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)

An antisense oligonucleotide against the glutamate receptor delta 2 subunit mRNA, which is selectively expressed only in Purkinje neurons, suppressed the induction of long-term depression (LTD) of glutamate responsiveness in the rat cerebellar culture. LTD of glutamate response is induced by pairing glutamate application and depolarization of a Purkinje cell. Treatment of the culture with the antisense oligonucleotide exerted no appreciable effect on basic physiological and morphological properties of Purkinje cells, except for LTD induction and reduction of delta immunoreactivity which was intense in distal dendrites. Sense and missense oligonucleotides, which were used as controls, did not block LTD induction. These results suggest that the glutamate receptor delta 2 subunit is involved in the cerebellar LTD.
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PMID:Involvement of the glutamate receptor delta 2 subunit in the long-term depression of glutamate responsiveness in cultured rat Purkinje cells. 771 4

Of the six glutamate receptor (GluR) channel subunit families identified by molecular cloning, five have been shown to constitute either the AMPA, kainate, or NMDA receptor channel, whereas the function of the delta subunit family remains unknown. The selective localization of the delta 2 subunit of the GluR delta subfamily in cerebellar Purkinje cells prompted us to examine its possible physiological roles by the gene targeting technique. Analyses of the GluR delta 2 mutant mice reveal that the delta 2 subunit plays important roles in motor coordination, formation of parallel fiber-Purkinje cell synapses and climbing fiber-Purkinje cell synapses, and long-term depression of parallel fiber-Purkinje cell synaptic transmission. These results suggest a close relationship between synaptic plasticity and synapse formation in the cerebellum.
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PMID:Impairment of motor coordination, Purkinje cell synapse formation, and cerebellar long-term depression in GluR delta 2 mutant mice. 773 76

The discovery that blockade of N-methyl-D-aspartate (NMDA) receptors protects brain tissue against ischaemic damage has triggered enormous interest; and with the advance of intracerebral microdialysis, hundreds of studies have investigated changes in the extracellular levels of glutamate and other neurotransmitters during and after cerebral ischaemia. This work has made it apparent that the current concept of ischaemia-induced excitotoxicity, centred on excessive efflux of glutamate from nerve terminals, fails to correspond with reality since it conflicts with a number of key findings: (a) Excessive effluxes during ischaemia are not specific to excitatory amino acids--inhibitory transmitters are released to a similar extent; (b) neuronal death can occur several hours after a short ischaemic episode, whereas glutamate and aspartate accumulation in the neuronal microenvironment is cleared within minutes of reperfusion; (c) the penumbra is most receptive to cerebroprotection with glutamate receptor antagonists, but extracellular glutamate levels may not reach critical levels in this region; and (d) postischaemic treatment with glutamate receptor antagonists were neuroprotective in a number of studies. It has also become evident that most of the glutamate released in ischaemia is of metabolic origin, which questions the validity of therapeutic strategies aimed at preventing or reducing excessive release of neurotransmitter glutamate in ischaemia. However, the possibility that glutamate changes at the synaptic level may be small but pathologically important cannot be totally refuted. Apart from increased extracellular glutamate, the exceptional complexity of glutamate-operated ion channels can give rise to many potentially damaging mechanisms. Of particular interest are the possibilities of recurrent spreading depression in focal ischaemia, widespread and persistent strengthening of glutamatergic transmission, and abnormal modulation of the NMDA receptor-ionophore complex. There is also considerable evidence that, in certain brain regions, monoamines or their metabolic by-products may become neurotoxic either directly or from interplay with glutamatergic systems. All these processes deserve further examination to identify the most damaging and to indicate possible methods of intervention.
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PMID:Extracellular neurotransmitter changes in cerebral ischaemia. 774 71

Involvement of the glutamate receptor channel delta 2 subunit in cerebellar long-term depression (LTD) was studied in cultures prepared from wild-type and mutant mice deficient in the delta 2 subunit. LTD of the glutamate response was induced by pairing glutamate applications and depolarization of a Purkinje cell in wild-type culture. However, in cultured Purkinje cells prepared from mutant mice, the same conditioning failed to induce LTD. Immunocytological staining showed that mutant Purkinje cells develop and express calbindin (a marker protein for Purkinje cells) as do wild-type cells, but they express no delta 2 subunit protein. The results indicate that the glutamate receptor channel delta 2 subunit is involved in the postsynaptic down-regulation of glutamate sensitivity, presumably during cerebellar LTD.
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PMID:Suppression of LTD in cultured Purkinje cells deficient in the glutamate receptor delta 2 subunit. 776 57

1. We studied adenosine's action on synaptic transmission from primary afferent fibers to neurons of the substantia gelatinosa (SG) using tight-seal whole cell recordings in transverse slices of hamster spinal cord. Adenosine had two actions, hyperpolarization of the postsynaptic membrane and depression of the excitatory postsynaptic currents (EPSCs) evoked by dorsal root stimulation. 2. Under voltage clamp adenosine elicited a sustained outward current at a holding potential of -70 mV. The outward current was blocked by a combination of intracellular cesium and tetraethylammonium, an effect characteristic of potassium channels. The adenosine-induced current reversed at -97 +/- 6 (SD) mV, close to the potassium equilibrium potential. These observations suggest that adenosine activates a potassium conductance in SG neurons so as to inhibit primary afferent synaptic transmission postsynaptically. 3. Adenosine reduced the miniature EPSC frequency without significantly changing the amplitude. In contrast, the glutamate receptor competitive antagonist 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX) substantially reduced the amplitudes of miniature EPSCs while producing a much smaller effect on the miniature frequency than adenosine. In evoked EPSCs adenosine reduced unitary content without reducing unitary amplitude. The effects on both miniature and evoked EPSCs suggest that adenosine inhibits synaptic currents by suppressing presynaptic transmitter release. 4. EPSCs evoked by dorsal root stimuli were subdivided into monosynaptic and polysynaptic categories. Adenosine at superfusion concentrations of 20-300 microM suppressed all polysynaptic EPSCs. Less than half of monosynaptic EPSCs were inhibited, usually those evoked by the slowest-conducting primary afferents. These observations were interpreted to indicate that a principal action of adenosine in SG is on interneuronal communication.
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PMID:Adenosine inhibition of synaptic transmission in the substantia gelatinosa. 782 90

1. The properties of stimulus-evoked and spontaneous inhibitory synaptic potentials were examined in guinea-pig substantia nigra dopamine neurones in sagittal and coronal midbrain slices in the presence of glutamate receptor antagonists. 2. Focal electrical stimulation within the substantia nigra, cerebral peduncle, internal capsule or the striatum evoked a biphasic IPSP consisting of a fast and a slow component, with peak latencies of about 30 and 250 ms, respectively. The fast component was sensitive to chloride injection, reversed polarity at -79.4 +/- 1.1 mV and was blocked by the GABAA receptor antagonists picrotoxin and bicuculline. The slow IPSP reversed at -99.3 +/- 5.4 mV and was blocked by the GABAB receptor antagonists 2-hydroxysaclofen and CGP 35348. 3. Spontaneous IPSPs were observed in many neurones. These events reversed polarity at -77.5 +/- 2.6 mV and were completely blocked by bicuculline and/or picrotoxin. In the presence of TTX, small spontaneous events remained which probably represent miniature IPSPs. In coronal slices, application of 4-aminopyridine raised the frequency of spontaneous IPSPs, presumably by activating nigral interneurones, but failed to reveal spontaneous biphasic IPSPs or spontaneous pure slow IPSPs. 4. The amplitude of the fast IPSPs fluctuated from trial to trial. Amplitude histograms of minimal fast IPSPs displayed evenly spaced peaks, suggesting that synaptic transmission is quantal at these synapses. The measured peak spacing depended on the driving force for Cl-. 5. The fast IPSP showed little or no paired-pulse depression, and in the presence of 2-hydroxysaclofen (400-600 microM) showed paired-pulse facilitation. The GABAB agonist baclofen inhibited the fast IPSP via a presynaptic mechanism. The pharmacologically isolated slow IPSP showed marked paired-pulse facilitation. 6. It is concluded that synaptic inhibition in the substantia nigra is mediated by GABA, is relatively resistant to frequency-dependent depression and is regulated by presynaptic GABAB autoreceptors. Striatonigral and pallidonigral fibres activate both GABAA and GABAB receptors, while intranigral pathways appear to activate predominantly GABAA receptors.
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PMID:Inhibitory synaptic potentials in guinea-pig substantia nigra dopamine neurones in vitro. 783 97

1. The properties of evoked excitatory postsynaptic currents (EPSCs) and spontaneous miniature excitatory postsynaptic currents (mEPSCs) have been studied in neurons of the nucleus magnocellularis (nMAG), one of the avian cochlear nuclei which receive somatic, calyceal innervation from auditory nerve fibres. Whole-cell patch clamp techniques were used to voltage clamp visually identified neurons in brain slices. 2. EPSCs resulting from activation of single axonal inputs were on average -5.3 nA at a driving force of -25 mV. Current-voltage relationships for the peak of the EPSC were linear with a peak conductance of 211 nS. The rate of EPSC decay showed a linear increase with temperature, with a temperature coefficient (Q10) of 2.2 between 25 and 35 degrees C; in vivo (41 degrees C) the EPSC would decay in 0.2 ms. 3. The EPSC was composed of two pharmacologically and kinetically distinct components: an early phase due to non-NMDA (N-methyl-D-aspartate) receptors and a late phase resulting from NMDA receptors. Both components reversed near 0 mV. While both subtypes of glutamate receptor were activated by transmitter, NMDA receptors had a peak conductance at positive potentials which was only 11% of the peak non-NMDA receptor component. 4. EPSCs during trains of stimuli exhibited a progressive decrease in amplitude. The extent of depression increased with the frequency of stimulation and was reduced by drugs which prevent receptor desensitization, indicating that, in part, postsynaptic factors limit synaptic strength during repetitive synaptic activity. Additionally, the coefficient of variation of the EPSC amplitude increased during trains, consistent with presynaptic depression. 5. mEPSCs occurred randomly in the presence of tetrodotoxin and presumably correspond to transmitter quanta. These synaptic events rose (10-90%) within 100 microseconds and decayed with an exponential of 180 microseconds at 29-32 degrees C. Despite the somatic location of the synapse, mEPSCs varied widely in amplitude, suggesting differences in the quantal synaptic current at each synaptic site. The ratio of the average peak conductance of the EPSC and mEPSC gave an estimated quantal content of 103.
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PMID:Voltage clamp analysis of excitatory synaptic transmission in the avian nucleus magnocellularis. 785 16

Adenosine is present in the mammalian brain in large amounts and has potent effects on neuronal activity, but its role in neural signaling is poorly understood. The glutamate receptor agonist N-methyl-D-aspartate (NMDA) caused a presynaptic depression of excitatory synaptic transmission in the CA1 region of guinea pig hippocampal slices. This depression was blocked by an adenosine A1 receptor antagonist, which suggests that activation of the NMDA subtype of glutamate receptor raises the concentration of extracellular adenosine, which acts on presynaptic inhibitory A1 receptors. Strong tetanic stimulation caused a heterosynaptic inhibition that was blocked by both NMDA and A1 receptor antagonists. Enkephalin, which selectively inhibits interneurons, antagonized the heterosynaptic inhibition. These findings suggest that synaptically released glutamate activates NMDA receptors, which in turn releases adenosine, at least in part from interneurons, that acts at a distance to inhibit presynaptically the release of glutamate from excitatory synapses. Thus, interneurons may mediate a widespread purinergic presynaptic inhibition.
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PMID:Release of adenosine by activation of NMDA receptors in the hippocampus. 791 85

Dorsal horn sensitization following somatic noxious stimuli is partly mediated by the N-methyl-D-aspartate (NMDA) sub-type of glutamate receptor. This phenomenon has been comparatively sparsely investigated in the area of visceral pain. We have therefore investigated the role of spinal NMDA receptors in central sensitization in an animal model of persistent visceral pain. In anaesthetized rats the lumbosacral spinal cord was exposed by laminectomy and the pre-emptive effect of intrathecal AP-5 upon the hyper-reflexia associated with chemical inflammation of the bladder was investigated. The effect of intrathecal AP-5 (an NMDA receptor antagonist) upon the normal cystometrogram (CMG) was also measured. AP-5 (125-1000 micrograms) prevented the hyper-flexia associated with bladder inflammation in a dose-dependant fashion. In general, within the dose range 62.5-1000 micrograms, AP-5 had no significant effect upon the normal micturition reflex. However, at the top of this dose range a minor non-significant depression of this reflex was noted. NMDA receptors do not appear to mediate the micturition reflex at a spinal cord level. However, they are involved in the induction of hyper-reflexia following urinary bladder inflammation, this hyper-reflexia can be prevented by pre-emptive intrathecal administration of AP-5.
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PMID:Pre-emptive intrathecal administration of an NMDA receptor antagonist (AP-5) prevents hyper-reflexia in a model of persistent visceral pain. 793 11

1. Gamma-aminobutyric acid-B (GABAB) autoreceptor-dependent and -independent components of paired-pulse depression (PPD) at inhibitory synapses in area CA3 of the rat hippocampus were studied using whole-cell recording techniques. Inhibitory fibers were activated directly in the presence of the ionotropic glutamate receptor antagonists 6,7-dinitroquinoxaline-2,3,dione (20 microM) and D-2-amino-5-phosphonovalerate (20 microM). 2. When pairs of monosynaptic inhibitory postsynaptic currents (eIPSCs) were evoked with an interstimulus interval of 200 ms, the amplitude of the second response (eIPSC2) was depressed when compared with the first (eIPSC1). The GABAB receptor agonist baclofen (10 microM) depressed both responses, but eIPSC1 was depressed more than eIPSC2, resulting in PPD that was comparatively smaller. Addition of the GABAB receptor antagonist CGP 55845A (1 microM) completely reversed depression of eIPSC1 by baclofen and increased the amplitude of eIPSC2 above the control value, such that PPD in the combination of baclofen and CGP 55845A was equivalent to that in baclofen alone. The ratio eIPSC2/eIPSC1 was 0.64 under control conditions, 0.77 in the presence of baclofen, and 0.79 in the presence of baclofen and CGP 55845A. These results demonstrate the existence of two components of PPD at inhibitory synapses, one that depends on activation of GABAB autoreceptors (GABAB receptor-dependent PPD) and one that does not (GABAB receptor-independent PPD). 3. When the number of inhibitory fibers activated was lowered by decreasing the stimulus intensity, eIPSC2/eIPSC1 was 0.76 under control conditions, 0.75 in the presence of baclofen, and 0.76 in the presence of baclofen and CGP 55845A. These results indicate that GABAB receptor-dependent PPD requires activation of several presynaptic inhibitory neurons, whereas GABAB receptor-independent PPD does not. 4. The time-courses of the GABAB-dependent and -independent components of PPD were compared by varying the interstimulus interval in the absence and presence of CGP 55845A. GABAB-dependent PPD was maximal at an interstimulus interval of 100 ms and was undetectable at 1 s. In contrast, GABAB-independent PPD was maximal at 5 ms and 1 s, was slightly less pronounced at intermediate intervals (50-200 ms), and was present at intervals as long as 5 s. 5. GABAB-independent PPD was not blocked by antagonists at opioid receptors (10 microM naloxone) or muscarinic acetylcholine receptors (10 microM atropine). GABAB-independent PPD could not be accounted for by a decrease in driving force because of Cl- redistribution.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Temporally distinct mechanisms of use-dependent depression at inhibitory synapses in the rat hippocampus in vitro. 796 97


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