Differential effects of kainic acid on benzodiazepine receptors, GABA receptors, and GABA-modulin in the cerebellar cortex.
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Inhibition in postischemic rat hippocampus: GABA receptors, GABA release, and inhibitory postsynaptic potentials.
We have investigated the GABAergic system in rat hippocampus at 1 hour and up to 21 days following 20 min of global cerebral ischemia. Distribution of 3H-GABA (in excess of unlabeled baclofen) and 3H-Ro-15-1788 (benzodiazepine antagonist) binding sites in hippocampus was studied utilizing quantitative autoradiography. The 3H-GABA binding was unchanged (p greater than 0.01) after ischemia, whereas the 3H-Ro-15-1788 binding decreased significantly (p less than 0.01) in all hippocampal subfields 1-21 days after ischemia. Using microdialysis in CA1, we found that K(+)-stimulated GABA release at 1 hour and 1 day after ischemia was unchanged (p greater than 0.01) in comparison to preischemic controls. Electrophysiological recordings were made from CA1 of hippocampal slices prepared from rats sacrificed 1 hour, 1 day and 2 days after ischemia. Field potentials evoked by stimulation of the Schaffer collaterals showed no differences (p greater than 0.01) from those taken from controls. Postischemic intracellular recordings from the CA1 pyramidal cells showed that fast and slow inhibitory postsynaptic potentials were readily evoked on orthodromic stimulation. Together with our previous morphological results, demonstrating survival of hippocampal interneurons following ischemia, we conclude that hippocampal GABAergic interneurons preserve their inhibitory potential in the period preceding delayed CA1 pyramidal cell death. This conclusion taken together with the observation that postischemic 3H-Ro-15-1788 binding in hippocampus declined, suggest that benzodiazepines (by increasing the receptor affinity), GABA analogs, and GABA uptake inhibitors may be useful in the treatment of ischemic CA1 pyramidal cell death in the rat.
Animals↗
[Glutamate receptor and GABA receptor expressed in amphibian oocytes after injection of chicken retina mRNA].
The glutamate receptor and GABA receptor of chicken retina were studied with the expression system of amphibian oocyte. Some important results were obtained: L-glutamate, kainate, AMPA and quisqualate could all induce rapid and smooth depolarizing currents in oocytes. NMDA, L-AP4, trans-ACPD and L-aspartate had no effects. The antagonism of kainate response by AMPA and quisqualate was found, and it seemed that AMPA, quisqualate and KA could act on the same receptor. Comparing the responses to L-Glu and NMDA, it was found that the mRNA abundance of metabotropic glutamate receptor and NMDA receptor in chicken retina was much lower than that of chicken brain. The GABA receptor in chicken retina was very different from that of bovine retina. And although about 10% of the GABA response was insensitive to bicuculline, but most GABA receptors in chicken retina were proved as GABAA receptors.
Animals↗
Marlin-1, a novel RNA-binding protein associates with GABA receptors.
GABA(B) receptors are heterodimeric G protein-coupled receptors that mediate slow synaptic inhibition in the central nervous system. Whereas heterodimerization between GABA(B) receptor GABA(B)R1 and GABA(B)R2 subunits is essential for functional expression, how neurons coordinate the assembly of these critical receptors remains to be established. Here we have identified Marlin-1, a novel GABA(B) receptor-binding protein that associates specifically with the GABA(B)R1 subunit in yeast, tissue culture cells, and neurons. Marlin-1 is expressed in the brain and exhibits a granular distribution in cultured hippocampal neurons. Marlin-1 binds different RNA species including the 3'-untranslated regions of both the GABA(B)R1 and GABA(B)R2 mRNAs in vitro and also associates with RNA in cultured neurons. Inhibition of Marlin-1 expression via small RNA interference technology results in enhanced intracellular levels of the GABA(B)R2 receptor subunit without affecting the level of GABA(B)R1. Together our results suggest that Marlin-1 functions to regulate the cellular levels of GABA(B) R2 subunits, which may have significant effects on the production of functional GABA(B) receptor heterodimers. Therefore, our observations provide an added level of regulation for the control of GABA(B) receptor expression and for the efficacy of inhibitory synaptic transmission.
Adaptor Proteins, Signal Transducing↗
Astrocytic GABA receptors.
GABA receptors are distributed widely throughout the central nervous system on a variety of cell types. It has become increasingly clear that astrocytes, both in cell culture and tissue slices, express abundant GABAA receptors. In astrocytes, GABA activates Cl(-)-specific channels that are modulated by barbiturates and benzodiazepines; however, the neuronal inverse agonist methyl-4-ethyl-6, 7-dimethoxy-beta-carboline-3-carboxylate enhances the current in a subpopulation of astrocytes. The properties of astrocytic GABAA receptors, therefore, are remarkably similar to their neuronal counterparts, with only a few pharmacological exceptions. In stellate glial cells of the pituitary pars intermedia, GABA released from neuronal terminals activates postsynaptic potentials directly. The physiological significance of astrocytic GABAA-receptor activation remains unknown, but it may be involved in extracellular ion homeostasis and pH regulation. At present, there is considerably less evidence for the presence of GABAB receptors on astrocytes. The data that have emerged, however, indicate a prominent role for second-messenger regulation by this receptor.
Animals↗
Activation of picrotoxin-resistant GABA receptors by GABA and related compounds induces modulation of cockroach dorsal paired median (DPM) neuron firing.
Activation of gamma-aminobutyric acid (GABA) receptors in insect dorsal paired median (DPM) neurons induced two types of response which appeared to be mediated by two different GABA receptor subtypes. When activated by bath application of GABA, one receptor subtype, insensitive to picrotoxin (PTX), mediated a drastic reduction in the firing frequency, leading to a blockade of the spontaneous electrical activity. These effects were accompanied by decreases in the amplitude and duration of the plateau action potential (AP) and the spike after-hyperpolarization (AHP). In most cases, a slight depolarization of the resting membrane potential occurred. Bath application of the vertebrate GABA(B) receptor agonists 3-aminopropyl(methyl)phosphinic acid (SKF 97541) and 3-aminopropylphosphinic acid (CGA 147823/CGP 27492) induced similar responses. Another GABA receptor subtype, less sensitive to GABA, mediated a chloride dependent hyperpolarization that was suppressed by bath application of PTX. The approximate locations of these two GABA receptor subtypes were determined by local pressure microapplications of GABA and vertebrate GABAergic agonists. The PTX-sensitive receptors were located predominantly on the surface of the ganglion where the apical pole of the soma is situated, while the PTX-resistant receptors appeared to be located deeper within the ganglion.These results reveal the existence of two GABA receptor subtypes on the DPM neurons and provide evidence for a functional role for PTX-resistant GABA receptors in the regulation of spontaneous firing.
Journal Article↗
GABAergic modulation of the activity of globus pallidus neurons in primates: in vivo analysis of the functions of GABA receptors and GABA transporters.
Neurons in the external and internal segment of the globus pallidus (GPe and GPi, respectively) receive substantial GABAergic inputs from the striatum and through axon collaterals of neighboring pallidal neurons. The effects of GABA on pallidal activity depend on the synaptic localization of GABA receptors and the distribution and activity of GABA transporters (GATs). To explore the contribution of GABA receptors and transporters to pallidal function, we recorded the activity of single neurons in GPe or GPi before, during, and after local microinjections of GABAergic compounds in awake rhesus monkeys. Activation of GABA(A) or GABA(B) receptors with muscimol or baclofen, respectively, inhibited pallidal activity. These effects were reversed by concomitant infusion of the respective GABA receptor antagonists, gabazine and CGP-55845. Given alone, the antagonists were without consistent effect. Application of the selective GAT-1 inhibitor, SKF-89976A, and the semiselective GAT-3 blocker, SNAP-5114, decreased pallidal activity. Both GAT inhibitors increased GABA levels in the pallidum, as measured by microdialysis. Electron microscopic observations revealed that these transporters are located on glial processes and unmyelinated axonal segments, but rarely on terminals. Our results indicate that activation of GABA(A) and GABA(B) receptors inhibits neuronal activity in both segments of the pallidum. GAT-1 and GAT-3 are involved in the modulation of endogenous GABA levels and may be important in regulating the extrasynaptic levels of GABA. Together with previous evidence that a considerable proportion of pallidal GABA receptors are located outside the synaptic cleft, our experiments strongly support the importance of extrasynaptic GABAergic transmission in the primate pallidum.
Action Potentials↗
Effects of learned helplessness on brain GABA receptors.
GABA is involved in both clinical depression and in animal models of depression; however, the roles of GABA(A) and GABA(B) receptors in specific brain regions are not clear. Changes in densities of both GABA(A) and GABA(B) receptors have been reported with the learned helplessness animal model of depression and with chronic antidepressant drug treatment. However, some of these findings are discrepant. Thus, we used quantitative autoradiography to study the GABA(A) and GABA(B) receptors in learned helplessness and we used an experimental paradigm that allows non-specific effects of stress to be differentiated from learned helplessness. Densities of GABA binding were measured in prefrontal cortex, septum, hippocampus, hypothalamus and amygdala. In the septum, learned helpless rats had increased densities of GABA(A) receptors and rats that did not become helpless after inescapable stress had decreased GABA(B) receptor densities. No significant group differences of GABA(A) or GABA(B) receptor densities were observed in any other brain region studied. These results suggest a unique role for the septum in modulating GABA in the learned helplessness animal model of depression.
Animals↗
The alpha5 subunit of the murine type A GABA receptor.
GABA[A] receptors in the brain convert binding of GABA (gamma-aminobutyric acid) to inhibition by chloride currents. Several important classes of drugs, including benzodiazepines and alcohol, modulate these receptors, which have also been implicated in epilepsy. We describe the alpha5 subunit of GABAA receptors in mice, comparing inbred DBA/2J mice, prone to juvenile audiogenic seizures, with seizure resistant C57BL/6J mice. We find no sequence differences between the strains, although there are several interesting amino acid differences from the rat. We also compare the expression of the alpha5 subunit in whole brains of DBA/2J mice to that in C57BL/6J mice at 21 days, the peak of the former's seizure susceptibility, again finding no significant difference. We further describe the pattern of expression of alpha5 mRNA during mouse brain development, with a peak at 3 days after birth, and among five brain regions in the adult mouse, with the highest levels in the hippocampus. Finally, we present preliminary evidence for rare alternative splicing of this subunit's message, in the N-terminal extracellular domain, to give a form not translatable into a functional protein.
Alternative Splicing↗
Cerebral GABA receptors.
GABA (gamma-aminobutyric acid) receptors in the brain have been classified into GABAA and GABAB types. The GABAA receptor is an ionotropic type that forms the GABA-gated Cl- channel. The structure of GABAA receptor has been intensively analyzed and found to consist of several subunits and the combination of these subunits is heterogeneous. Therefore, it is likely that multiple GABAA receptors are present and exert various inhibitory actions in the brain. On the other hand, the GABAB receptor, a metabotropic type, inhibits cAMP formation as well as inositol phosphates turnover. The inhibition of adenylyl cyclase activity is mediated by GTP-binding protein such as Gi and/or Go which is coupled with GABAB receptor. Studies of the purified GABAB receptor obtained by baclofen-affinity and immunoaffinity column chromatographic procedures have indicated that this receptor protein is approximately 80 kDa in molecular weight and heterogeneous as determined by SDS-polyacrylamide gel electrophoresis. Alcohol induces the activation of GABA-gated Cl- channel but this activation is found to be diminished following the establishment of alcohol dependence. Furthermore, alcohol dependence induces the increase of GABAB receptor binding, while suppressing the functional coupling between GABAB receptor and adenylyl cyclase, possibly altering the function of Gi/Go type of GTP-binding protein which is coupled to GABAB receptor in the brain. The pathophysiological significance of these changes in the establishment of alcohol dependence and/or alcohol withdrawal syndrome is also briefly discussed.
Animals↗
Differential regulation of AMPA receptor and GABA receptor trafficking by tumor necrosis factor-alpha.
The proinflammatory cytokine tumor necrosis factor-alpha (TNFalpha) causes a rapid exocytosis of AMPA receptors in hippocampal pyramidal cells and is constitutively required for the maintenance of normal surface expression of AMPA receptors. Here we demonstrate that TNFalpha acts on neuronal TNFR1 receptors to preferentially exocytose glutamate receptor 2-lacking AMPA receptors through a phosphatidylinositol 3 kinase-dependent process. This increases excitatory synaptic strength while changing the molecular stoichiometry of synaptic AMPA receptors. Conversely, TNFalpha causes an endocytosis of GABA(A) receptors, resulting in fewer surface GABA(A) receptors and a decrease in inhibitory synaptic strength. These results suggest that TNFalpha can regulate neuronal circuit homeostasis in a manner that may exacerbate excitotoxic damage resulting from neuronal insults.
Animals↗
Graded response to GABA by native extrasynaptic GABA receptors.
GABA is the main inhibitory neurotransmitter in the mammalian CNS. GABA in the brain is commonly associated with a fast, point-to-point form of signalling called synaptic transmission (phasic inhibition), but there is growing evidence that GABA participates in another, slower and more diffuse form of signalling often referred to as tonic inhibition. Unresolved questions regarding tonic neuronal inhibition concern activation and functional properties of extrasynaptic GABAA receptors (GABARex) present on neurones. Extrasynaptic receptors are exposed to submicromolar GABA concentrations and may modulate the overall excitability of neurones and neuronal networks. Here, we examined GABA-activated single-channel currents in dentate gyrus granule neurones in rat hippocampal slices. We activated three types (I, II, III) of GABARex channels by nanomolar GABA concentrations (EC50 I: 27 +/- 12; II: 4 +/- 3; III: 43 +/- 19 nm). The channels opened after a delay and the single-channel conductance was graded (gammamax I: 61 +/- 3; II: 85 +/- 8, III: 40 +/- 3 pS). The channels were differentially modulated by 1 microm diazepam, 200 nm zolpidem, 1 microm flumazenil and 50 nm THDOC (3alpha, 21-dihydroxy-5alpha-pregnan-20-one), consistent with the following minimal subunit composition of GABARex I alpha1betagamma2, GABARex II alpha4betagamma2 and GABARex III alphabetadelta channels.
Animals↗
Synaptogenesis in the rat retina: subcellular localization of glycine receptors, GABA(A) receptors, and the anchoring protein gephyrin.
The mechanisms by which neurotransmitter receptors are clustered at postsynaptic sites of neurons are largely unknown. The 93-kDa peripheral membrane protein gephyrin has been shown to be essential for the formation of postsynaptic glycine receptor clusters, and there is now evidence that gephyrin can also be found at gamma-aminobutyric acid (GABA)ergic synapses. In this study, we have analyzed the synaptic localization of glycine receptors, GABA(A) receptors, and the anchoring protein gephyrin in the inner plexiform layer of the developing rat retina, by using immunofluorescence with subunit specific antibodies. At early postnatal stages, the antibodies produced a diffuse staining, suggesting that early retinal neurons can express glycine and GABA(A) receptors. A clustered distribution of the subunits in "hot spots" was also observed. The number of "hot spots" increased during development and reached adult levels in about 2 weeks. Electron microscopy showed that synapses of the conventional type are present in the inner plexiform layer of the postnatal retina and that the hot spots correspond to an aggregation of receptors at postsynaptic sites. Gephyrin was also localized to "hot spots," and double immunofluorescence revealed a colocalization of gephyrin with the alpha2 subunit of the GABA(A) receptor. These results indicate that clustering of receptor subunits occurs in parallel with the formation of morphologically identifiable synaptic specializations and suggest that gephyrin may be involved in clustering of GABA(A) receptors at postsynaptic sites.
Animals↗
Stoichiometry of GABA-receptor interactions: GABA modulates the glycine-receptor interaction allosterically in a vertebrate neuron.
1. Measurement of steady-state conductance changes provides a reliable method for determination of transmitter-receptor stoichiometry in general and for GABA and its receptor interactions in particular. Log-log plotting of steady-state conductance changes as a function of decreasing transmitter concentration gives the molecularity of the interaction as a limiting slope. 2. Suitable measurements of GABA action in locust muscle show a molecularity of 3 with strong positive cooperativity. One molecule of picrotoxin is sufficient to block this reaction. Kinetic studies reveal the presence of occult desensitization. Thermodynamic studies reveal strong negative heats of interaction compatible with conformational changes in a multi-subunit receptor. 3. Measurements in the lateral dendrite of the goldfish Mauthner cell reveal that glycine has a more powerful action than GABA. Both interactions, however, utilize 4 molecules of amino acid with strong positive cooperativity to activate its receptors. The receptors are apparently distinct and there appears to be a higher glycine-receptor density. 4. In addition to its action on its own receptor, GABA allosterically modulates the glycine-receptor interaction in the Mauthner cell by lowering the energy barrier for the binding of the first glycine molecule, thereby increasing the affinity of glycine for its receptor.
Allosteric Regulation↗
Glycine receptors and GABA receptor alpha 1 and gamma 2 subunits during the development of mouse hypoglossal nucleus.
In the hypoglossal nucleus, GABA and glycine mediate inhibition at separate or mixed synapses containing glycine receptors (GlyRs) and/or GABA(A) receptors (GABA(A)Rs). The functional development of mixed inhibitory synapses depends on the brain area studied, but their relative proportion to total synapses generally decreases with time. We have determined the sequential process of inhibitory synapse maturation in the hypoglossal nucleus in vivo. Immunocytochemistry and confocal microscopy were used for codetection of VIAAT, the common presynaptic vesicular transporter of glycine and GABA, GlyRs, GABA(A)R alpha1 and gamma2 subunits, and gephyrin, the scaffold protein implicated in the synaptic localization of inhibitory receptors. In E17 embryos, GlyRs were already clustered while GABA(A)R alpha1 and gamma2 subunit immunoreactivity (IR) displayed both diffuse and clustered patterns. Quantitative analysis at this stage revealed that the majority of GlyR clusters were apposed to VIAAT-IR accumulation and that 30% of them colocalized with gamma2GABA(A)R clusters. This proportion increased with age to 50% at P30. GlyR clusters that did not colocalize with gamma2GABA(A)R clusters were associated with GABA(A)R gamma2 diffuse IR. Interestingly, the percentage of GlyR clusters surrounded by GABA(A)R gamma2 diffuse IR decreased with age, while GlyR clusters colocalized with gamma2GABA(A)R clusters increased. The developmental coclustered pattern of gephyrin and GABA(A)R alpha1 and gamma2 subunits paralleled the coclustered pattern of GlyRs and GABA(A)R alpha1 and gamma2 subunits. Our results indicate that the proportion of GlyR-GABA(A)R coclusters increases until adulthood. A developmental sequence of the postsynaptic events is proposed in which diffuse extrasynaptic GABA(A)Rs accumulate at inhibitory synapses to form postsynaptic clusters, most of them being colocalized with GlyR clusters in the adult.
Animals↗
Zn2+ differentially modulates glycine receptors versus GABA receptors in isolated carp retinal third-order neurons.
It was previously reported that strychnine-sensitive glycine receptors and GABAA receptors co-existed on carp retinal third-order neurons (amacrine/ganglion cells) (Li, P. and Yang, X.-L., Strong synergism between GABAA and glycine receptors on isolated carp third-order neurons. NeuroReport, 9 (1998) 2785-2789.). In this study, the effects of the divalent cation Zn2+ on these two receptors were studied in amacrine/ganglion cells acutely isolated from carp, with the use of the whole-cell patch clamp recording technique. The glycine-induced currents were steadily potentiated by Zn2+ of lower concentrations (0.1-10 microM), while being dose-dependently inhibited by Zn2+ of higher concentrations ( > 100 microM). Both the effects involved changes in apparent glycine affinity of the glycine receptor. In contrast, Zn2+ consistently suppressed the GABA(A) mediated currents of these cells, and did not show similar dual effect. The differential modulation by Zn2+ of glycine receptors versus GABA(A) receptors provides a versatility for regulating inhibitory glycinergic and GABAergic inputs converging on most amacrine/ganglion cells.
Animals↗
Inhibitory postsynaptic currents of rat substantia nigra pars reticulata neurons: role of GABA receptors and GABA uptake.
Whole-cell patch-clamp recordings were made from substantia nigra pars reticulata neurons in midbrain slices of young rats to study the characteristics of spontaneous and evoked inhibitory postsynaptic currents and factors which govern their decay kinetics. In the presence of the glutamate receptor antagonists D, L-2-amino-5-phosphonopentanoic acid (20 microM) and 6-cyano-7-nitroquinoxaline-2,3-dione (20 microM), bicuculline-sensitive spontaneous inward inhibitory postsynaptic currents were often observed using high Cl(-) electrodes. Application of the selective GABA(B) receptor antagonist CGP55845A (2 microM) did not alter the half decay time of these inhibitory postsynaptic currents, which however was prolonged by the potent GABA uptake blocker tiagabine (1 microM). In addition, the frequencies and amplitudes of the inhibitory postsynaptic currents were significantly reduced by tiagabine but these effects were prevented by CGP55845A. Inhibitory postsynaptic currents with similar sensitivity to bicuculline could also be evoked intranigrally. Similar to the spontaneous currents, the decay time of evoked inhibitory postsynaptic currents was not affected by 2 microM CGP55845A. However, in the absence of CGP55845A, tiagabine shortened the IPSC decay time but had an opposite effect if CGP55845A was present. These data suggest that the spontaneous and evoked inhibitory postsynaptic currents recorded from substantia nigra pars reticulata neurons are mediated mainly by GABA(A) receptors. Uptake of GABA helps to terminate these currents. When the uptake mechanism is blocked, accumulation of GABA would lead to activation of presynaptic GABA(B) receptors and reduction in GABA release. The role of postsynaptic GABA(B) receptors in substantia nigra pars reticulata of young rats seems to be minimal.
Animals↗
Molecular pharmacology of the GABA receptors and GABA agonists.
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