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)

Poly(A(+)) RNA was extracted from the temporal lobe (TL) of medically intractable epileptic patients which underwent surgical TL resection. Injection of this mRNA into Xenopus oocytes led to the expression of ionotropic receptors for gamma-aminobutyric acid (GABA), kainate (KAI) and alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA). Membrane currents elicited by GABA inverted polarity at -15 mV, close to the oocyte's chloride equilibrium potential, were inhibited by bicuculline, and were potentiated by pentobarbital and flunitrazepam. These basic characteristics were also displayed by GABA currents elicited in oocytes injected with mRNAs isolated from human TL glioma (TLG) or from mouse TL. However, the GABA receptors expressed by the epileptic TL mRNA exhibited some unusual properties, consisting in a rapid current run-down after repetitive GABA applications and a large EC(50) (125 microM). AMPA alone evoked very small or nil currents, whereas KAI induced larger currents. Nevertheless, upon cyclothiazide treatment, AMPA elicited substantial currents that, like the KAI currents, were inhibited by 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX). Furthermore, the glutamate receptor 5 (GluR5) agonist, ATPA, failed to evoke an obvious current although both RT-PCR and Western blot analyses showed GluR5 expression in the epileptic TL. Oocytes injected with mouse TL or human TLG mRNAs generated KAI and AMPA currents similar to those evoked in oocytes injected with epileptic TL mRNA but, in contrast to these, the mouse TL and human TLG oocytes were also responsive to ATPA. Our findings are in accord with the concept that both a depression of GABA inhibition and a dysfunction of the KAI-receptor system maintain a high neuronal excitability that results in epileptic seizures.
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PMID:Expression of human epileptic temporal lobe neurotransmitter receptors in Xenopus oocytes: An innovative approach to study epilepsy. 1240 14

Fast synaptic inhibition in the brain is largely mediated by ionotropic GABA receptors, which can be subdivided into GABAA and GABAC receptors based on pharmacological and molecular criteria. GABAA receptors are important therapeutic targets for a range of sedative, anxiolytic, and hypnotic agents and are implicated in several diseases including epilepsy, anxiety, depression, and substance abuse. In addition, modulating the efficacy of GABAergic neurotransmission may play a key role in neuronal plasticity. Recent studies have begun to reveal that the accumulation of ionotropic GABAA receptors at synapses is a highly regulated process that is facilitated by receptor-associated proteins and other cell-signaling molecules. This review focuses on recent experimental evidence detailing the mechanisms that control the assembly and transport of functional ionotropic GABAA receptors to cell surface sites, in addition to their stability at synaptic sites. These regulatory processes will be discussed within the context of the dynamic modulation of synaptic inhibition in the central nervous system (CNS).
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PMID:Mechanisms of GABAA receptor assembly and trafficking: implications for the modulation of inhibitory neurotransmission. 1242 59

Preconditioning of the cerebral cortex was induced in mice by repeated cortical spreading depression (CSD), and the major ionotropic glutamate (GluRs) and nicotinic acetylcholine receptor (nAChRs) subunits were compared by quantitative immunoblotting between sham- and preconditioned cortex, 24 h after treatment. A 30% reduction in alpha-amino-3-hydroxy-5-methyl-4-iso- xazolepropionate (AMPA) GluR1 and 2 subunit immunoreactivities was observed in the preconditioned cortex (p < 0.03), but there was no significant change in the NMDA receptor subunits, NR1, NR2A and NR2B. A 12-15-fold increase in alpha7 nAChR subunit expression following in vivo CSD (p < 0.001) was by far the most remarkable change associated with preconditioning. In contrast, the alpha4 nAChR subunit was not altered. These data point to the alpha7 nAChR as a potential new target for neuroprotection because preconditioning increases consistently the tolerance of the brain to acute insults such as ischaemia. These data complement recent studies implicating alpha7 nAChR overexpression in the amelioration of chronic neuropathologies, notably Alzheimer's disease (AD).
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PMID:Spreading depression-induced preconditioning in the mouse cortex: differential changes in the protein expression of ionotropic nicotinic acetylcholine and glutamate receptors. 1243 95

Information processing in the nervous system is achieved primarily at chemical synapses between neurons. Recent evidence suggests that glia-neuron interactions contribute in multiple ways to the synaptic process. In the present study we used the frequency of spontaneous postsynaptic currents (sPSC) in Purkinje neurons in acute cerebellar brain slices from juvenile rats (13-19 days old) as a measure of synaptic activity. Following 50 depolarizing pulses to an adjacent Bergmann glial cell (50 mV; duration 0.5 s; 1 Hz) the sPSC frequency of the Purkinje neuron was reduced to 65 +/- 7 % of control values within 10 min after glial stimulation and remained depressed for at least 40 min. Depolarizing pulses to 0 mV had a comparable effect (70 +/- 5 % of control). The frequency of miniature PSCs, as recorded in 300 nM TTX, was not modulated after glial stimulation. Blockade of ionotropic glutamate receptors (iGluRs) with kynurenic acid (1 mM) or 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX, 5 microM) suppressed the reduction of neuronal activity induced by glial depolarization, whereas the glial modulation of synaptic activity was not inhibited by a block of N-methyl-D-aspartate iGluRs, metabotropic glutamate receptors, cannabinoid receptors or GABA(B) receptors. Fluorometric measurements of the intraglial Ca(2+) concentration revealed no glial Ca(2+) transients during the depolarization series, and glial cell stimulation reduced the neuronal sPSC frequency even after loading the glial cell with 20 mM of the Ca(2+) chelator BAPTA. Our results indicate a glia-induced long-lasting depression of neuronal communication mediated by iGluRs.
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PMID:Long-lasting modulation of synaptic input to Purkinje neurons by Bergmann glia stimulation in rat brain slices. 1245 36

In the mammalian olfactory bulb, mitral cell dendrites release glutamate onto the dendritic spines of granule cells, which in turn release GABA back onto mitral dendrites. This local synaptic circuit forms the basis for reciprocal dendrodendritic inhibition mediated by ionotropic GABA(A) receptors in mitral cells. Surprisingly little is known about neurotransmitter modulation of dendrodendritic signaling in the olfactory bulb. In this study, we examine whether metabotropic GABA(B) receptors modulate dendrodendritic signaling between mitral and granule cells. We find that the selective GABA(B) agonist baclofen reduces mitral cell recurrent inhibition mediated by dendrodendritic synapses. GABA(B) receptor activation causes only a weak inhibition of field EPSCs in the external plexiform layer and only slightly reduces glutamate-mediated mitral cell self-excitation. Although GABA(B) receptors depress mitral cell glutamate release only weakly, baclofen causes a marked reduction in the amplitude of granule-cell-evoked, GABA(A)-mediated IPSCs in mitral cells. In addition to reducing the amplitude of granule-cell-evoked IPSCs, baclofen causes a change from paired-pulse depression to paired-pulse facilitation, suggesting that GABA(B) receptors modulate GABA release from granule cells. To explore the mechanism of action of GABA(B) receptors further, we show that baclofen inhibits high-voltage-activated calcium currents in granule cells. Together, these findings suggest that GABA(B) receptors modulate dendrodendritic inhibition primarily by inhibiting granule cell calcium channels and reducing the release of GABA. Furthermore, we show that endogenous GABA regulates the strength of dendrodendritic inhibition via the activation of GABA(B) autoreceptors.
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PMID:GABA(B) receptors inhibit dendrodendritic transmission in the rat olfactory bulb. 1265 61

It is well documented that prolonged treatment with antagonists of ionotropic glutamate receptors activates a number of homeostatic mechanisms including alteration of glutamatergic transmission. We studied whether this treatment can also affect GABAergic transmission. Using whole-cell voltage clamp recording and local extracellular stimulation we investigated evoked inhibitory postsynaptic currents (IPSCs) in cultured rat hippocampal neurons grown in the presence of ionotropic glutamate receptor antagonist kynurenate (1 mM) and in control conditions. Chronic kynurenate treatment did not significantly affect the amplitude of evoked IPSCs and IPSC reversal potentials. In contrast we found that the paired-pulse depression was increased by 67% in cultures treated with kynurenic acid. We conclude that additional mechanism(s), alteration of GABAergic synaptic transmission, may contribute to homeostatic plasticity induced by chronic block of ionotropic glutamate receptors.
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PMID:Chronic treatment with ionotropic glutamate receptor antagonist kynurenate affects GABAergic synaptic transmission in rat hippocampal cell cultures. 1267 44

1. The group II metabotropic glutamate (mGlu) receptor antagonist (2S,1'S,2'S)-2-(2-carboxycyclopropyl)-2-(9H-xanthen-9-yl)glycine (LY341495) also has activity at group I and III mGlu receptors at higher concentrations and can be used to discriminate between mGlu receptor subtypes. We report the antagonist action of LY341495 on glutamate receptors expressed in the neonatal rat spinal cord preparation and the use of this antagonist to investigate the group III mGlu receptor subtypes responsible for mediating the depression of synaptic transmission in the spinal cord mediated by the group III mGlu receptor agonists (S)-2-amino-4-phosphonobutanoic acid ((S)-AP4) and (1S,3R,4S)-1-aminocyclopentane-1,2,4-tricarboxylic acid (ACPT-I). 2. LY341495 antagonised mGlu receptor agonist-induced responses in the spinal cord with a rank order of potency of group II > group III > group I, which is the same as that observed in human cloned mGlu receptor cell lines. Antagonism of group II and III mGlu receptor-mediated effects were time dependent when low-nanomolar concentrations of LY341495 were used. Although the rank order of potency of LY341495 was the same on native rat and cloned human mGlu receptors, there was a compression in the selectivity between group II and III mGlu receptors, expressed in the spinal cord. 3. In agreement with a previous study on cloned ionotropic glutamate receptors 100 microM LY341495 had little or no effect on N-methyl-D-aspartate, (S)-2-amino-3-(3-hydroxy-5-methylisoxazol-4-yl) propionic acid or kainate receptor-mediated responses on motoneurones. 4. LY341495 exhibited low-nanomolar potency antagonist activity against (S)-AP4 and ACPT-I suggesting that these agonists are activating predominantly mGlu8 and that mGlu4 receptors do not play a role in modulating synaptic transmission in the pathways stimulated in the experiments described here.
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PMID:Actions of LY341495 on metabotropic glutamate receptor-mediated responses in the neonatal rat spinal cord. 1274 33

Release of the neuromodulator dopamine (DA) is critical to the control of locomotion, motivation, and reward. However, the probability of DA release is not well understood. Current understanding of neurotransmitter release probability in the CNS is limited to the conventional synaptic amino acid transmitters (e.g., glutamate and GABA). These fast neurotransmitters are released with a repertoire of probabilities according to synapse type, and these probabilities show activity-dependent plasticity according to synapse use. Synapses for neuromodulators such as DA, however, are designed for signaling that diverges temporally and spatially from that for fast neurotransmitters: DA receptors are exclusively metabotropic and at sites that extend to extrasynaptic locations and neighboring synapses. In this study, the release probability of DA was explored in real time in limbicversus motor-associated functional domains of the striatum of a primate (marmoset; Callithrix jacchus) using fast-scan voltammetry at a carbon-fiber microelectrode. We show that the probability of axonal DA release varies with striatal domain. Furthermore, release probability exhibits a short-term, activity-dependent plasticity that ranges from depression to facilitation in motor-through limbic-associated regions, respectively. Rapid plasticity does not result from metabotropic D2-like DA receptor activation or ionotropic GABA(A) receptor effects but is dependent on Ca2+ availability. These data reveal that rapid dynamics in DA release probability will participate in the transmission of the patterns and frequencies encoded by DA neuron action potential discharge. Furthermore, the regional variation in these features indicates that limbic-versus motor-associated DA neurons are permitted to generate diverse DA signals in response to a given firing pattern.
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PMID:Variable dopamine release probability and short-term plasticity between functional domains of the primate striatum. 1276 27

It is commonly thought that a persistent change in the efficacy of the synaptic transmission is the basic mechanism underlying learning and memory. The cerebellum, key structure of the motor function, exhibits a synaptic plasticity named cerebellar long-term depression or LTD. This phenomenon appears in the Purkinje cell when the two main excitatory inputs (one consists of the parallel fibers which relay information on the task to accomplish and the other one includes the climbing fiber which conveys error signals) are activated in combination, resulting in a persistent decrease of the efficacy of the parallel fiber-Purkinje cell synapse. Studies made in the last 20 years show that activation of ionotropic and metabotropic glutamate receptors triggers complex signal transduction processes, leading to the phosphorylation and the internalization of AMPA receptors, a subtype of glutamatergic receptors. The aim of this paper is firstly to present mechanisms involved in LTD induction and maintenance. The second part introduces briefly experimental data that show that LTD is indeed strongly associated with motor learning. Recent studies on the involvement of the cerebellum in cognitive tasks also suggest that LTD may play some role other than that in the sole motor learning.
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PMID:[Cerebellar long-term depression: a mechanism for learning and memory]. 1283 16

Most conventional antidepressant drugs influence serotoninergic, adrenergic, and/or dopaminergic systems, increasing serotonin, norepinephrine and dopamine synaptic availability. More recently attention has focused on glutamatergic system. Both preclinical and clinical studies, showing antidepressant-like actions of compounds which reduce transmission at N-methyl-D-aspartate (NMDA) receptors, indicate possible involvement of glutamatergic system in the etiology of depression. Since glutamatergic transmission is controlled not only by ionotropic but also by metabotropic glutamate receptors (mGluR), their involvement in the etiology and the therapy of depression was also postulated. Recent studies, showing that antidepressant treatment may influence mGlu receptors, together with the findings that group I mGluR antagonists, may possess antidepressant-like action, support this hypothesis.
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PMID:On the role of metabotropic glutamate receptors in the mechanisms of action of antidepressants. 1286 12


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