Showing papers on "GABAergic published in 1991"

Interplay between glutamate and gamma-aminobutyric acid transmitter systems in the physiological regulation of brain-derived neurotrophic factor and nerve growth factor synthesis in hippocampal neurons.

Abstract: In the central nervous system brain-derived neurotrophic factor (BDNF) and nerve growth factor (NGF) are predominantly located in neurons. Here we demonstrate that the balance between the activity of the glutamatergic and gamma-aminobutyric acid (GABA)ergic systems controls the physiological levels of BDNF and NGF mRNAs in hippocampal neurons in vitro and in vivo. The blockade of the glutamate receptors and/or stimulation of the GABAergic system reduces BDNF and NGF mRNAs in hippocampus and NGF protein in hippocampus and septum. The reduction of NGF in the septum reflects the diminished availability of NGF in the projection field of NGF-dependent septal cholinergic neurons. These neurons do not synthesize NGF themselves but accumulate it by retrograde axonal transport. The refined and rapid regulation of BDNF and NGF synthesis by the glutamate and GABA transmitter systems suggests that BDNF and NGF might be involved in activity-dependent synaptic plasticity.

Excitatory synaptic responses mediated by GABAA receptors in the hippocampus.

Abstract: Gamma-aminobutyric acid (GABA) is a major inhibitory neurotransmitter in the cortex. Activation of postsynaptic GABAA receptors hyperpolarizes cells and inhibits neuronal activity. Synaptic responses mediated by GABAA receptors also strongly excited hippocampal neurons. This excitatory response was recorded in morphologically identified interneurons in the presence of 4-aminopyridine or after elevation of extracellular potassium concentrations. The synaptic excitation sustained by GABAA receptors synchronized the activity of inhibitory interneurons. This synchronized discharge of interneurons in turn elicited large-amplitude inhibitory postsynaptic potentials in pyramidal and granule cells. Excitatory synaptic responses mediated by GABAA receptors may thus provide a mechanism for the recruitment of GABAergic interneurons through their recurrent connections.

Synchronized overproduction of neurotransmitter receptors in diverse regions of the primate cerebral cortex.

Abstract: A remarkable diversity of neurotransmitter receptors develops concurrently in disparate areas of the primate cerebral cortex. The density of dopaminergic, adrenergic, serotonergic, cholinergic, and GABAergic receptors (where GABA is gamma-aminobutyric acid) in rhesus monkey reaches a maximum level between 2 and 4 months of age and then declines gradually to adult levels in all layers of sensory, motor, and association regions. The synchronized development of neurotransmitter receptors in diverse layers and regions of the neocortex occurs pari passu with synaptogenesis, demonstrating unusual coordination of biochemical and structural maturation and supporting the hypothesis that the entire cerebral cortex matures as an integrated network, rather than as a system-by-system cascade.

Ciliary neurotrophic factor enhances neuronal survival in embryonic rat hippocampal cultures.

Abstract: First described as a survival factor for chick ciliary ganglion neurons, ciliary neurotrophic factor (CNTF) has recently been shown to promote survival of chick embryo motor neurons. We now report neurotrophic effects of CNTF toward three populations of rat hippocampal neurons, the first demonstration of effects of CNTF upon rodent CNS neurons in culture. CNTF elicited an increase in the neurofilament content of hippocampal cultures prepared from embryonic day 18 (E18) rat brain. This was accompanied by increases of 2-, 28-, and 3-fold in the number of GABAergic, cholinergic, and calbindin- immunopositive cells, respectively. CNTF totally prevented the 67% loss of GABAergic neurons that occurred in control cultures over 8 d. CNTF also increased high-affinity GABA uptake and glutamic acid decarboxylase activity. Effects of CNTF were in all cases dose dependent, with maximal stimulation at approximately 100 pg/ml. When addition was delayed for 3 d, CNTF failed to elicit increases either in the number of cholinergic neurons or in GABA uptake.

The GABAergic cerebello-olivary projection in the rat

Abstract: Immunocytochemical detection of glutamate decarboxylase (GAD), the predominant biosynthetic enzyme of gamma-aminobutyric acid (GABA), reveals the presence of a dense GABAergic innervation in all parts of the inferior olive. One brain center that provides a substantial projection to the inferior olive is the cerebellar nuclei, which contain many small GABAergic neurons. These neurons were tested as a source of GABAergic olivary afferents by combining retrograde tract tracing with GAD immunocytochemistry. As expected from previous studies, injections of wheat germ agglutinin-conjugated horseradish peroxidase (WGA-HRP) into the inferior olive retrogradely label many small neurons in the interposed and lateral cerebellar nuclei and the dorsal part of the lateral vestibular nucleus, and fewer neurons in the ventro-lateral region of the medial cerebellar nucleus. These projections are predominantly crossed and are topographically arranged. The vast majority, if not all, of these projection neurons are also GAD-positive. The relative contribution of this projection to the GABAergic innervation of the inferior olive was tested by lesion of the cerebellar nuclei, or the superior cerebellar peduncle. Within 10 days the lesion eliminates most GAD-immunoreactive boutons in the principal olive, the rostral lamella of the medial accessory olive, the ventrolateral outgrowth, and the lateral part of the dorsal accessory olive ventral fold. Thus, the effectiveness of this depletion demonstrates that the cerebellar nuclei provide most of the GABAergic innervation to regions of the inferior olive known to receive a cerebellar projection. Moreover, when the lateral vestibular nucleus is damaged, the dorsal fold of the dorsal accessory olive is depleted of GABAergic boutons. The synaptic relations that boutons of the GABAergic cerebello-olivary projection share with olivary neurons were investigated at the electron microscopic level by GAD-immunocytochemistry, anterograde degeneration of the cerebellar axons or anterograde transport of WGA-HRP. All of these methods confirm that GABAergic, cerebello-olivary axon terminals contain pleomorphic vesicles, and synapse on various portions of olivary neurons, and especially on dendritic spines within glomeruli, often in very close proximity to the gap junctions that characteristically couple the dendritic profiles. These results demonstrate four major points: that virtually all of the GABAergic, and presumably inhibitory, neurons of the cerebellar and dorsal lateral vestibular nuclei are projection neurons; that a large portion of the inferior olive receives GABAergic afferents from the cerebellar nuclei; that a portion of the dorsal accessory olive receives GABAergic afferents from the dorsal lateral vestibular nucleus; and that cerebello-olivary fibers often synapse near gap junctions, and therefore could influence electrical coupling of olivary neurons.

Structural and Functional Considerations of GABA in Islets of Langerhans: β-Cells and Nerves

Abstract: gamma-Aminobutyric acid (GABA), a prominent inhibitory neurotransmitter, is present in high concentrations in beta-cells of islets of Langerhans. The GABA shunt enzymes, glutamate decarboxylase (GAD) and GABA transaminase (GABA-T), have also been localized in islet beta-cells. With the recent demonstration that the 64,000-M, antigen associated with insulin-dependent diabetes mellitus is GAD, there is increased interest in understanding the role of GABA in islet function. Only a small component of beta-cell GABA is contained in insulin secretory granules, making it unlikely that GABA, coreleased with insulin, is physiologically significant. Our immunohistochemical study of GABA in beta-cells of intact islets indicates that GABA is associated with a vesicular compartment distinctly different from insulin secretory granules. Whether this compartment represents a releasable pool of GABA has yet to be determined. GAD in beta-cells is associated with a vesicular compartment, similar to the GABA vesicles. In addition, GAD is found in a unique extensive tubular cisternal complex (GAD complex). It is likely that the GABA-GAD vesicles are derived from this GAD-containing complex. Physiological studies on the effect of extracellular GABA on islet hormonal secretion have had variable results. Effects of GABA on insulin, glucagon, and somatostatin secretion have been proposed. The most compelling evidence for GABA regulation of islet hormone secretion comes from studies on somatostatin secretion, where it has an inhibitory effect. We present new evidence demonstrating the presence of GABAergic nerve cell bodies at the periphery of islets with numerous GABA-containing processes extending into the islet mantle. This close association between GABAergic neurons and islet alpha- and delta-cells strongly suggests that GABA inhibition of somatostatin and glucagon secretion is mediated by these neurons. Intracellular beta-cell GABAA and its metabolism may have a role in beta-cell function. New evidence indicates that GABA shunt activity is involved in regulation of insulin secretion. In addition, GABA or its metabolites may regulate proinsulin synthesis. These new observations provide insight into the complex nature of GABAergic neurons and beta-cell GABA in regulation of islet function.

A quantitative study of synaptic contacts on interneurons and relay cells of the cat lateral geniculate nucleus.

Abstract: The relative proportions of synapses made by retinal and extraretinal terminals on interneurons and relay cells in lamina A of the dorsal lateral geniculate nucleus (LGN) of the cat were estimated quantitatively in a sample of 4003 synapses. Processes of interneurons or relay cells were identified by presence or absence of GABA immunoreactivity, respectively, in thin sections treated with post-embedding anti-GABA immunogold. On the basis of ultrastructural features, synaptic terminals were interpreted as belonging to retinal axons, cortical axons or axon collaterals of relay cells. GABAergic terminals were positively identified by being immunoreactive. GABA(-) terminals with heterogeneous and poorly defined characteristics, which could not be identified in the above classes, were grouped together in an “undetermined” category. Among the total synaptic inputs to interneurons, the following relative percentages of synapses from different terminals were obtained: retinal 25%, cortical 37%, GABAergic 26%, axon collaterals 2%, undetermined 6%. The vast majority of retinal terminals synapse on dendritic appendages of interneurons rather than on their dendritic trunks (about 20∶1). By contrast, the majority of cortical terminals synapse on dendrites rather than on dendritic appendages (about 5∶1). Virtually all axon-collaterals synapses were established on dendritic appendages. 17% of the dendritic profiles of interneurons contain synaptic vesicles; many of these profiles were seen in postsynaptic relation to cortical axons and in presynaptic relation with relay dendrites. Given the extensive electrotonic lengths of these cells observed by others, and the expected high electric resistance of the slender stalks that are known to connect the dendritic appendages to interneurons, these results suggest that microcircuits involving the interneuronal dendritic appendages with dendrites of relay cells are under predominantly retinal control. The microcircuits established by presynaptic dendritic trunks with relay dendrites, are under predominantly cortical control. The axonal (spiking) output of interneurons would be under control of the few retinal synapses on proximal dendrites of these cells. Among the total synaptic inputs to relay cells, the following relative percentages of different synapses were obtained: retinal 12%, cortical 58%, GABAergic 24%, axon collaterals 0.3%, undetermined 5%. Relay cells receive twice the number of cortical synapses than interneurons, suggesting that direct cortical excitatory influences on relay cells are more preponderant than cortico-interneuron mediated inhibition on these cells. The observed proportions of dendritic profiles of relay cells and interneurons (80% and 20%, respectively) in the geniculate neuropil are similar to the known proportions of somata of both types of cells in the A-laminae. This suggests a similarity in the average dendritic branching of relay cells and interneurons.

GABAergic interneurons containing calbindin D28K or somatostatin are major targets of GABAergic basal forebrain afferents in the rat neocortex

Abstract: The arborization pattern and postsynaptic targets of the GABAergic component of the basal forebrain projection to neo- and mesocortical areas have been studied by the combination of anterograde tracing and pre- and postembedding immunocytochemistry. Phaseolus vulgaris leucoagglutinin (PHAL) was iontophoretically delivered into the region of the diagonal band of Broca, with some spread of the tracer into the substantia innominata and ventral pallidum. A large number of anterogradely labelled varicose fibres were visualized in the cingulate and retrosplenial cortices, and a relatively sparse innervation was observed in frontal and occipital cortical areas. Most of the labelled axons were studded with large en passant varicosities (Type 1), whereas the others (Type 2) had smaller boutons often of the drumstick type. Type 1 axons were distributed in all layers of the mesocortex with slightly lower frequency in layers 1 and 4. In the neocortex, layer 4, and to a smaller extent upper layer 5 and layer 6 contained the largest number of labelled fibres, whereas only a few fibres were seen in the supragranular layers. Characteristic type 2 axons were very sparse but could be found in all layers. Most if not all boutons of PHAL-labelled type 1 axons were shown to be GABA-immunoreactive by immunogold staining for GABA, Altogether 73 boutons were serially sectioned and found to make symmetrical synaptic contacts mostly with dendritic shafts (66, 90% of total targets), cell bodies (6, 8.2% of total), and with one spine. All postsynaptic cell bodies, and the majority of the dendritic shafts (44, 60.3% of total targets) were immunoreactive for GABA. Thus at least 68.5% of the total targets were GABA-positive, but the majority of the dendrites not characterized immunocytochemically for technical reasons (15.1%) also showed the fine structural characteristics of nonpyramidal neurons. The target interneurons included some of the somatostatin- and calbindin-containing subpopulations, and a small number of parvalbumin-containing neurons, as shown by double immunostaining for PHAL and calcium-binding proteins or neuropeptides. We suggest that the innervation of inhibitory interneurons having extensive local axon arborizations may be a mechanism by which basal forebrain neurons–most notably those containing GABA–have a powerful global effect on the majority of principal cells in the entire cortical mantle.

Calcium binding proteins and neuropeptides as molecular markers of GABAergic interneurons in the cat visual cortex.

Abstract: In the cat visual cortex, almost all parvalbumin-positive cells are GABAergic, and about 80% of the calbindin D-28K-positive neurons are also GABA-immunoreactive. About 37% of the GABAergic neurons contain parvalbumin and a smaller fraction (about 18%) contains calbindin. Furthermore, parvalbumin and calbindin are localized in two separate neuronal populations in the cat visual cortex, suggesting that two GABAergic populations can be distinguished, one containing parvalbumin and one containing calbindin. Double staining for parvalbumin and neuropeptides (CCK, SRIF and NPY), revealed no double-labeled cells, with the exception of a few SRIF- and parvalbumin-positive neurons. These results show that cortical GABAergic cells can be differentiated on basis of their calcium binding protein and neuropeptide immunoreactivity.

Enrichment of cholinergic synaptic terminals on GABAergic neurons and coexistence of immunoreactive GABA and choline acetyltransferase in the same synaptic terminals in the striate cortex of the cat.

Abstract: The synaptic circuits underlying cholinergic activation of the cortex were studied by establishing the quantitative distribution of cholinergic terminals on GABAergic inhibitory interneurons and on non-GABAergic neurons in the striate cortex of the cat. Antibodies to choline acetyltransferase and GABA were used in combined electron microscopic immunocytochemical experiments. Most of the cholinergic boutons formed synapses with dendritic shafts (87.3%), much fewer with dendritic spines (11.5%), and only occasional synapses were made on neuronal somata (1.2%). Overall, 27.5% of the postsynaptic elements, all of them dendritic shafts, were immunoreactive for GABA, thus demonstrating that they originate from inhibitory neurons. This is the highest value for the proportion of GABAergic postsynaptic targets obtained so far for any intra- or subcortical afferents in cortex. There were marked variations in the laminar distribution of targets. Spines received synapses most frequently in layer IV (23%) and least frequently in layers V–VI (3%); most of these spines also received an additional synapse from a choline acetyltransferase-negative bouton, The proportion of GABA-positive postsynaptic elements was highest in layer IV (49%, two-thirds of all postsynaptic dendritic shafts), and lowest in layers V–VI (14%). The supragranular layers showed a distribution similar to that of the average of all layers. The quantitative distribution of targets postsynaptic to choline acetyltransferase-positive terminals is very different from the postsynaptic targets of GABAergic boutons, or from the targets of all boutons in layer IV reported previously. In both cases the proportion of GABA-positive dendrites was only 8–9% of the postsynaptic elements. At least 8% of the total population of choline acetyltransferase-positive boutons, presumably originating from the basal forebrain, were also immunoreactive for GABA. This raises the possibility of cotransmission at a significant proportion of cholinergic synapses in the cortex. The present results demonstrate that cortical GABAergic neurons receive a richer cholinergic synaptic input than non-GABAergic cells. The activation of GABAergic neurons by cholinergic afferents may increase the response specificity of cortical cells during cortical arousal thought to be mediated by the basal forebrain. The laminar differences indicate that in layer IV, at the first stage of the processing of thalamic input, the cholinergic afferents exert substantial inhibitory influence in order to raise the threshold and specificity of cortical neuronal responses. Once the correct level of activity has been set at the level of layer IV, the influence can be mainly facilitatory in the other layers.

Ultrastructural evidence for GABAergic brain stem projections to spinal motoneurons in the rat

Abstract: In the present ultrastructural study in the rat, it was determined whether GABA was present in projections descending from the ventromedial reticular formation of the lower brain stem to motoneuronal cell groups in the lumbar spinal cord. For this purpose, the anterograde transport of WGA-HRP was combined with the postembedding immunogold technique for GABA, with the advantage that both markers could be visualized simultaneously in a single terminal. In 4 rats, WGA-HRP was injected in the ventromedial part of the brain stem reticular formation at levels between the rostral inferior olive and the caudal part of the facial nucleus. Vibratome sections were cut from the lumbar spinal cord, reacted for WGA-HRP, and processed for electron microscopy. Ultrathin sections containing the lateral motoneuronal cell groups were cut and treated following the immunogold technique using a polyclonal antibody directed against GABA. It was found that nearly 40% of the terminal profiles that were labeled with WGA-HRP reaction products from the ventromedial brain stem were also labeled for GABA (double labeled). Most of the double-labeled terminals (81%) were F-type (containing many flattened vesicles), 12% were G-type (containing many granular vesicles), and 7% were S-type (containing many spherical vesicles). The majority of the double-labeled terminals contacted proximal dendrites. It is argued that the descending GABAergic projection produces a general inhibitory effect on spinal motoneurons, counteracting the general facilitation produced by the serotonergic projection derived from the same brain stem area.(ABSTRACT TRUNCATED AT 250 WORDS)

Glutamic acid and gamma-aminobutyric acid neurotransmitters in central control of breathing.

Abstract: We review recent cross-disciplinary experimental and theoretical investigations on metabolism of the amino acid neurotransmitters glutamic acid and gamma-aminobutyric acid (GABA) in the brain during hypoxia and hypercapnia and their possible role in central control of breathing. The roles of classical modifiers of central chemical drive to breathing (H+ and cholinergic mechanisms) are summarized. A brief perspective on the current widespread interest in GABA and glutamate in central control is given. The basic biochemistry of these amino acids and their roles in ammonia and bicarbonate metabolism are discussed. This review further addresses recent work on central respiratory effects of inhibitory GABA and excitatory glutamate. Current understanding of the sites and mechanisms of action of these amino acids on or near the ventral surface of the medulla is reviewed. We focus particularly on tracer kinetic investigations of glutamatergic and GABAergic mechanisms in hypoxia and hypercapnia and their possible role in the ventilatory response to hypoxia. We conclude with some speculative remarks on the critical importance of these investigations and suggest specific directions of research in central mechanisms of respiratory control.

The involvement of GABAB receptors and coupled G-proteins in spinal GABAergic presynaptic inhibition

Abstract: GABA acts as a presynaptic inhibitory transmitter in the spinal cord. In the lamprey, it has recently been shown that it acts in this way at both primary sensory and motor system synapses and is important in the generation of a locomotor rhythm. Both GABAA and GABAB receptors are activated at these sites by GABA released during physiological activity. In some systems, GABAB receptor activation has been shown to lead to modulation of ion channel function indirectly through the action of a pertussis toxin (PTX)-sensitive G-protein. Here we have studied the mechanism of action of the presynaptic GABAB receptor in this system. GABAB receptor activation leads to a decrease in axonal membrane impedance and also to a reduction in the axonal action potential duration. The ionic basis for this response remains unknown, though it is not, unlike the response to GABAA receptor activation, mediated by an increase in conductance to Cl-. The effects of GABAB receptor antagonism with phaclofen are mimicked by pretreatment of the spinal cord with PTX. Because this procedure inactivates certain classes of G-proteins, it seemed likely that the GABAB receptor- mediated effects are initiated via a presynaptic population of PTX- sensitive G-proteins. Experiments in which only presynaptic G-proteins were interfered with indicate that this is so. Stable analogs of GTP and GDP were used to activate permanently or to antagonize, respectively, the GTP binding site in the presynaptic component of these spinal synapses. We conclude that GABAB receptor-mediated synaptic suppression in the spinal cord is caused by GTP binding to presynaptic G-proteins linked to the GABAB receptor.(ABSTRACT TRUNCATED AT 250 WORDS)

Gamma-aminobutyric acid neurons in the preoptic/anterior hypothalamic area synchronize the phasic activity of the gonadotropin-releasing hormone pulse generator in ovariectomized rats.

Abstract: To achieve a bolus-type release of gonadotropin-releasing hormone (GnRH) into the portal vessels it is required that GnRH neurons exert phasic and synchronous activity. The activity of GnRH neurons appears to be under an inhibitory influence of the amino acid neurotransmitter gamma-aminobutyric acid (GABA). Preoptic GABA concentrations in ovariectomized (OVX) rats decrease prior to a luteinizing hormone (LH) episode. This reduction of GABAergic activity in the preoptic/anterior hypothalamic area (PO/AH) may be the synchronizing signal for the simultaneous release of GnRH from the hypothalamus. To further study the role of GABA in controlling the GnRH pulse generator we applied GABA, 3-mercaptopropionic acid (MPA) or bicuculline (BIC) locally into the PO/AH by means of push-pull cannulae (PPC). PPC were implanted into the PO/AH of OVX rats and the contralateral, not PPC-implanted PO/AH was lesioned electrochemically. The effects of GABA, MPA or BIC on the GnRH pulse generator were determined by measuring LH levels in blood samples collected in 5-min intervals. Local application of GABA into the PO/AH caused a pronounced reduction of average LH secretion and abolished LH pulsatility. This inhibitory effect was completely reversible. Results of intrapreoptic MPA application on GABA secretion were variable. In only 45% of treated rats MPA caused a reduction of GABA secretion which was associated with a cessation of pulsatile LH release. A pronounced reduction of LH secretion and pulsatility was observed upon local application of the GABA antagonist BIC. Based on these data we propose that oscillating GABA levels in the PO/AH may be the synchronizing signal which triggers bolus release of GnRH into the portal vessels.(ABSTRACT TRUNCATED AT 250 WORDS)

Patterns of synaptic input on corticocortical and corticothalamic cells in the cat visual cortex. I. The cell body.

Abstract: Immunocytochemical and electron microscopic methods were used to examine the ultrastructure and synaptology of callosal and corticothalamic pyramidal cell somata in the cat visual cortex (area 17). Callosal and corticothalamic cells were labeled after injection of horseradish peroxidase (HRP) in the contralateral visual cortex or in the ipsilateral lateral geniculate nucleus. The synaptic relationship between each of the two populations of pyramidal cells and cells containing the inhibitory neurotransmitter gamma-aminobutyric acid (GABA) was examined at the light and electron microscope level using the combined techniques of retrograde transport of HRP and GABA immunocytochemistry. We found that callosal and corticothalamic cell somata have an ultrastructure and synaptology that distinguishes them from each other. Reconstructions from electron micrographs of serial sections revealed that the vast majority of synapses (89-96%) on the cell body of pyramidal cells were formed by GABAergic axon terminals, and that within each population of pyramidal cells there was variability in the number and density of axosomatic synapses. Callosal pyramidal cells received a greater number and higher density of axosomatic synapses than corticothalamic cells. These data suggest that callosal cells receive more inhibition than corticothalamic cells at the level of their somata.

Role of solitarial GABAergic mechanisms in control of swallowing

Abstract: The role of solitarial gamma-aminobutyric acid (GABA)-ergic mechanisms in deglutition was investigated in urethane-anesthetized rats. When applied to the dorsal extraventricular surface of the nucleus tractus solitarii (NTS), muscimol reversibly inhibited 1) buccopharyngeal swallows evoked by either electrical or chemical stimulation of the NTS and 2) esophageal peristalsis evoked by muscarinic agonists. Bicuculline (5-1,000 pmol) applied to the NTS surface evoked rhythmic swallowing, which was reversibly blocked by DL-2-amino-7-phosphonoheptanoic acid (5-500 pmol). Methscopolamine (5-100 pmol) applied at the same site abolished the esophageal component of the response. Intrasolitarial application of bicuculline at s-glutamate-responsive loci in the intermediate and central subnuclei gave rise to buccopharyngeal and esophageal responses, respectively, and to a concomitant facilitation of glutamate-evoked responses. In subliminal doses ejected at esophageal loci, bicuculline induced deglutitive esophageal peristalsis during elicitation of buccopharyngeal swallowing by chemical (kainate or norepinephrine) or electrical stimulation of the NTS. We conclude that solitarial GABA neurons exert a tonic inhibition of the medullary deglutitive pattern generator and control buccopharyngeal-esophageal coupling.

GABA neurons in seizure disorders: a review of immunocytochemical studies.

Abstract: Immunocytochemical studies have identified alterations in GABA neurons in several models of seizure disorders. However, the changes have varied among different epilepsy models, and these variations presumably reflect the diversity of mechanisms that can lead to seizure disorders. In models of cortical focal epilepsy, there is strong evidence fordecreases in the number of GABAergic elements, and the changes closely parallel the time course of seizure development. By contrast, in some genetic models of epilepsy,increases in the number of immunocytochemically-detectable neurons have been observed in selected brain regions. In several models of temporal lobe epilepsy, there presently is little immunocytochemical evidence for alterations of GABA neurons within the hippocampal formation despite physiological demonstrations of decreased GABA-mediated inhibition in this region. However, it remains possible that certain types of GABA neurons could be differentially affected in some seizure disorders while other types are preserved. Thus, distinguishing between different classes of GABA neurons and determining their functional roles represent major challenges for future studies of GABA neurons in seizure disorders.

Electrophysiology of GABA-mediated synaptic transmission and possible roles in epilepsy

Abstract: Epileptogenic conditions come about from a disequilibrium between excitatory and inhibitory mechanisms, creating a state of neuronal hypersynchrony. From experimental studies in animal models of epilepsy it appears that several mechanisms, alone or in combination, could be responsible for this imbalance. An alteration of GABA-mediated inhibition has long been considered to be one of the most likely candidates. We review recent data on the synaptic physiology of GABA-mediated inhibition, with emphasis on GABAA and GABAB receptors and their conductances. We describe the integrative role of GABAergic local-circuit neurons in the normal control of recurrent excitation. We then discuss possible alterations in GABAA-mediated inhibition in two chronic animal models of epilepsy, the kindled rat and the kainate-treated rat. Finally, we review studies on GABA inhibition in human epileptic cortex resected for the treatment of intractable epilepsy.

Enhanced GABAergic inhibition preserves hippocampal structure and function in a model of epilepsy

Abstract: Extensive electrical stimulation of the perforant pathway input to the hippocampus results in a characteristic pattern of neuronal death, which is accompanied by an impairment of cognitive functions similar to that seen in human temporal lobe epilepsy. The excitotoxic hypothesis of epileptic cell death [Olney, J. W. (1978) in Kainic Acid as a Tool in Neurobiology, eds. McGeer, E., Olney, J. W. & McGeer, P. (Raven, New York), pp. 95-121; Olney, J. W. (1983) in Excitotoxins, eds. Fuxe, K., Roberts, P. J. & Schwartch, R. (Wenner-Gren International Symposium Series, Macmillan, London), Vol. 39, pp. 82-96; and Rothman, S. M. & Olney, J. W. (1986) Ann. Neurol. 19, 105-111] predicts an imbalance between excitation and inhibition, which occurs probably as a result of hyperactivity in afferent pathways or impaired inhibition. In the present study, we investigated whether the enhancement of gamma-aminobutyric acid (GABA)-mediated (GABAergic) inhibition of neurotransmission by blocking the GABA-metabolizing enzyme, GABA transaminase, could influence the histopathological and/or the behavioral outcome in this epilepsy model. We demonstrate that the loss of pyramidal cells and hilar somatostatin-containing neurons can be abolished by enhancing the level of synaptically released GABA, and that the preservation of hippocampal structure is accompanied by a significant sparing of spatial memory as compared with placebo-treated controls. These results suggest that enhanced GABAergic inhibition can effectively block the pathophysiological processes that lead to excitotoxic cell death and, as a result, protect the brain from seizure-induced cognitive impairment.

GABAergic Control of Receptivity in the Female Rat

Abstract: GABAergic neurotransmission has been implicated in the control of the steroid-dependent behavior, lordosis. GABA has dual effects on lordosis: it facilitates lordosis through actions in the medial hyp