Showing papers on "GABAergic published in 1997"

GABAergic cell subtypes and their synaptic connections in rat frontal cortex.

Abstract: Physiological, morphological and immunohistochemical characteristics of non-pyramidal cells in frontal cortex of young rats were studied in vitro by whole-cell recording and biocytin injection. Several groups of GABAergic non-pyramidal cells were identified: (i) parvalbumin fast-spiking (FS) cells with low input resistances and spikes of short duration, including extended plexus (basket) cells and chandelier cells. These cells showed abrupt episodes of non-adapting repetitive discharges; (ii) late-spiking (LS) cells exhibiting slowly developing ramp depolarizations, including neurogliaform cells; (iii) the remaining groups contained both burst-spiking (BS) or regular-spiking (RS) non-pyramidal (NP) cells. BSNP cells exhibited bursting activity (two or more spikes on slow depolarizing humps) from hyperpolarized potentials. Both these physiological types corresponded to a range of morphologies: (i) somatostatin-containing Martinotti cells with ascending axonal arbors to layer I (some were also positive for calbindin D28k); (ii) VIP-containing double bouquet cells with descending axonal arbors as well as arcade cells (these included small cells immunoreactive for CCK or calretinin). Each subtype of cells made GABAergic synapses onto relatively specific portions of cortical cells, but similar domains were innervated by multiple classes of GABA cells.

Three distinct families of GABAergic neurons in rat visual cortex.

Abstract: In the cortex inhibition is mediated predominantly by GABAergic interneurons. Although all of these neurons use the same neurotransmitter, studies in the rat frontal cortex have shown that they are molecularly and physiologically diverse. It is not known whether similar subgroups of GABAergic neurons exist in primary visual cortex and how these different inhibitory neurons are inserted into specific cortical circuits. We have used immunostaining with antibodies against gamma aminobutyric acid (GABA), parvalbumin (PV), calretinin (CR), somatostatin (SOM), calbindin (CB) and nitric oxide synthase (NOS) to probe for colocalization of known markers of GABAergic interneurons. The results show that the majority of PV (100%), SOM (89.8%) and CR (93.9%) staining neurons are GABA positive. PV immunoreactive neurons constitute a distinct group that show no overlap with CR, SOM and NOS expressing cells and only a minor overlap (5.3%) with CB. PV immunoreactive cells account for 50.8% of GABAergic neurons. A second group of SOM expressing neurons accounts for 16.9% of GABAergic cells. None of these cells colocalize PV or CR, but 1.7% of SOM neurons stain for NOS and 86.3% show CB immunoreactivity. The third distinct group of CR expressing cells accounts for 17.0% of GABAergic neurons. All of these are PV, CB, SOM and NOS negative. CB expressing neurons represent a heterogeneous group that includes GABAergic and non-GABAergic cells. Our findings indicate that GABAergic neurons in rat area 17 are organized in at least three separate families that can be identified by the expression of PV, CR and SOM. These cells account for 84.9% of GABAergic neurons. These results extend previous observations in rat frontal agranular cortex and suggest that in visual cortex the inhibitory network is composed of similar cell types.

How opioids inhibit GABA-mediated neurotransmission

Abstract: The midbrain region periaqueductal grey (PAG) is rich in opioid receptors and endogenous opioids and is a major target of analgesic action in the central nervous system. It has been proposed that the analgesic effect of opioids on the PAG works by suppressing the inhibitory influence of the neurotransmitter GABA (gamma-aminobutyric acid) on neurons that form part of a descending antinociceptive pathway. Opioids inhibit GABA-mediated (GABAergic) synaptic transmission in the PAG and other brain regions by reducing the probability of presynaptic neurotransmitter release, but the mechanisms involved remain uncertain. Here we report that opioid inhibition of GABAergic synaptic currents in the PAG is controlled by a presynaptic voltage-dependent potassium conductance. Opioid receptors of the mu type in GABAergic presynaptic terminals are specifically coupled to this potassium conductance by a pathway involving phospholipase A2, arachidonic acid and 12-lipoxygenase. Furthermore, opioid inhibition of GABAergic synaptic transmission is potentiated by inhibitors of the enzymes cyclooxygenase and 5-lipoxygenase, presumably because more arachidonic acid is available for conversion to 12-lipoxygenase products. These mechanisms account for the analgesic action of cyclooxygenase inhibitors in the PAG and their synergism with opioids.

Brain-Derived Neurotrophic Factor Mediates the Activity-Dependent Regulation of Inhibition in Neocortical Cultures

Abstract: The excitability of cortical circuits is modulated by interneurons that release the inhibitory neurotransmitter GABA. In primate and rodent visual cortex, activity deprivation leads to a decrease in the expression of GABA. This suggests that activity is able to adjust the strength of cortical inhibition, but this has not been demonstrated directly. In addition, the nature of the signal linking activity to GABA expression has not been determined. Activity is known to regulate the expression of the neurotrophin brain-derived neurotrophic factor (BDNF), and BDNF has been shown to influence the phenotype of GABAergic interneurons. We use a culture system from postnatal rat visual cortex to test the hypothesis that activity is regulating the strength of cortical inhibition through the regulation of BDNF. Cultures were double-labeled against GABA and the neuronal marker MAP2, and the percentage of neurons that were GABA-positive was determined. Blocking spontaneous activity in these cultures reversibly decreased the number of GABA-positive neurons without affecting neuronal survival. Voltage-clamp analysis of inhibitory currents demonstrated that activity blockade also decreased GABA-mediated inhibition onto pyramidal neurons and raised pyramidal neuron firing rates. All of these effects were prevented by incubation with BDNF during activity blockade, but not by neurotrophin 3 or nerve growth factor. Additionally, blockade of neurotrophin signaling mimicked the effects of activity blockade on GABA expression. These data suggest that activity regulates cortical inhibition through a BDNF-dependent mechanism and that this neurotrophin plays an important role in the control of cortical excitability.

The Cortical Dopamine System: Role in Memory and Cognition

Abstract: Publisher Summary There are three distinct possible cellular mechanisms that have so far been identified for dopamine modulation of working memory function in the prefrontal cortex. These are: direct synaptic modulation of receptors on the distal dendrites and spines of pyramidal neurons, direct nonsynaptic modulation of pyramidal neurons, and indirect synaptic modulation of pyramidal neurons via feedforward inhibition from GABAergic interneurons. As the majority of the dopamine synapses appear to be formed on pyramidal neurons, dopamine axons are thus placed in direct contact with the major projection neurons of the prefrontal cortex. Nonsynaptic neurotransmission may be the more pervasive means of altering pyramidal cell activity, because numerous dopamine varicosities are observed in nonsynaptic relationship to cortical elements. Members of the D1 family of dopamine receptors have been found to be particularly prominent in the prefrontal cortex of primates, and both D1 and D5 receptor proteins have been localized to the distal dendrites and spines of pyramidal cells. A third mechanism of dopamine action is indirect, appearing to involve feedforward inhibition on pyramidal neurons from nonpyramidal neurons. The indirect action of dopamine on this circuit derives from the identification of dopamine synapses on nonpyramidal GABAergic neurons in the prefrontal cortex and the finding that the D4 member of the D2 family of dopamine receptors is localized postsynaptically on a subset of GABA interneurons. These findings provide suggestive evidence that feedforward inhibition may play a role in the construction of a memory field in prefrontal neurons. The different effects of dopamine may depend on the subtype of interneuron engaged, and future studies may indicate the basis for the differential modulation of interneurons by dopamine.

The 5-HT3 receptor is present in different subpopulations of GABAergic neurons in the rat telencephalon.

Abstract: The type 3 serotonin receptor (5-HT3R) is a ligand-gated ion channel whose presence in the CNS has been established by radioligand binding, in situ hybridization, and immunohistochemical analysis. To analyze further the role of the 5-HT3R in the CNS, we used in situ hybridization and immunocytochemistry to determine that 5-HT3R-expressing neurons are mainly GABA-containing cells in the rat telencephalon. We determined that 5-HT3R/GABA-containing neurons do not exhibit somatostatin immunoreactivity but often contain cholecystokinin (CCK) immunoreactivity. 5-HT3R-expressing cells with CCK immunoreactivity were observed in the neocortex, olfactory cortex, hippocampus, and amygdala. The 5-HT3R/CCK interneurons represent between 35 and 66% of the total population of CCK-containing cells in the neocortex. Further characterization of the 5-HT3R/GABAergic neurons was based on their calcium-binding protein immunoreactivity and showed that these neurons lack parvalbumin (PV) and represent a subpopulation of calbindin (CB)-containing interneurons that were preferentially present in the CA1-CA3 subfield of the hippocampus. Although some 5-HT3R/GABAergic neurons with calretinin (CR) were found in the neocortex, olfactory cortex, hippocampus, and amygdala, these neurons were more often present in the agranular insular and piriform cortices. We conclude that the neuronal expression of the 5-HT3R is selective within the GABA neuron population in the rat telencephalon. These 5-HT3R-expressing interneurons might contain CCK, CB, and CR. We suggest that serotonin through the 5-HT3R may regulate GABA and CCK neurotransmission in the telencephalon.

GABA in the mammalian suprachiasmatic nucleus and its role in diurnal rhythmicity

Abstract: Mammals manifest circadian behaviour timed by an endogenous clock in the hypothalamic suprachiasmatic nucleus (SCN). Considerable progress has been made in identifying the molecular basis of the circadian clock, but the mechanisms by which it is translated into cyclic firing activity, high during the day and low at night, are still poorly understood. GABA (gamma-aminobutyric acid), a common inhibitory neurotransmitter in the central nervous system, is particularly densely distributed within the SCN, where it is located in the majority of neuronal somata and synaptic terminals. Using an in vitro brain-slice technique, we have now studied the effect of bath-applied GABA on adult SCN neurons at various times of the day. We find that GABA acts as an inhibitory neurotransmitter at night, decreasing the firing frequency; but during the day GABA acts as an excitatory neurotransmitter, increasing the firing frequency. We show that this dual effect, which is mediated by GABA(A) receptors, may be attributed to an oscillation in intracellular chloride concentration. A likely explanation is that the amplitude of the oscillation in firing rate, displayed by individual neurons, is amplified by the dual effect of GABA in the SCN's GABAergic network.

Neuronal nicotinic acetylcholine receptor activation modulates gamma -aminobutyric acid release from ca1 neurons of rat hippocampal slices

Abstract: In the present study we investigated electrophysiologically the nicotinic responses of pyramidal neurons and interneurons visualized by infrared-assisted videomicroscopy and fluorescence in the CA1 field of hippocampal slices obtained from 8- to 24-day-old rats. Application of nicotinic agonists to CA1 neurons evoked at least four types of nicotinic responses. Of major interest was the ability of these agonists to induce the release of gamma-aminobutyric acid (GABA) from interneurons. Slowly decaying ACh whole-cell currents and GABA-mediated postsynaptic currents could be recorded from pyramidal neurons and interneurons, whereas fast-decaying nicotinic currents and fast current transients were recorded only from interneurons. Nicotinic responses were sensitive to blockade by d-tubocurarine (10 microM), which indicated that they were mediated by nicotinic acetylcholine receptors (nAChRs). The slowly decaying currents, the postsynaptic currents and the fast current transients were insensitive to blockade by the alpha-7 nAChR-specific antagonist methyllycaconitine (up to 1 microM) or alpha-bungarotoxin (100 nM). On the other hand, the slowly decaying nicotinic currents recorded from the interneurons were blocked by the alpha4beta2 nAChR-specific antagonist dihydro-beta-erythroidine, and the fast-desensitizing nicotinic currents were evoked by the alpha-7 nAChR-specific agonist choline. In experimental conditions similar to those used to record nicotinic responses from neurons in slice (i. e., in the absence of tetrodotoxin), we observed that nicotinic agonists can also induce the release of GABA from hippocampal neurons in culture. In summary, these results provide direct evidence for more than one subtype of functional nAChR in CA1 neurons and suggest that activation of nAChRs present in GABAergic interneurons can evoke inhibitory activity in CA1 pyramidal neurons, thereby modulating processing of information in the hippocampus.

Functional dynamics of GABAergic inhibition in the thalamus

Abstract: The inhibitory gamma-aminobutyric acid-containing (GABAergic) neurons of the thalamic reticular and perigeniculate nuclei are involved in the generation of normal and abnormal synchronized activity in thalamocortical networks. An important factor controlling the generation of activity in this system is the amplitude and duration of inhibitory postsynaptic potentials (IPSPs) in thalamocortical cells, which depend on the pattern of activity generated in thalamic reticular and perigeniculate cells. Activation of single ferret perigeniculate neurons generated three distinct patterns of GABAergic IPSPs in thalamocortical neurons of the dorsal lateral geniculate nucleus: Low-frequency tonic discharge resulted in small-amplitude IPSPs mediated by GABAA receptors, burst firing resulted in large-amplitude GABAA IPSPs, and prolonged burst firing activated IPSPs mediated by GABAA and GABAB receptors. These functional properties of GABAergic inhibition can reconfigure the operations of thalamocortical networks into patterns of activity associated with waking, slow-wave sleep, and generalized seizures.

Spinal cord stimulation attenuates augmented dorsal horn release of excitatory amino acids in mononeuropathy via a GABAergic mechanism

Abstract: Neuropathic pain may be effectively relieved by electric stimulation of the spinal cord (SCS). However, the underlying mechanisms for the ensuing pain relief are poorly understood. In a rat model of neuropathy displaying hypersensitivity to innocuous tactile stimuli, (allodynia), we have earlier demonstrated that SCS may normalise withdrawal response thresholds. In the present study, using microdialysis, it is shown that SCS induces a decreased release of the dorsal horn excitatory amino acids (EAA), glutamate and aspartate, concomitant with an increase of the GABA release. Local perfusion with a GABA(B)-receptor antagonist in the dorsal horn transiently abolishes the SCS-induced suppression of the EAA release. Thus, the effect of SCS on neuropathic pain and allodynia may be due to an activation of local GABAergic mechanisms inhibiting the EAA release which is chronically elevated in such conditions.

GABAergic and other noncholinergic basal forebrain neurons, together with cholinergic neurons, project to the mesocortex and isocortex in the rat

Abstract: The extrathalamic relay from the brainstem reticular formation to the cerebral cortex in the basal forebrain has been thought to be constituted predominantly, if not exclusively, by cholinergic neurons. In contrast, the septohippocampal projection has been shown to contain an important contingent of gamma-aminobutyric acid (GABA)ergic neurons. In the present study, we investigated whether GABAergic neurons also contribute to the projection from the basal forebrain to neocortical regions, including the mesocortex (limbic) and the isocortex in the rat. For this purpose, retrograde transport of cholera toxin (CT) was examined from the medial prefrontal cortex for the mesocortex and from the parietal cortex for the isocortex and was combined with dual-immunohistochemical staining for either choline acetyltransferase (ChAT) or glutamic acid decarboxylase (GAD) in adjacent series of sections. Retrogradely labelled GAD+ neurons were codistributed with retrogradely labelled ChAT+ neurons through the basal forebrain from both the prefrontal and the parietal cortex, suggesting parallel, widespread cortical projections. The GAD+ cortically projecting cells were similar in size to the ChAT+ cells, thereby indicating that they comprise a contingent of the magnocellular basal cell complex. The proportions of retrogradely labelled neurons that were GAD+ (approximately one-third) were equal to or greater than those that were ChAT+ from both the prefrontal cortex and the parietal cortex. In addition, the total of GAD+ and ChAT+ neurons did not account for the total number of cortically projecting cells, indicating that another equivalent proportion of chemically unidentified noncholinergic neurons also contributes to the basalocortical projection. Accordingly, as in the allocortex, GABAergic, cholinergic, and other unidentified noncholinergic neurons may have the capacity to modulate activity in the mesocortex (limbic) and the isocortex through parallel, widespread projections.

Fast IPSPs elicited via multiple synaptic release sites by different types of GABAergic neurone in the cat visual cortex.

Abstract: 1. The effects of synapses established by smooth dendritic neurones on pyramidal and spiny stellate cells were studied in areas 17 and 18 of the cat visual cortex in vitro. Paired intracellular recordings with biocytin-filled electrodes and subsequent light and electron microscopic analysis were used to determine the sites of synaptic interaction. 2. All smooth dendritic cells established type II synapses previously shown to be made by terminals containing GABA, therefore the studied cells are probably GABAergic. Three classes of presynaptic cell could be defined, based on their efferent synaptic target preference determined from random samples of unlabelled postsynaptic cells. (a) Basket cells (n = 6) innervated mainly somata (49.9 +/- 13.8%) and dendritic shafts (45.2 +/- 10.7%) and, to a lesser extent, dendritic spines (4.9 +/- 4.6%). (b) Dendrite-targeting cells (n = 5) established synapses predominantly on dendritic shafts (84.3 +/- 9.4%) and less frequently on dendritic spines (11.2 +/- 6.7%) or somata (4.5 +/- 4.7%). (c) Double bouquet cells (n = 4) preferred dendritic spines (69.2 +/- 4.2%) to dendritic shafts (30.8 +/- 4.2%) as postsynaptic targets and avoided somata. 3. Interneurones formed 5240 +/- 1600 (range, 2830-9690) synaptic junctions in the slices. Based on the density of synapses made by single interneurones and the volume density of GABAergic synapses, it was calculated that an average interneurone provides 0.66 +/- 0.20% of the GABAergic synapses in its axonal field. 4. The location of synaptic junctions on individual, identified postsynaptic cells reflected the overall postsynaptic target distribution of the same GABAergic neurone. The number of synaptic junctions between pairs of neurones could not be predicted from light microscopic examination. The number of electron microscopically verified synaptic sites was generally smaller for the dendritic domain and larger for the somatic domain than expected from light microscopy. All presynaptic cells established multiple synaptic junctions on their postsynaptic target cells. A basket cell innervated a pyramidal cell via fifteen release sites; the numbers of synapses formed by three dendrite-targeting cells on pyramidal cells were seventeen and eight respectively, and three on a spiny stellate cell; the interaction between a double bouquet cell and a postsynaptic pyramidal cell was mediated by ten synaptic junctions. 5. All three types of interneurone (n = 6; 2 for each type of cell) elicited short-latency IPSPs with fast rise time (10-90%; 2.59 +/- 1.02 ms) and short duration (at half-amplitude, 15.82 +/- 5.24 ms), similar to those mediated by GABAA receptors. 6. Average amplitudes of unitary IPSPs (n = 6) were 845 +/- 796 microV (range, 134-2265 microV). Variability of IPSP amplitude was moderate, the average ratio of IPSP and baseline noise variance was 1.54 +/- 0.96. High frequency activation of single presynaptic dendrite-targeting cells led to an initial summation followed by use-dependent depression of the averaged postsynaptic response. Double bouquet cell-evoked IPSPs, recorded in the soma, had a smaller amplitude than those evoked by the other two cell types. In all connections, transmission failures were rare or absent, particularly when mediated by a high number of release sites. 7. The results demonstrate that different types of neocortical GABAergic neurones innervate distinct domains on the surface of their postsynaptic target cells. Nevertheless, all three types of cell studied here elicit fast IPSPs and provide GABAergic input through multiple synaptic release sites with few, if any, failures of transmission.

Dopaminergic Neurons Intrinsic to the Primate Striatum

Abstract: Intrinsic, striatal tyrosine hydroxylase-immunoreactive (TH-i) cells have received little consideration. In this study we have characterized these neurons and their regulatory response to nigrostriatal dopaminergic deafferentation. TH-i cells were observed in the striatum of both control and 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-treated monkeys; TH-i cell counts, however, were 3.5-fold higher in the striatum of MPTP-lesioned monkeys. To establish the dopaminergic nature of the TH-i cells, sections were double-labeled with antibodies to dopamine transporter (DAT). Immunofluorescence studies demonstrated that nearly all TH-i cells were double-labeled with DAT, suggesting that they contain the machinery to be functional dopaminergic neurons. Two types of TH-i cells were identified in the striatum: small, aspiny, bipolar cells with varicose dendrites and larger spiny, multipolar cells. The aspiny cells, which were more prevalent, corresponded morphologically to the GABAergic interneurons of the striatum. Double-label immunofluorescence studies using antibodies to TH and glutamate decarboxylase (GAD67), the synthetic enzyme for GABA, showed that 99% of the TH-i cells were GAD67-positive. Very few (

Dopaminergic neurons intrinsic to the primate striatum

Abstract: Intrinsic, striatal tyrosine hydroxylase-immunoreactive (TH-i) cells have received little consideration. In this study we have characterized these neurons and their regulatory response to nigrostriatal dopaminergic deafferentation. TH-i cells were observed in the striatum of both control and 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-treated monkeys; TH-i cell counts, however, were 3.5-fold higher in the striatum of MPTP-lesioned monkeys. To establish the dopaminergic nature of the TH-i cells, sections were double-labeled with antibodies to dopamine transporter (DAT). Immunofluorescence studies demonstrated that nearly all TH-i cells were double-labeled with DAT, suggesting that they contain the machinery to be functional dopaminergic neurons. Two types of TH-i cells were identified in the striatum: small, aspiny, bipolar cells with varicose dendrites and larger spiny, multipolar cells. The aspiny cells, which were more prevalent, corresponded morphologically to the GABAergic interneurons of the striatum. Double-label immunofluorescence studies using antibodies to TH and glutamate decarboxylase (GAD67), the synthetic enzyme for GABA, showed that 99% of the TH-i cells were GAD67-positive. Very few (

Role of Ca2+ ions in nicotinic facilitation of GABA release in mouse thalamus.

Abstract: Presynaptic nicotinic acetylcholine receptors (nAChRs) are present in many regions of the brain and potentially serve as targets for the pharmacological action of nicotine in vivo To investigate their mechanism of action, we performed patch-clamp recordings in relay neurons from slices of thalamus sensory nuclei In these nuclei, nAChR activation facilitated the release of the inhibitory neurotransmitter GABA Micromolar concentrations of nicotinic agonists increased the frequency of miniature GABAergic synaptic currents and decreased the failure rate of evoked synaptic currents These actions of nicotinic agonists were not observed in knock-out mice lacking the beta 2 nAChR subunit gene Nicotinic effects were dependent on extracellular calcium ions, and they persisted when calcium was replaced by strontium or barium but not by magnesium Furthermore, in high extracellular calcium concentrations, nicotinic agonists evoked an increase in spontaneous release lasting for minutes after removal of the agonist This supports the view that presynaptic nAChRs facilitate the release of neurotransmitter by increasing the calcium concentrations in presynaptic nerve endings With use of cadmium and nickel ions as selective blockers, it was found that in different sensory nuclei the presynaptic influx of calcium could result either from the activation of voltage-dependent calcium channels or from a direct influx through nAChR channels Finally, we propose that the nicotinic facilitation of GABAergic transmission may contribute to the increase of signal-to-noise ratio observed in the thalamus in vivo during arousal

Selective cholinergic modulation of cortical GABAergic cell subtypes.

Abstract: Kawaguchi, Yasuo. Selective cholinergic modulation of cortical GABAergic cell subtypes. J. Neurophysiol. 78: 1743–1747, 1997. Acetylcholine from the basal forebrain and γ-aminobutyric acid (GABA) f...

A monosynaptic gabaergic input from the inferior colliculus to the medial geniculate body in rat

Abstract: The goal was to investigate possible monosynaptic GABAergic projections from the inferior colliculus (IC) to thalamocortical neurons of the medial geniculate body (MGB) in the rat. Although there is little evidence for such a projection in other sensory thalamic nuclei, a GABAergic, ascending auditory projection was reported recently in the cat. In the present study, immunohistochemical and tract-tracing methods were used to identify neurons in the IC that contain GABA and project to the MGB. GABA-positive projection neurons were most numerous in the central nucleus and less so in the dorsal and lateral cortex. They were rare in the lateral tegmental system and brachium of the IC. The dorsal nucleus of the lateral lemniscus also contained GABA-positive projection neurons. In brain slices, stimulation of the brachium produced monosynaptic inhibitory postsynaptic potentials in morphologically identified thalamocortical relay neurons. The inhibitory potentials cannot originate locally, because they persisted when ionotropic glutamatergic transmission was blocked. Typically, brachium stimulation elicited a GABAA-mediated inhibitory potential followed by an excitatory potential and a longer latency GABAB-mediated inhibitory potential. We conclude that the GABA-containing neurons of the IC make short-latency, monosynaptic inputs to the thalamocortical projection neurons in the MGB. Such inputs may distinguish the main auditory pathway from indirect or tegmental auditory pathways as well as from other sensory systems. Monosynaptic inhibitory inputs to the medial geniculate may be important for the regulation of firing patterns in thalamocortical neurons.

The effects of inhibitors of GABAergic transmission and stress on brain and plasma allopregnanolone concentrations

Abstract: 1. This study was undertaken to investigate the relationship between a reduction in brain GABAA receptor function and the cerebro-cortical content of 3 alpha-hydroxy-5 alpha-pregnan-20 one (allopregnanolone, AP), a potent endogenous positive modulator of 7-aminobutyric acid (GABA) action at GABAA receptors, with anticonflict and anticonvulsant effects in rodents. 2. An acute depletion of the cerebral content of GABA or an attenuation of GABAA receptor-mediated transmission by systemic injections of isoniazid (375 mg kg-1, s.c.) or FG 7142 (15 mg kg-1, i.p.) induced a transient increase in the cerebro-cortical and plasma concentrations of AP in handling-habituated (not stressed) rats. 3. Two stress paradigms, handling in naive rats and mild foot shock in handling-habituated rats, that reduce central GABAergic tone mimicked the effects of isoniazid and FG 7142 on cortical AP content; foot shock in handling-habituated rats, but not handling in naive animals, also increased plasma AP. Isoniazid, FG 7142, and foot shock also each increased the concentrations of the AP precursors, pregnenolone and progesterone, in both brain and plasma of handling-habituated rats, whereas handling in naive rats increased the concentrations of these steroids only in brain. 4. Pretreatment of handling-habituated rats with the anxiolytic beta-carboline derivative abecarnil, a positive allosteric modulator of GABAA receptors, which per se failed to affect the AP concentration in brain or plasma, prevented the increase in brain and plasma AP induced by foot shock or isoniazid. 5. In adrenalectomized and castrated rats foot shock or isoniazid failed to increase AP both in brain cortex and plasma. 6. These observations indicate that inhibition of GABAergic transmission, induced by foot shock or pharmacological manipulations, results in an increase in the concentrations of AP in brain and plasma, possibly via a modulation of hypothalamic-pituitary-adrenal (HPA) axis. 7. Given that AP enhances GABAA receptor function with high efficacy and potency, an increase in brain AP concentration may be important in the fine tuning of the GABA-mediated inhibitory transmission in the central nervous system.

Nitric oxide regulates NMDA-driven GABAergic inputs to type I neurones of the rat paraventricular nucleus.

Abstract: 1. Whole-cell recordings were obtained from type I paraventricular nucleus (PVN) neurones in coronal slices of rat hypothalamus to study the involvement of nitric oxide (NO) in the modulation of inhibitory transmission resulting from the activation of N-methyl-D-aspartate (NMDA) receptors by the high affinity receptor agonist D,L-tetrazol-5-ylglycine. 2. A brief pulse of NMDA agonist (0.1-10 microM) faithfully elicited increases in action potential firing frequency in all type I cells tested (n = 55). In cells with membrane potentials positive to -75 mV, this excitation was accompanied by an underlying depolarization (> 2 mV) in the majority of cases (n = 45). At membrane potentials negative to -75 mV, NMDA agonist application elicited an initial monotonie depolarization, which was auxiliary to profound, rhythmic oscillations of the membrane potential, resulting in the emergence of burst-like activity in these cells (n = 8). 3. In addition to depolarizing the neurones, the NMDA agonist also elicited inhibitory postsynaptic potentials (IPSPs) in 40% (n = 22) of the cells tested. The IPSPs were inhibited by the GABAA receptor antagonist bicuculline methiodide (BMI). 4. Microdialysis of NO into the PVN has been shown to increase local levels of inhibitory neurotransmitters, including GABA. The possibility that NO-induced increases in GABA lead to an increase in inhibitory synaptic activity in PVN was investigated by administering NO by three different methods. Bath application of the donor compound, S-nitroso-N-acetyl-penicillamine (SNAP; n = 7), bubbled NO solution (n = 5), or the NO precursor L-arginine (n = 6) all elicited increases in IPSP frequency. 5. Production of NO in other brain centres has been linked to the activation of the NMDA receptor. In order to determine whether the increase in IPSPs following NMDA was the result of activation of NO, the production of NO was blocked with the NO synthase inhibitor N omega-nitro-L-arginine methylester (L-NAME). Subsequent NMDA receptor activation elicited more pronounced depolarizations, but there was no accompanying increase in IPSP frequency (n = 5). 6. This study demonstrates that GABAergic inhibition resulting from NMDA receptor activation can be regulated profoundly by NO. By increasing inhibitory transmission within a nucleus, NO may serve as an important intermediary in the regulation of neuronal excitability in the central nervous system.

A Pacemaker Current in Dye-Coupled Hilar Interneurons Contributes to the Generation of Giant GABAergic Potentials in Developing Hippocampus

Abstract: The establishment of synaptic connections and their refinement during development require neural activity. Increasing evidence suggests that spontaneous bursts of neural activity within an immature network are mediated by γ-aminobutyric acid via a paradoxical excitatory action. Our data show that in the developing hippocampus such synchronous burst activity is generated in the hilar region by transiently coupled cells. These cells have been identified as neuronal elements because they fire action potentials and they are not positive for the glial fibrillary acidic protein staining. Oscillations in hilar cells are “paced” by a hyperpolarization-activated current, with properties of I h. Coactivated interneurons synchronously release GABA, which via its excitatory action may serve a neurotrophic function during the refinement of hippocampal circuitry.