Showing papers on "GABAergic published in 1989"

Ultrastructural study of the GABAergic, cerebellar, and mesodiencephalic innervation of the cat medial accessory olive: anterograde tracing combined with immunocytochemistry.

Abstract: The rostral medial accessory olive (MAO) of the cat was studied by using an ultrastructural technique combining wheat germ agglutinin-coupled horseradish peroxidase (WGA-HRP) anterograde tracing and postembedding GABA immunocytochemistry. One group of cats received a WGA-HRP injection in the posterior interposed nucleus of the cerebellum and another group received an injection in the nucleus of Darkschewitsch. Based on differences in their morphology three types of GABAergic and three types of nonGABAergic terminals were observed. One type of GABAergic terminal was often GABA/WGA-HRP double-labeled in the cerebellar experiments, and one type of nonGABAergic terminal was often WGA-HRP-labeled in the mesodiencephalic experiments. Following injections of WGA-HRP in the cerebellar nuclei virtually all WGA-HRP-labeled terminals were GABA positive. Quantification of these GABA/WGA-HRP-double-labeled terminals showed that 1) 30% of the GABAergic terminals randomly selected from the entire neuropil were double-labeled, 2) 13% of the GABAergic terminals adjacent to perikarya were double-labeled, and 3) 34% of the GABAergic terminals strategically located next to both of the dendritic elements linked by a gap junction were double-labeled. Statistical analysis of the above data showed that significantly fewer GABAergic terminals adjacent to perikarya were double-labeled (P less than .001) than would be expected from the double-labeled proportion of the randomly selected GABAergic terminals. Following injection of WGA-HRP in the nucleus of Darkschewitsch, all WGA-HRP-labeled terminals were GABA-negative. Quantification of these terminals showed that 1) 26% of the randomly selected nonGABAergic terminals were WGA-HRP labeled, 2) 20% of the nonGABAergic terminals adjacent to perikarya were WGA-HRP labeled, and 3) 23% of the nonGABAergic terminals strategically located next to a gap junction were WGA-HRP labeled. No significant differences were found among these populations. Quantification of terminals of both groups of experiments mentioned above showed that GABAergic terminals composed 1) 38% of the randomly selected terminals, 2) 64% of the terminals apposed to perikarya, and 3) 53% of the terminals strategically located next to gap junctions. Statistical analysis of the above data showed that significantly more GABAergic terminals were located adjacent to perikarya (P less than .001) and strategically next to a gap junction (P less than .05) than would be expected from the random GABAergic innervation. The above findings of the GABAergic, cerebellar, and mesodiencephalic input are discussed with regard to their functional role in the neuronal circuitry of the ros

Organization of the septal region in the rat brain: Cholinergic-GABAergic interconnections and the termination of hippocampo-septal fibers

Abstract: This study deals with two characteristic cell types in the rat septal complex i.e., cholinergic and GABAergic neurons, and their synaptic connections. Cholinergic elements were labeled with a monoclonal antibody against choline acetyltransferase (ChAT), the acetylcholine synthesizing enzyme. Antiserum against glutamate decarboxylase (GAD), the GABA synthesizing enzyme, was employed to identify GABAergic perikarya and terminals, by using either the peroxidase-antiperoxidase (PAP) technique or a biotinylated second antiserum and avidinated gold or ferritin. With these contrasting immunolabels we have studied the cholinergic-GABAergic interconnections in double-labeled sections of intact septal regions and the GABAergic innervation of medial septal area cholinergic neurons in sections taken from animals 1 week following lateral septal area lesion. In other electron microscopic experiments we have studied cholinergic and GABAergic neurons in the septal complex for synaptic contacts with hippocamposeptal fibers, which were identified by anterograde degeneration following fimbria-fornix transection. Our results are summarized as follows: (1) GAD-positive terminals form synaptic contacts on ChAT-immunoreactive dendrites in the medial septum/diagonal band complex (MSDB), (2) surgical lesion of the lateral septal area resulted in a dramatic decrease of the number of GABAergic boutons on MSDB cholinergic neurons, (3) cholinergic terminals establish synaptic contacts with GAD immunoreactive cell bodies and proximal dendrites in the MSDB as well as in the lateral septum (LS), (4) degenerated terminals of hippocampo-septal fibers were mainly observed in the LS, where they formed asymmetric synaptic contacts on dendrites of GABAergic neurons and on nonimmunoreactive spines. We did not observe degenerated boutons in contact with ChAT-positive dendrites or cell bodies in the MSDB. From these results and from data in the literature we conclude that excitatory hippocampo-septal fibers activate GABAergic cells, and as yet unidentified spiny neurons in the LS, which may control the discharge of medial septal cholinergic neurons known to project back to the hippocampal formation.

GABAergic mechanisms in the pathogenesis and treatment of epilepsy.

Abstract: 1. Evidence relating to the role of GABA in the pathogenesis of epilepsy is reviewed. 2. Impaired GABAergic function appears to contribute to seizure susceptibility in a variety of genetically-determined syndromes in animals, e.g. genetically epilepsy prone rats showing sound-induced seizures, gerbils with genetically determined epilepsy, and baboons, Papio papio, with photosensitive epilepsy. 3. In epilepsy secondary to a cerebral insult there is some morphological and biochemical evidence for impaired GABAergic function in experimental situations, but little definitive evidence in man. 4. Pharmacological approaches to enhancing GABAergic inhibition include the use of GABA agonists (or prodrugs), GABA-transaminase inhibition, GABA uptake inhibition, and action at the GABA/benzodiazepine allosteric site. 5. Experimental data suggest that the best prospect for potent anticonvulsant action with fewest side effects (myoclonus, sedation, ataxia) is at present offered by GABA-transaminase inhibitors or novel agents acting on the benzodiazepine receptor site.

Distribution of GABAergic neurons and terminals in the auditory system of the barn owl

Abstract: Antisera to GAD (glutamic acid decarboxylase) and GABA were used to determine the distribution of GABAergic cells and terminals in the brainstem and midbrain auditory nuclei of the barn owl. The owl processes time and intensity components of the auditory signal in separate pathways, and each pathway has a distinctive pattern of GAD- and GABA-like immunoreactivity. In the time pathway, all the cells of the cochlear nucleus magnocellularis and nucleus laminaris receive perisomatic GABAergic terminals, and small numbers of GABAergic neurons surround both nuclei. The ventral nucleus of the lateral lemniscus (anterior division) contains both immunoreactive terminals and some GABAergic neurons. In the intensity pathway, dense immunoreactive terminals are distributed throughout the cochlear nucleus angularis, which also contains a small number of GABAergic neurons. The superior olive contains two GABAergic cell types and immunoreactive terminals distributed throughout the neuropil. All the neurons of the nucleus of the lateral lemniscus (ventral part) appear to be GABAergic, and this nucleus also contains a moderate number of immunoreactive terminals. Immunoreactive terminals are distributed throughout the neuropil of the ventral nucleus of the lateral lemniscus (posterior division), whereas multipolar and small fusiform GABAergic neurons predominate in the dorsal regions of the nucleus. The time and intensity pathways combine in the inferior colliculus. The central nucleus of the inferior colliculus contains a large number of fusiform and stellate GABAergic neurons and a dense plexus of immunoreactive terminals, whereas the external nucleus contains slightly fewer immunoreactive cells and terminals. The superficial nucleus contains dense, fine immunoreactive terminals and a small number of GABAergic neurons.

The gabaergic hypothesis of depression

Abstract: 1. GABAergic mechanisms have been generally ignored in the study of mood disorders and antidepressant drug (AD) action. Recently data have accumulated indicating that GABAergic mechanisms may be involved in both of these. 2. Mood disorders: GABA levels are reported to be low in the CSF and plasma of depressed patients and are related to mood changes. GABA B receptors are decreased in the frontal cortex in two rodent behavioral models of depression and GABA release is reported diminished in the hippocampus. GABAergic drugs (progabide, fengabine) reverse the behavioral deficits in the rodent models and exert clear therapeutic effects in depressed patients. 3. AD action: In behavioral models imipramine upregulates GABA B receptors only in those animals which respond behaviorally to the AD. In naive rats repeated administration of varied ADs upregulates GABA B receptors in the frontal cortex whereas non-ADs (including amphetamine) do not. Bicuculline inhibits the action of imipramine in the learned helplessness model. GABA A receptor stimulation enhances noradrenaline release in the ventral NA pathway. 4. Conclusions: GABAergic mechanisms likely play a role in the modulation of mood and increasing GABAergic tone exerts an antidepressant effect. Actions at GABA synapses appear to be a fundamental facet of ADs, perhaps together with s-adrenoceptor mediated events.

Organization and synaptic interconnections of GABAergic and cholinergic elements in the rat amygdaloid nuclei: single- and double-immunolabeling studies.

Abstract: The aim of this study was to describe the localization of cholinergic and GABAergic neurons and terminals in the amygdaloid nuclei of the rat. Double immunolabeling was performed to study cholinergic-GABAergic synaptic interconnections. Cholinergic elements were labeled by using a monoclonal antibody to choline acetyltransferase (ChAT), the acetylcholine synthesizing enzyme. Antibodies against glutamate decarboxylase (GAD), the GABA- synthesizing enzyme, were employed to identify GABAergic perikarya and terminals. The tissue sites of the antibody bindings were detected by using either Sternberger's peroxidase-antiperoxidase (PAP) method or a biotinylated secondary antibody and avidinated ferritin. These two contrasting immunolabels allowed us to study GABAergic-cholinergic interconnections at the electron microscopic level. Our study revealed a characteristic distribution of GABAergic and cholinergic elements in the various amygdaloid nuclei: 1) Large, ChATimmunopositive cells with heavily labeled dendrites were observed in the anterior amygdaloid area and in the lateral and medial zones of the central nucleus. These cells seem to constitute the intraamygdaloid extension of the magnocellular basal nucleus. Their dendrites invaded other amygdaloid nuclei, in particular the intercalated nuclei, the lateral olfactory tract nucleus, and the central zone of the central nucleus. These ChAT-immunoreactive dendrites formed synaptic contacts with GAD-positive terminals. GABAergic terminals probably thus exert an inhibitory amygdaloid influence onto cholinergic neurons of the magnocellular basal nucleus. 2) Two amygdaloid nuclei-the basal dorsal nucleus and the lateral olfactory tract nucleus-contained a dense network of ChAT-immunoreactive fibers and terminals, but they also contained numerous GAD-positive perikarya. Double-immunolabeling experiments revealed cholinergic terminals forming synaptic contacts on GAD-immunopositive cell bodies, dendritic shafts, and spines. 3) The central and medial nucleus seem to be the main target of GABAergic fibers to the amygdala. Both nuclei contained a dense plexus of GAD-immunoreactive terminals that may arise, at least in part, from the GABAergic neurons in the basal dorsal nucleus. Inhibition of the centromedial “excitatory” region through intraamygdaloid GABAergic connections may reduce excitatory amygdaloid influence onto hypothalamus and brainstem.

Immunocytochemical localization of GABAA receptors in goldfish and chicken retinas.

Abstract: A monoclonal antibody (mAb 62-3G1) to the GABAA receptor/benzodiazepine receptor/Cl- channel complex from bovine brain was used with light and electron microscopy in goldfish retina and light microscopy in chicken retina to localize GABAA receptor immunoreactivity (GABAr-IR). GABAr-IR was found in the outer plexiform layer (OPL) in both species, in three broad bands in the inner plexiform layer (IPL) of goldfish, and in seven major bands of the chicken IPL. A small percentage of amacrine cell bodies (composing at least three types) were stained in chicken. In goldfish OPL, GABAr-IR was localized intracellularly and along the plasma membrane of cone pedicles, whereas rod spherules were lightly stained, but always only intracellularly. In chicken, all three sublayers of the OPL were GABAr-IR. The presence of GABAr-IR on photoreceptor terminals is consistent with data indicating feedback from GABAergic horizontal cells to cones. In the goldfish IPL, GABAr-IR was localized to postsynaptic sites of amacrine cell synapses; intracellular staining of processes in the IPL also was observed in presumed "GABAergic" targets. A comparison of GABAr-IR with the distributions of 3H-muscimol uptake/binding, glutamate decarboxylase-IR, GABA-IR, and 3H-GABA uptake in the IPL showed either a reasonable correspondence or mismatch, depending on the marker, species, and lamina within the IPL. The distribution of GABAr-IR in the retina corresponded better with the 3H-muscimol than with 3H-benzodiazepine binding patterns yet overall was in excellent agreement with many other physiological and anatomical indicators of GABAergic function. We suggest that intracellular GABAr-IR represents the biosynthetic and/or degradative pathway of the receptor and we conclude that mAb 62-3G1 is a valid marker of GABAA receptors in these retinas and will serve as a useful probe with which to address the issue of mismatches between the localization of GABAA receptors and indicators of presynaptic GABAergic terminals.

Development of GABA immunoreactivity in brainstem auditory nuclei of the chick: ontogeny of gradients in terminal staining.

Abstract: The development of gamma-aminobutyric acid-immunoreactivity (GABA-I) in nucleus magnocellularis (NM) and nucleus laminaris (NL) of the chick was studied by using an antiserum to GABA In posthatch chicks, GABA-I is localized to small, round punctate structures in the neuropil and surrounding nerve cell bodies Electron microscopic immunocytochemistry demonstrates that these puncta make synaptic contact with neuronal cell bodies in NM; thus, they are believed to be axon terminals GABAergic terminals are distributed in a gradient of increasing density from the rostromedial to the caudolateral regions of NM The distribution of GABA-I was studied during embryonic development At embryonic days (E) 9-11, there is little GABA-I staining in either NM or NL Around E12-14, a few fibers are immunopositive but no gradient is seen More GABA-I structures are present at E14-15 They are reminiscent of axons with varicosities along their length, preterminal axonal thickenings and fiber plexuses At E15, terminals become apparent circumscribing neuronal somata and are also discernible in the neuropil of both nuclei In E16-17 embryos, terminals are the predominantly labeled GABA-I structures and they are uniformly distributed throughout NM The density of GABAergic terminals increases in caudolateral regions of NM such that by E17-19, there is a gradient of increasing density of GABA-I terminals from the rostromedial to caudolateral regions of NM The steepness of this gradient increases during development and is the greatest in posthatch (P) chicks Cell bodies labeled with the GABA antiserum are located around the borders of both NM and NL and in the neuropil between these two nuclei Occasionally, GABA-I neurons can be found within these auditory brainstem nuclei in both embryonic and posthatch chicks Nucleus angularis (NA) contains some GABAergic cells The appearance of GABA-I terminals around E15 is correlated in time with the formation of end-bulbs of Held on NM neurons Thus, the ontogeny of presumed inhibitory inputs to chick auditory brainstem nuclei temporally correlates with, and could modulate the development of, excitatory auditory afferent structure and function

GABAergic neocortical neurons are resistant to NMDA receptor‐mediated injury

Abstract: N-methyl-D-aspartate (NMDA) receptors are thought to mediate much of the central neuronal loss produced by certain neurologic insults, including hypoxia-ischemia, hypoglycemia, and trauma. Therefore, the specific vulnerability of GABAergic inhibitory neurons to NMDA receptor-mediated toxicity might be an important determinant of the potential for epileptogenesis following these insults. We have examined the fate of GABAergic cortical neurons in mouse cell cultured neuronal population) were identified either by immunoreactivity with antisera to GABA or by autoradiography following high-affinity uptake of 3H-GABA. Cultures exposed for 5 min to 20 to 750 microM NMDA showed NMDA concentration-dependent, widespread neuronal loss. However, GABAergic neurons were relatively spared, and thus represented an enhanced fraction of neuronal survivors. These observations suggest that GABAergic cortical neurons may possess some intrinsic resistance to NMDA receptor-mediated neurotoxicity, a property which might convey an anticonvulsant "inhibitory safety factor" to neocortex against certain forms of injury.

Neuropeptide Y in the cerebral cortex and the caudate-putamen nuclei: ultrastructural basis for interactions with GABAergic and non-GABAergic neurons

Abstract: In the cerebral cortex and caudate-putamen (CP) nuclei, neuropeptide Y (NPY) immunoreactivity is detectable within 1–2% of all neurons. The NPY-immunoreactive neurons are interneuronal and are believed to be mostly GABAergic in the cerebral cortex but not in the CP nuclei. Thus NPY and GABA may play different roles in the circuitry within these 2 regions. We tested this possibility by comparing the ultrastructure of NPY-containing neurons between (1) cortex (somatosensory and anterior cingulate areas) versus dorsolateral CP; and (2) GABAergic versus non- GABAergic NPY neurons within each area. Single coronal sections through the rat forebrain were dually labeled for GABA and NPY by combining immunoautoradiography with the immunoperoxidase method. NPY-containing neurons with or without GABA occurred throughout the rostrocaudal portions of CP and all laminae of somatosensory and anterior cingulate cortex. Comparisons between the areas confirmed that somata and terminals dually labeled for GABA and NPY were more prevalent in the cortex. NPY terminals lacking detectable GABA immunoreactivity also were found within the cortex, thus suggesting additional heterogeneity in cortical NPY innervation. The ultrastructural features of NPY perikarya in both regions were morphologically similar regardless of whether the cells also contained GABA. Most synaptic inputs to NPY neurons occurred at distal dendrites. In comparison to neighboring neurons, synaptic inputs to proximal dendrites and somata of NPY neurons of cortex and CP were rare, suggesting that fewer and weaker inputs may modulate the excitability of NPY-containing neurons. In both regions, nearly all NPY- and NPY-GABA-labeled terminals formed symmetric junctions suggestive of inhibitory action. The majority of these junctions were with dendrites containing neither NPY nor GABA. NPY terminals formed few contacts on proximal dendrites and somata of GABAergic neurons (8% of 179 contacts in cortex; 12% of 73 contacts in CP) which, unlike most singly-labeled GABAergic neurons, were sparsely innervated. Thus, NPY may play a more prominent role in modulation of certain GABAergic neurons than would be predicted by the observed frequency of NPY-to-GABA contacts in the two regions. One notable regional difference was the greater prevalence in cortex of axoaxonic associations between NPY-immunoreactive terminals and other terminals, some of which also contained NPY. These nonsynaptic associations may be involved in the modulation of (1) the release of NPY by another transmitter or (2) NPY's modulation of release of other transmitters in cortex.

Genetic control of hippocampal cholinergic and dynorphinergic mechanisms regulating novelty-induced exploratory behavior in house mice.

Abstract: Neurobehavioral genetics endeavors to trace the pathways from genetic and environmental determinants to neuroanatomical and neurophysiological systems and, thence, to behavior. Exploiting genetic variation as a tool, the behavioral sequelae of manipulating these neuronal systems by drugs and antisera are analyzed. Apart from research in rats, this paper deals mainly with the genetically-influenced regulation in mice of exploratory behaviors that are adaptive in novel surroundings and are hippocampally-mediated. Special attention is paid to neuropeptidergic, GABAergic, and cholinergic synaptic functions in the mouse hippocampus. The behaviorally different inbred mouse strains C57BL/6 and DBA/2 show opposite reactions (reductions and increases, respectively, in exploration rates) to peripheral and intrahippocampal injections with agents that interfere with peptidergic, cholinergic, and GABAergic neurotransmission. These findings can be explained by an interdependent over-release of opioids, arrested GABA release, and excess acetylcholine in the hippocampal neuronal network of DBA/2 mice, as compared to C57BL/6 mice where these systems are functionally well balanced. Very similar results have been obtained with the lines SRH and SRL, derived from C57BL/6 and DBA/2, and genetically selected for rearing behavior. Most probably, the opioids act to disinhibit exploratory responses. An additional genetic approach is mentioned, in which four inbred mouse strains and one derived heterogeneous stock are used for estimating genetic correlations between structural properties of the hippocampal mossy fibers and levels of hippocampal dynorphin B, on the one hand, and frequencies of exploratory responses to environmental novelty, on the other.

A novel class of "GABAergic" agents: 1-aryl-3-(aminoalkylidene)oxindoles.

Abstract: Antagonism of mercaptopropionic acid (MPA) induced convulsions, reflecting a GABAergic mechanism, was observed in a series of 1-aryl-3-(aminoalkylidene)oxindoles. Optimal MPA antagonism was associated with 3-halo, 3-alkyl, and/or 4-alkoxy substituents in the pendant aryl ring and with (dimethylamino)methylene, 1-(dimethylamino)-ethylidene and N-methyl-2-pyrrolidinylidene side chains. The precise mechanism of action of these agents is unclear at this time; however, they are not GABA mimics and they do not affect GABA levels. Like other GABAergic agents, these compounds are potent enhancers of benzodiazepine binding and they antagonize cyclic GMP elevations induced by isoniazid. Compounds from this series may therefore have potential therapeutic utility as anticonvulsants or anxiolytics.

GABAergic neurons in the rat hippocampal formation: ultrastructure and synaptic relationships with catecholaminergic terminals

Abstract: Numerous studies indicate that gamma-aminobutyric acid (GABA) can either hyperpolarize or depolarize hippocampal pyramidal and granule cells While the inhibitory action of GABA may occur directly on these cells, the excitatory action may be mediated by interactions of GABAergic neurons with each other or with catecholaminergic afferents We sought to examine the cellular basis for these interactions and their relative frequency Thus, the ultrastructural morphology of GABAergic neurons and their relation to terminals exhibiting immunoreactivity for the catecholamine-synthesizing enzyme tyrosine hydroxylase (TH) were examined in the rat hippocampal formation using combined immunoautoradiographic and peroxidase-antiperoxidase labeling methods By light microscopy, GABAergic perikarya and processes codistributed most noticeably with TH-containing processes in the hilus of the dentate gyrus (DG) and in strata lucidum, radiatum, and lacunosum-moleculare of the CA3 region of the hippocampus Thus, these regions were examined further by electron microscopy In the ultrastructural analysis, GABA-like immunoreactivity (GABA-LI) was detected in neuronal perikarya, dendrites, axons, and axon terminals The GABA-containing perikarya were large, ovoid (20-40 microns in diameter), and contained abundant cytoplasm and an indented nucleus with one nucleolus Synaptic junctions on the perikarya and dendrites with GABA-LI were both symmetric and asymmetric Approximately equal numbers of TH-labeled terminals (19% of 133 in DG; 39% of 26 in CA3) and GABA-containing terminals (19% DG, 15% CA3) formed synapses with GABA-labeled perikarya The remainder of the presynaptic terminals (62% DG, 46% CA3) were unlabeled, ie, contained unidentified transmitters Terminals with GABA-LI (05-16 microns) contained numerous small clear vesicles and from 0 to 2 large dense-core vesicles The types of associations formed by terminals with GABA-LI were remarkably similar in the DG and hippocampus proper despite differences in intrinsic cell type and function Terminals with GABA-LI formed associations with unlabeled perikarya and dendrites (24% of 151 in DG, 25% of 75 in CA3) and synapses with GABA-containing perikarya and dendrites (18% DG, 5% CA3) Additionally, GABAergic terminals converged upon the same perikarya or dendrite as a TH-containing terminal (15% DG, 21% CA3) and were in direct apposition to TH-labeled terminals (19% DG, 20% CA3) The remaining GABAergic terminals (24% DG, 28% CA3) were without any apparent synaptic relations In both the DG and CA3, the junctions formed by GABAergic terminals were symmetric Terminals showing colocalization of GABA-LI and TH-I were also detected although rarely(ABSTRACT TRUNCATED AT 400 WORDS)

The distribution of GABA-like-immunoreactive neurons in the brain of the newt, Triturus cristatus carnifex, and the green frog, Rana esculenta.

Abstract: The distribution of γ-aminobutyric acid (GABA) immunoreactivity was studied in the brain of two amphibian species (Triturus cristatus carnifex, Urodela; Rana esculenta, Anura) by employing a specific GABA antiserum. A noteworthy immunoreactive neuronal system was found in the telencephalic dorsal and medial pallium (primordium pallii dorsalis and primordium hippocampi) and in the olfactory bulbs. In the diencephalic habenular nuclei there was a rich GABAergic innervation, and immunoreactive neurons were observed in the dorsal thalamus. In the hypothalamus the GABA immunoreactivity was found in the preoptic area, the paraventricular organ and in the hypothalamo-hypophysial complex. In the preoptic area of the frog some GABA-immunoreactive CSF-contacting cells were shown. In the optic tectum immunolabeled neurons were present in all the cellular layers. A rich GABAergic innervation characterized both the fibrous layers of the tectum and the neuropil of the tegmentum and interpeduncular nucleus. In the cerebellum, in addition to the Purkinje cells showing a variable immunopositivity, some immunoreactive cell bodies appeared in the central grey. Abundant immunolabeled nerve fibers in the acoustico-lateral area and some immunopositive neurons in the region of the raphe nucleus were observed. In conclusion, the GABAergic central systems, well-developed in the amphibian species studied, were generally characterized by close similarities to the pattern described in mammals.