial cells were also mGluR2/3-immunoreactive. The reaction obtained with an antiserum directed against mGluR4a, a member of class III mGluRs, was confined to the mossy fiber projection field in CA3 stratum lucidum. These data demonstrate differential expression of mGluR variants in the human hippocampus and may provide an important basis for future studies of mGluRs under various neuropathological conditions such as temporal lobe epilepsy, ischemia and neurodegenerative disorders.
 ...
PMID:Immunohistochemical distribution of metabotropic glutamate receptor subtypes mGluR1b, mGluR2/3, mGluR4a and mGluR5 in human hippocampus. 893 Mar 27

Eicosanoids, produced from arachidonic acid by cyclooxygenases (COXs) and lipoxygenases (LIPOXs), are involved in numerous brain processes. To explore if brief and noninjurious stimuli chronically alter expression of these enzymes, we examined the induction of COX-2 and LIPOX expression following unilateral neocortical spreading depression (SD). Expression was examined over time and in regions not experiencing SD (hippocampus) but synaptically connected to the site of stimulation (cortex). One hundred six male Wistar rats had SD induced via microinjection of 0.5 M KCl (0.5 M NaCl for sham) into left parietal cortex every 9 minutes for 1 or 3 hours. One hour before SD some animals received dexamethasone (Dex), mepacrine (Mep), indomethacin (Indo), nordihydroguaiaretic acid (Ndga), phenylephrine (Pe), sodium nitroprusside (Snp) with Pe, or N omega-nitro-L-arginine methyl ester (Lnam). Animals survived for 0, 3, or 6 hours, or 1, 2, 3, 7, 14, 21, or 28 days. Brains were processed immunohistochemically for COX-2 and LIPOX, and the optical density (OD) of the left and right cortex, dentate gyrus (DG), CA3, and CA1 immunoreactivity (IR) were measured. Induction was expressed as the log of left divided by right side OD for each region. COX-2 IR in the left cortex was elevated rapidly and was sustained for 21 days following SD. COX-2 IR was also elevated in the ipsilateral hippocampus not experiencing SD, with the rank order of induction as follows: DG > CA3 > CA1. Dex, Snp, and/or Pe significantly reduced the induction of COX-2. No changes in LIPOX IR were observed. These results show that long-term changes in COX-2 expression are induced by SD and these changes decrease with synaptic distance. Benign stimuli increase COX-2 expression and thus may influence brain function for extended periods and at distant locations.
 ...
PMID:Long-term elevation of cyclooxygenase-2, but not lipoxygenase, in regions synaptically distant from spreading depression. 895 10

THE response of hippocampal CA3 neurones to commissural stimulation, as expressed by the orthodromic population spike (PS2) recorded in anaesthetized rats, was increased when the recording micropipette contained the nitric oxide (NO) synthase inhibitor N omega-nitro-L-arginine methyl ester (20 mM). The increase was stable upon repeated stimulation. When the recording micropipette contained the NO donor sodium nitroprusside (SNP; 10 mM) the amplitude of PS2 elicited by low and middle stimulus strength (Istim) rapidly decreased, while remaining unchanged at higher Istim. When the SNP-containing microelectrode was maintained in place for longer, the depression of PS2 observed at low and medium Istim disappeared and PS2 increased at high Istim. This long-term SNP-induced increase in PS2 at high Istim was reduced by pretreatment with cycloheximide (5 mg kg-1, i.p.). These data, which provide the first demonstration that in situ manipulation of NO produces dual effects on neuronal responsiveness in a highly seizure-prone brain region, suggest that tonic levels of endogenous NO reduce the excitability of CA3 pyramidal neurones, whereas long-term overexposure to NO causes hyperexcitability possibly via genomic mechanisms.
 ...
PMID:Effects of in situ manipulation of nitric oxide on rat hippocampal CA3 neurone excitability. 898 58

1. Excitatory synaptic transmission between pairs of monosynaptically coupled pyramidal cells was examined in rat hippocampal slice cultures. Action potentials were elicited in single CA3 pyramidal cells impaled with microelectrodes and unitary excitatory postsynaptic currents (EPSCs) were recorded in whole-cell voltage-clamped CA1 or CA3 cells. 2. The amplitude of successive unitary EPSCs in response to single action potentials varied. The amplitude of EPSCs was altered by adenosine or changes in the [Mg2+]/[CA2+] ratio. We conclude that single action potentials triggered the release of multiple quanta of glutamate. 3. When two action potentials were elicited in the presynaptic cell, the amplitude of the second EPSC was inversely related to the amplitude of the first. Paired-pulse facilitation (PPF) was observed when the first EPSC was small, i.e. the second EPSC was larger than the first, whereas paired-pulse depression (PPD) was observed when the first EPSC was large. 4. The number of trials displaying PPD was greater when release probability was increased, and smaller when release probability was decreased. 5. PPD was not postsynaptically mediated because it was unaffected by decreasing ionic flux with 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX) or receptor desensitization with aniracetam. 6. PPF was maximal at an interstimulus interval of 70 ms and recovered within 500 ms. Recovery from PPD occurred within 5 s. 7. We propose that multiple release sites are formed by the axon of a CA3 pyramidal cell and a single postsynaptic CA1 or CA3 cell. PPF is observed if the first action potential fails to release transmitter at most release sites. PPD is observed if the first action potential successfully triggers release at most release sites. 8. Our observations of PPF are consistent with the residual calcium hypothesis. We conclude that PPD results from a decrease in quantal content, perhaps due to short-term depletion of readily releasable vesicles.
 ...
PMID:Paired-pulse facilitation and depression at unitary synapses in rat hippocampus: quantal fluctuation affects subsequent release. 901 8

The object of this study was to compare the postnatal development of mossy fiber potentiation (MFP) and paired-pulse facilitation in the CA3 region of control and led-exposed rats. The postnatal development of MFP was not influenced by the chronic pre- and postnatal lead exposure nor did we find a statistically significant impairment of MFP in region CA3 following lead exposure in the four age groups studied. In contrast to the adult animals, in the three immature groups of the control as well as the lead-exposed animals MFP was preceded by a posttetanic depression after which MFP developed slowly. The results of the paired-pulse procedure depended both on the age and on the interstimulus interval (ISI) in control and lead-exposed animals. The differences between control and lead-exposed rats were statistically significant only in the adult animals at an ISI of 10 ms. In this case paired-pulse stimulation resulted in an increase of the second evoked response relative to the first response in the lead-exposed animals while the same procedure decreased the second evoked response in the control animals. It is concluded that although low lead exposure had no effect on the expression of MFP in hippocampal CA3 region, inhibitory mechanisms as revealed by paired-pulse stimulation are impaired by lead in adult rats.
 ...
PMID:Postnatal development of synaptic plasticity in the CA3 hippocampal region of control and lead-exposed Wistar rats. 902 7


<< Previous 1 2 3 4 5 6 7 8 9 10