Colocalization of synaptic GABAC-receptors with GABAA-receptors and glycine-receptors in the rodent central nervous system

Fast inhibition in the nervous system is preferentially mediated by GABA- and glycine-receptors. Two types of ionotropic GABA-receptor, the GABA_A-receptor and GABA_C-receptor, have been identified; they have specific molecular compositions, different sensitivities to GABA, different kinetics, and distinct pharmacological profiles. We have studied, by immunocytochemistry, the synaptic localization of glycine-, GABA_A-, and GABA_C-receptors in rodent retina, spinal cord, midbrain, and brain-stem. Antibodies specific for the α1 subunit of the glycine-receptor, the γ2 subunit of the GABA_A-receptor, and the ρ subunits of the GABA_C-receptor have been applied. Using double-immunolabeling, we have determined whether these receptors are expressed at the same postsynaptic sites. In the retina, no such colocalization was observed. However, in the spinal cord, we found the colocalization of glycine-receptors with GABA_A- or GABA_C-receptors and the colocalization of GABA_A- and GABA_C-receptors in approximately 25% of the synapses. In the midbrain and brain-stem, GABA_A- and GABA_C-receptors were colocalized in 10%–15% of the postsynaptic sites. We discuss the possible expression of heteromeric (hybrid) receptors assembled from GABA_A- and GABA_C-receptor subunits. Our results suggest that GABA_A- and GABA_C-receptors are colocalized in a minority of synapses of the central nervous system.     

Viscerosomatic somatic convergence at lumbar interneurons in the dorsal horn of the cat and rat spinal cord

In experiments on spinal cats, when branches of the pelvic nerve innervating the rectum were electrically stimulated at the same time as the peroneal nerve it was found that 12 out of 20 neurons, to which the effects of both these supplies converged, were activated by both A- and C-fibers. Responses to stimulation of the pelvic nerve were apparently mediated via fibers with a conduction velocity not less than 2.2 m·s^–1. In studies in spinal rats it was shown that distension of the more distal regions of the large intestine could excite neurons in laminae IV–V, and inhibit neurons in deeper laminae. In seven out of 18 cases the inhibition evoked by visceral stimulation was due to a direct effect on the postsynaptic membrane of these cells, and in 11 cases it was localized to presynaptic structures. Naloxone, strychnine, and atropine did not block this inhibition, thus providing evidence against the possible participation of opioids, glycine, and acetylcholine in its generation. Phaclofen, a GABA_B-receptor antagonist, was also without effect, but bicuculline suppressed this inhibition in three out of 12 cases, indicating that GABA_A-receptors are involved.I. M. Sechenov Medical Academy, Russian Ministry of Public Health, Moscow. Translated from Neirofiziologiya, Vol. 24, No. 1, pp. 3–11, January–February, 1992.     

GABAergic Modulation of Striatal Cholinergic Interneurons: An In Vivo Microdialysis Study

Abstract: Striatal cholinergic interneurons have been shown to receive input from Striatal γ-aminobutyric acid (GABA)-containing cell elements. GABA is known to act on two different types of receptors, the GABA_A and the GABA₆ receptor. Using in vivo microdialysis, we have studied the effect of intrastriatal application of the GABA_A-selective compounds muscimol and bicuculline and the GA- BA_B-selective compounds baclofen and 2-hydroxysaclofen, agonists and antagonists, respectively, at GABA receptors, on the output of Striatal acetylcholine (ACh). Intrastriatal infusion of 1 and 10 μmol/L concentrations of the GABA_A antagonist bicuculline resulted in a significant increase in Striatal ACh output, whereas infusion of 1 and 10 /μmol/L concentrations of the GABA_A agonist muscimol significantly decreased the output of Striatal ACh. Both compounds were ineffective in changing the output of Striatal ACh at lower concentrations. Infusion of concentrations up to 100 μmol/L of the GABA_B-selective antagonist 2-hydroxy-saclofen failed to affect Striatal ACh output, whereas infusion of 10 and 100 μmol/L baclofen, but not 0.1 and 1 μmol/L baclofen, significantly decreased the output of Striatal ACh. Thus, agonist-stimulation of GABAA and GABA_B receptors decreases the output of striatal ACh in a dose-dependent fashion, whereas the GABAergic system appears to inhibit tonically the output of striatal ACh via GABA_A receptors, but not via GABA_B receptors. We hypothesize that although GABA_A mediated regulation of striatal ACh occurs via GABA receptors on the cholinergic neuron, the GABA_B mediated effects may be explained by presynaptic inhibition of the glutamatergic input of the striatal cholinergic neuron.     

Immunohistochemical demonstration of GABAB receptors in the rat gastrointestinal tract

Immunohistochemical localization of GABA_B-receptors was demonstrated in the rat gastrointestinal tract using a monoclonal antibody (GB-1) raised against the purified GABA_B-receptor. Immunoreactive staining for GABA_B-receptors was found in some populations of endocrine, muscular and neuronal components in the stomach and gut wall. Positive mucosal epithelial, probably endocrine, cells were distributed throughout the stomach and intestine. Double immunostaining indicated that such positive cells for GABA_B-receptors often co-possessed serotonin in the small intestine but not in the gastric body. In the muscular layer of the digestive canal, positive staining was seen as dotty granules punctuated on the surface of muscle fibers. In the enteric nervous system, positive neuronal somata were found in both submucosal and myenteric ganglia throught the entire canal extending from the stomach to the rectum. This is the first report to visualize the cellular localization of GABA_B-receptors in the gastrointestinal system of the rat, and should provide a fundamental basis for future studies on gastrointestinal functions regulated by GABA_B-receptors. Special issue dedicated to Dr. Kinya Kuriyama.     

Gamma-aminobutyric acid and GABAA receptors are involved in directional selectivity of pretectal neurons in pigeons

The present study describes the effects of gamma-aminobutyric acid (GABA) and its antagonists, bicuculline and 2-hydroxysaclofen, on visual responses of neurons in the pigeon nucleus lentiformis mesencephali (nLM). The results indicate that GABA significantly reduces both spontaneous activity and visual responsiveness, and GABA_A antagonist bicuculline but not GABA_B antagonist 2-hydroxysaclofen enhances visual responses of nLM cells examined. Furthermore, inhibition produced by motion in the null-direction of pretectal neurons is diminished by bicuculline but not by 2-hydroxysaclofen. It is therefore concluded that the null-direction inhibition of directional cells in the pigeon nLM is predominantly mediated by GABA and GABA_A receptors. This inhibition may at least in part underlie directional asymmetry of optokinetic responses.     

Effect of GABA Receptor Agonists or Antagonists Injected Spinally on the Blood Glucose Level in Mice

The possible roles of gamma-amino butyric acid (GABA) receptors located in the spinal cord for the regulation of the blood glucose level were studied in ICR mice. We found in the present study that intrathecal (i.t.) injection with baclofen (a GABA_B receptor agonist; 1–10 μg/5 μl) or bicuculline (a GABA_A receptor antagonist; 1–10 μg/5 μl) caused an elevation of the blood glucose level in a dose-dependent manner. The hyperglycemic effect induced by baclofen was more pronounced than that induced by bicuculline. However, muscimol (a GABA_A receptor agonist; 1–5 μg/5 μl) or phaclofen (a GABA_B receptor antagonist; 5–10 μg/5 μl) administered i.t. did not affect the blood glucose level. Baclofen–induced elevation of the blood glucose was dose-dependently attenuated by phaclofen. Furthermore, i.t. pretreatment with pertussis toxin (PTX; 0.05 or 0.1 μg/5 μl) for 6 days dose-dependently reduced the hyperglycemic effect induced by baclofen. Our results suggest that GABA_B receptors located in the spinal cord play important roles for the elevation of the blood glucose level. Spinally located PTX-sensitive G-proteins appear to be involved in hyperglycemic effect induced by baclofen. Furthermore, inactivation of GABA_A receptors located in the spinal cord appears to be responsible for tonic up-regulation of the blood glucose level.     

Presynaptic GABA(B) receptors modulate synaptic facilitation and depression at distinct synapses in fusiform cells of mouse dorsal cochlear nucleus

The mammalian dorsal cochlear nucleus (DCN) is considered to contribute to the localization of the sound sources. Fusiform cells (FCs), principal projection neurons in the DCN, integrate two excitatory inputs from auditory nerve fibers (ANFs) and parallel fibers (PFs). Although an immunohistochemical study suggested presence of GABA_B receptors at excitatory presynaptic terminals in the DCN, it has not been elucidated how GABA_B receptors modulate the synaptic transmission to FCs. Here, we examined effects of baclofen on the transmission in vitro. Baclofen reduced both PF-EPSC and ANF-EPSC by reducing transmitter releases, and it enhanced the facilitation in PF-FC synapses and prevented the depression in ANF-FC synapses. The enhancement and prevention were prominent during high-frequency (50 Hz) synaptic input, suggesting the activation of presynaptic GABA_B receptors may optimize both PF-FC and ANF-FC synapses for high-frequency transmission. Postsynaptic GABA_B receptors activated GIRK current and would further modulate the activity of FCs.     

GABA in Paraventricular Nucleus Regulates Adipose Afferent Reflex in Rats

Background

Chemical stimulation of white adipose tissue (WAT) induces adipose afferent reflex (AAR), and thereby causes a general sympathetic activation. Paraventricular nucleus (PVN) is important in control of sympathetic outflow. This study was designed to investigate the role of γ-aminobutyric acid (GABA) in PVN in regulating the AAR.

Methodology/Principal Findings

Experiments were carried out in anesthetized rats. Renal sympathetic nerve activity (RSNA) and mean arterial pressure (MAP) were continuously recorded. AAR was evaluated by the RSNA and MAP responses to electrical stimulation of the right epididymal WAT (eWAT) afferent nerve. Electrical stimulation of eWAT afferent nerve increase RSNA. Bilateral microinjection of the GABA_A receptor agonist isoguvacine or the GABA_B receptor agonist baclofen attenuated the AAR. The effect of isoguvacine on the AAR was greater than that of baclofen. The GABA_A receptor antagonist gabazine enhanced the AAR, while the GABA_B receptor antagonist CGP-35348 had no significant effect on the AAR. Bilateral PVN microinjection of vigabatrin, a selective GABA-transaminase inhibitor, to increase endogenous GABA levels in the PVN abolished the AAR. The inhibitory effect of vigabatrin on the AAR was attenuated by the pretreatment with gabazine or CGP-35348. Pretreatment with combined gabazine and CGP-35348 abolished the effects of vigabatrin.

Conclusions

Activation of GABA_A or GABA_B receptors in the PVN inhibits the AAR. Blockade of GABA_A receptors in the PVN enhances the AAR. Endogenous GABA in the PVN plays an important role in regulating the AAR.     

Localization and developmental expression of GABAB receptors in the rat olfactory bulb

In this study, we investigated the distribution and developmental expression of the GABA_B receptor subunits, GABA_B1 and GABA_B2, in the main and accessory olfactory bulbs of the rat. Antibodies raised against these subunits strongly labelled the glomerular layer, suggesting that olfactory and vomeronasal nerve fibers express functional GABA_B receptors. Using postembedding immunogold cytochemistry, we found that GABA_B receptors can be present at both extrasynaptic and presynaptic sites of olfactory nerve terminals, and in the latter case they are preferentially associated with the peripheral part of the synaptic specialization. Olfactory nerve fibers expressed GABA_B1 and GABA_B2 at early developmental stages, suggesting that GABA_B receptors may play a role in olfactory development. Output and local neurons of the main and accessory olfactory bulbs were also labelled for GABA_B1 and GABA_B2, although the subcellular distribution patterns of the two subunits were not completely overlapping. These results indicate that presynaptically located GABA_B receptors modulate neurotransmitter release from olfactory and vomeronasal nerve fibers and that, in addition to this presynaptic role, GABA_B receptors may regulate neuronal excitability in infraglomerular circuits.     

Propofol suppresses synaptic responsiveness of somatosensory relay neurons to excitatory input by potentiating GABAA receptor chloride channels

Propofol is a widely used intravenous general anesthetic. Propofol-induced unconsciousness in humans is associated with inhibition of thalamic activity evoked by somatosensory stimuli. However, the cellular mechanisms underlying the effects of propofol in thalamic circuits are largely unknown. We investigated the influence of propofol on synaptic responsiveness of thalamocortical relay neurons in the ventrobasal complex (VB) to excitatory input in mouse brain slices, using both current- and voltage-clamp recording techniques. Excitatory responses including EPSP temporal summation and action potential firing were evoked in VB neurons by electrical stimulation of corticothalamic fibers or pharmacological activation of glutamate receptors. Propofol (0.6 – 3 μM) suppressed temporal summation and spike firing in a concentration-dependent manner. The thalamocortical suppression was accompanied by a marked decrease in both EPSP amplitude and input resistance, indicating that a shunting mechanism was involved. The propofol-mediated thalamocortical suppression could be blocked by a GABA_A receptor antagonist or chloride channel blocker, suggesting that postsynaptic GABA_A receptors in VB neurons were involved in the shunting inhibition. GABA_A receptor-mediated inhibitory postsynaptic currents (IPSCs) were evoked in VB neurons by electrical stimulation of the reticular thalamic nucleus. Propofol markedly increased amplitude, decay time, and charge transfer of GABA_A IPSCs. The results demonstrated that shunting inhibition of thalamic somatosensory relay neurons by propofol at clinically relevant concentrations is primarily mediated through the potentiation of the GABA_A receptor chloride channel-mediated conductance, and such inhibition may contribute to the impaired thalamic responses to sensory stimuli seen during propofol-induced anesthesia.     

Effect of inhibitory amino acid antagonists on postsynaptic potentials of motoneurons of the frog Rana ridibunda

On preparations of the isolated spinal cord of the frog Rana ridibunda at intracellular recording from lumbar motoneurons, it is shown that response to the 10 mM GABA application decreased selectively by 40.7 ± 23.7% (n = 6) as a result of the spinal cord treatment with bicuculline (100–150 μM), while response to the Gly application decreased selectively by 50.7 ± 17.8% (n = 10) after the spinal cord treatment with strychnine (5–10 μM). Both strychnine and bicuculline produced potentiation of EPSP by amplitude and duration as well as paroxysmal depolarizational shifts (PDS). Strychnine produced more effectively the potentiation, while bicuculline—PDS. The inhibitory Gly effect decreased significantly the DR and RF EPSP (a decrease of amplitude and duration) as a result of the spinal cord treatment with strychnine (5–10 μM), but not with bicuculline. The inhibitory GABA effect on the DR and RF EPSP decreased as a result of the spinal cord treatment with bicuculline only in a half of the studied motoneurons and to the lesser degree than the inhibitory Gly effect on the same EPSP at the strychnine treatment. Based of the obtained data, it is suggested that the inhibitory effects on the excitatory inputs of the motoneuron in the frog are expressed weaker than in mammals and are related predominantly to the GABA and Gly effects on receptors of interneurons. It is suggested that GABA specifically acts mostly on GABA_A receptors, whereas Gly—on Gly receptors, although there is some part of cross-inhibition. Original Russian Text ? G. G. Kurchavyi, N. I. Kalinina, and N. P. Vesselkin, 2006, published in Zhurnal Evolyutsionnoi Biokhimii i Fiziologii, 2006, Vol. 42, No. 5, pp. 463–471. The present work is a continuation of the work [1].     

Postnatal maturation of gamma-aminobutyric acidA and B-mediated inhibition in the CA3 hippocampal region of the rat

In the adult central nervous system, GABAergic synaptic inhibition is known to play a crucial role in preventing the spread of excitatory glutamatergic activity. This inhibition is achieved by a membrane hyperpolarization through the activation of postsynaptic γ-aminobutyric acid_A (GABA_A) and GABA_B receptors. In addition, GABA also depress transmitter release acting through presynaptic GABA_B receptors. Despite the wealth of data regarding the role of GABA in regulating the degree of synchronous activity in the adult, little is known about GABA transmission during early stages of development. In the following we report that GABA mediates most of the excitatory drive at early stages of development in the hippocampal CA3 region. Activation of GABA_A receptors induces a depolarization and excitation of immature CA3 pyramidal neurons and increases intracellular Ca²⁺ ([Ca²⁺]_i) during the first postnatal week of life. During the same developmental period, the postsynaptic GABA_B-mediated inhibition is poorly developed. In contrast, the presynaptic GABA_B-mediated inhibition is well developed at birth and plays a crucial role in modulating the postsynaptic activity by depressing transmitter release at early postnatal stages. We have also shown that GABA plays a trophic role in the neuritic outgrowth of cultured hippocampal neurons. © 1995 John Wiley & Sons, Inc.     

GABAA Receptor in the Thalamic Specific Relay System Contributes to the Propofol-Induced Somatosensory Cortical Suppression in Rat

Interaction with the gamma-aminobutyric-acid-type-A (GABA_A) receptors is recognized as an important component of the mechanism of propofol, a sedative-hypnotic drug commonly used as anesthetic. However the contribution of GABA_A receptors to the central nervous system suppression is still not well understood, especially in the thalamocortical network. In the present study, we investigated if intracerebral injection of bicuculline (a GABA_A receptor antagonist) into the thalamus ventral posteromedial nucleus (VPM, a thalamus specific relay nuclei that innervated S1 mostly) could reverse propofol-induced cortical suppression, through recording the changes of both spontaneous and somatosensory neural activities in rat’s somatosensory cortex (S1). We found that after injection of bicuculline into VPM, significant increase of neural activities were observed in all bands of local field potentials (total band, 182±6%), while the amplitude of all components in somatosensory evoked potentials were also increased (negative, 121±9% and positive, 124±6%).These data support that the potentiation of GABA_A receptor-mediated synaptic inhibition in a thalamic specific relay system seems to play a crucial role in propofol-induced cortical suppression in the somatosensory cortex of rats.     

GABAergic signaling in primary lens epithelial and lentoid cells and its involvement in intracellular Ca2+ modulation

Primary lens epithelial cell (LEC) cultures derived from newborn (P0) and one-month-old (P30) mouse lenses were used to study GABA (gamma-aminobutyric acid) signaling expression and its effect on the intracellular Ca²⁺ ([Ca²⁺]_i) level. We have found that these cultures express specific cellular markers for lens epithelial and fiber cells, all components of the functional GABA signaling pathway and GABA, thus recapitulating the developmental program of the ocular lens. Activation of both GABA-A and GABA-B receptors (GABA_AR and GABA_BR) with the specific agonists muscimol and baclofen, respectively induces [Ca²⁺]_i transients that could be blocked by the specific antagonists bicuculline and CGP55845 and were dependent on extracellular Ca²⁺. Bicuculline did not change the GABA-evoked Ca²⁺ responses in Ca²-containing buffers, but suppressed them significantly in Ca²⁺-free buffers suggesting the two receptors couple to convergent Ca²⁺ mobilization mechanisms with different extracellular Ca²⁺ sensitivity. Prolonged activation of GABA_BR induced wave propagation of the Ca²⁺ signal and persistent oscillations. The number of cells reacting to GABA or GABA + bicuculline in P30 mouse LEC cultures expressing predominantly the synaptic type GABA_AR did not differ significantly from the number of reacting cells in P0 mouse LEC cultures. The GABA-induced Ca²⁺ transients in P30 (but not P0) mouse LEC could be entirely suppressed by co-application of bicuculline and CGP55845. The GABA-mediated Ca²⁺ signaling may be involved in a variety of Ca²⁺-dependent cellular processes during lens growth and epithelial cell differentiation.     

Reduction of Presynaptic Action Potentials by PAD: Model and Experimental Study

A compartmental model of myelinated nerve fiber was used to show that primary afferent depolarization (PAD), as elicited by axo-axonic synapses, reduces the amplitude of propagating action potentials primarily by interfering with ionic current responsible for the spike regeneration. This reduction adds to the effect of the synaptic shunt, increases with the PAD amplitude, and occurs at significant distances from the synaptic zone. PAD transiently enhances the sodium current activation, which partly accounts for the PAD-induced fiber hyperexcitability, and enhances sodium inactivation on a slower time course, thus reducing the amplitude of action potentials. In vivo, intra-axonal recordings from the intraspinal portion of group I afferent fibers were carried out to verify that depolarizations reduced the amplitude of propagating action potentials as predicted by the model. This article suggests PAD might play a major role in presynaptic inhibition.     

Presynaptic inhibition and the participation of GABAB receptors at neuromuscular junctions of the crab Eriphia spinifrons

Presynaptic inhibition exerted by the common inhibitor on the closer and opener muscles and by the specific inhibitor on the opener muscle was investigated in the crab Eriphia spinifrons. In the closer muscle, activation of GABA_B receptors by baclofen reduced the mean quantal content of excitatory junctional currents by about 25%. Blocking GABA_B receptors with CGP 55845 diminished presynaptic inhibition at a similar percentage. GABA_B receptor-mediated presynaptic inhibition is linked to G proteins. Application of pertussis toxin eliminated about 25% of the inhibition exerted by the common inhibitory neuron. GABA_B receptors participate in presynaptic inhibition at release boutons of the slow and the fast closer excitor at a similar percentage. In the opener muscle, presynaptic inhibition of transmitter release from the same endings of the opener excitor was about 15% stronger with the specific inhibitor than with the common inhibitor. About 10% of the presynaptic inhibition produced by either one of the two inhibitors could be abolished by blocking GABA_B receptors. The amplitudes of the excitatory junctional currents in the opener were reduced in the presence of baclofen by about 25%, suggesting that synaptic terminals of the opener excitor are endowed with a similar percentage of GABA_B receptors as terminals of the slow and the fast closer excitors. Baclofen had no effect on postsynaptic inhibition, indicating that GABA_B receptors are not involved in postsynaptic neuromuscular inhibition. Accepted: 8 January 2000     

Heterogeneity of GABAA-receptors: cell-specific expression,pharmacology, and regulation

Vigilance, anxiety, memory, epileptogenic activity and muscle tension can be regulated by a modulation of GABA_A-receptor function. A multitude of different GABA_A-receptors exist in the brain due to the combinatorial assembly of various subunits encoded by at least 15 genes. The clarification of the physiological and pharmacological significance of GABA_A-receptor subtypes, in combination with their cellular localization, will make it possible to identify the neuronal circuits regulating the respective CNS states and to provide strategies for the development of subtype-specific drugs for selective therapies.Special issue dedicated to Robert Balázs     

Regulation of GABAergic inhibition by serotonin signaling in prefrontal cortex: molecular mechanisms and functional implications

Serotonergic neurotransmission in prefrontal cortex (PFC) plays a key role in regulating emotion and cognition under normal and pathological conditios. Increasing evidence suggests that serotonin receptors are involved in the complex regulation of GABAergic inhibitory transmission in PFC. Activation of postsynaptic 5-HT₂ receptors in PFC pyramidal neurons inhibits GABA_A-receptor currents via phosphorylation of GABA_A receptor γ2 subunits by RACK1-anchored PKC. In contrast, activation of postsynaptic 5-HT₄ receptors produces an activity-dependent bi-directional regulation of GABA-evoked currents in PFC pyramidal neurons, which is mediated through phosphorylation of GABA_A-receptor β subunits by anchored PKA. On the presynaptic side, GABAergic inhibition is regulated by 5-HT through the activation of 5-HT₂, 5-HT₁, and 5-HT₃ receptors on GABAergic intereneurons. These data provide a molecular and cellular mechanism for serotonin to dynamically regulate synaptic transmission and neuronal excitability in the PFC network, which may underlie the actions of many antidepressant and antipsychotic drugs.     

An in vitro study of long-term potentiation in the carp (Cyprinus carpio L.) olfactory bulb

Long-term potentiation (LTP) of synaptic transmission is considered a cellular mechanism for neural plasticity and memory formation. Previously, we showed that in the carp olfactory bulb, LTP occurs at the dendrodendritic mitral-to-granule cell synapse following tetanic electrical stimulation applied to the olfactory tract, and suggested that it is involved in the process of olfactory memory formation. As a first step towards understanding mechanisms underlying plasticity at this synapse, we examined the effects of various drugs (glutamate and GABA receptor agonists and antagonists, noradrenaline, and drugs affecting cAMP signaling) on dendrodendritic mitral-to-granule cell synaptic transmission in an in vitro preparation. Two forms of LTP are involved: a postsynaptic form (tetanus-evoked LTP) and a presynaptic form. The postsynaptic form is evoked at the granule cell dendrite following tetanic olfactory tract stimulation and is suppressed by the NMDA receptor antagonist, D-AP5, enhanced by noradrenaline, and occluded by the metabotropic glutamate receptor agonist, trans-ACPD. The presynaptic form occurs at the mitral cell dendrite following blockade of the GABA_A receptor by picrotoxin and bicuculline, or via activation of cAMP signaling by forskolin and 8-Br-cAMP.     

Effects of taurine on GABA release from synaptosomes of rat olfactory bulb

Summary Superfusion of synaptosomes prepared from rat olfactory bulb revealed constant basal release of endogenous taurine (Tau), aspartate (Asp), glutamate (Glu) and-aminobutyrate (GABA): their release rates were 110.4 ± 13.0, 30.3 ± 6.7, 93.7 ± 13.1, and 53.3 ± 8.8 pmol/min/mg protein, respectively. The depolarizing-stimulation with 30mM KCl evoked 1.17-, 2.18-, 2.55- and 1.53-fold increases, respectively. Tau release was calcium-independent. However, the perfusion of synaptosomes with Tau (10µM) inhibited the evoked increase in GABA release by 63% without changing basal release, although it did not affect release of Asp and Glu. Phaclofen (10µM, a GABA_B receptor antagonist), but not bicuculline (10µM, a GABA_A receptor antagonist), counteracted the Tau-induced reduction in GABA release. These data suggest that Tau may be abundantly released from nerve endings of rat olfactory bulb and that it may regulate GABA release through the activation of presynaptic GABA_B autoreceptors.