Noradrenaline excites and inhibits GABAergic transmission in parvocellular neurons of rat hypothalamic paraventricular nucleus

Noradrenaline (NA) is a major neurotransmitter that regulates many neuroendocrine and sympathetic autonomic functions of the hypothalamic paraventricular nucleus (PVN). Previously NA has been shown to increase the frequency of excitatory synaptic activity of parvocellular neurons within the PVN, but little is known about its effects on inhibitory synaptic activity. In this work, we studied the effects of NA (1-100 microM) on the spontaneous inhibitory synaptic currents (sIPSC) of type II PVN neurons in brain slices of the rat using the whole cell patch-clamp technique. Spontaneous IPSCs were observed from most type II neurons (n = 121) identified by their anatomical location within the PVN and their electrophysiological properties. Bath application of NA (100 microM) increased sIPSC frequency by 256% in 59% of the neurons. This effect was blocked by prazosin (2-20 microM), the alpha(1)-adrenoceptor antagonist and mimicked by phenylephrine (10-100 microM), the alpha(1)-adrenoceptor agonist. However, in 33% of the neurons, NA decreased sIPSC frequency by 54%, and this effect was blocked by yohimbine (2-20 microM), the alpha(2)-adrenoceptor antagonist and mimicked by clonidine (50 microM), the alpha(2)-adrenoceptor agonist. The Na(+) channel blocker, tetrodotoxin (0.1 microM) blocked the alpha(1)-adrenoceptor-mediated effect, but not the alpha(2)-adreonoceptor-mediated one. Both of the stimulatory and inhibitory effects of NA on sIPSC frequency were observed in individual neurons when tested with NA alone, or both phenylephrine and clonidine. Furthermore, in most neurons that showed the stimulatory effects, the inhibitory effects of NA were unmasked after blocking the stimulatory effects by prazosin or tetrodotoxin. These data indicate that tonic GABAergic inputs to the majority of type II PVN neurons are under a dual noradrenergic modulation, the increase in sIPSC frequency via somatic or dendritic alpha(1)-adrenoceptors and the decrease in sIPSC frequency via axonal terminal alpha(2)-adrenoceptors on the presynaptic GABAergic neurons.     

Noradrenergic regulation of parvocellular neurons in the rat hypothalamic paraventricular nucleus

Noradrenergic projections to the hypothalamic paraventricular nucleus have been implicated in the secretory regulation of several anterior pituitary hormones, including adrenocorticotropin, thyroid-stimulating hormone, growth hormone and prolactin. In an attempt to elucidate the effects of norepinephrine on the central control of pituitary hormone secretion, we looked at the actions of norepinephrine on the electrical properties of putative parvocellular neurons of the paraventricular nucleus using whole-cell current-clamp recordings in hypothalamic slices. About half (51%) of the putative parvocellular neurons recorded responded to norepinephrine with either a synaptic excitation or a direct inhibition. Norepinephrine (30-300microM) caused a marked increase in the frequency of excitatory postsynaptic potentials in about 36% of the parvocellular neurons recorded. The increase in excitatory postsynaptic potentials was blocked by prazosin (10microM), but not by propranolol (10microM) or timolol (20microM), indicating that it was mediated by alpha(1)-adrenoreceptor activation. It was also blocked by ionotropic glutamate receptor antagonists, suggesting that the excitatory postsynaptic potentials were caused by glutamate release. The increase in excitatory postsynaptic potentials was completely abolished by tetrodotoxin, indicating the spike dependence of the norepinephrine-induced glutamate release. In a separate group comprising 14% of the parvocellular neurons recorded, norepinephrine elicited a hyperpolarization (6.2+/-0.69mV) that was blocked by the beta-adrenoreceptor antagonists, propranolol (10microM) and timolol (20microM), but not by the alpha(1)-receptor antagonist, prazosin (10microM). This response was not blocked by tetrodotoxin (1.5-3microM), suggesting that it was caused by a direct postsynaptic action of norepinephrine. The topographic distribution within the paraventricular nucleus of the norepinephrine-responsive and non-responsive parvocellular neurons was mapped based on intracellular biocytin labeling and neurophysin immunohistochemistry.These data indicate that one parvocellular subpopulation, consisting of about 36% of the paraventricular parvocellular neurons, receives an excitatory input from norepinephrine-sensitive local glutamatergic interneurons, while a second, separate subpopulation, representing about 14% of the parvocellular neurons in the paraventricular nucleus, responds directly to norepinephrine with a beta-adrenoreceptor-mediated inhibition. This suggests that excitatory inputs to parvocellular neurons of the paraventricular nucleus are mediated mainly by an intrahypothalamic glutamatergic relay, and that only a relatively small subset of paraventricular parvocellular neurons receives direct noradrenergic inputs, which are primarily inhibitory.     

Effect of hypertonic saline on rat hypothalamic paraventricular nucleus parvocellular neurons in vitro

The effects of hypertonic saline on hypothalamic paraventricular nucleus (PVN) parvocellular neurons were examined using whole-cell patch-clamp technique. Under current-clamp, 50% (41/82) of parvocellular neurons were depolarized than the predicted values by hypertonic saline, and associated with increasing action potential frequency. Under voltage-clamp, unless hypertonic saline induced a shift of reverse potential to more positive values, neither mannitol nor hypertonic saline obviously increased the conductance in parvocellular neurons. Moreover, spontaneous excitatory postsynaptic currents (sEPSCs) were increased by isotonic increases in [Na⁺]_o in the parvocellular neurons. Bath application AMPA receptor antagonist CNQX or non-selective glutamate antagonist kynurenic acid almost completely blocked the sEPSCs. Extracellular application of gadolinium (Gd³⁺) blocked the hypertonic saline-induced response. These results suggested that subpopulation of PVN parvocellular neurons are selectively sensitive to NaCl. Hypertonic saline excited the PVN parvocellular neurons through Na⁺-detection and the excitatory glutamatergic synaptic input.     

Vasopressin increases GABAergic inhibition of rat hypothalamic paraventricular nucleus neurons in vitro

This investigation used an in vitro hypothalamic brain slice preparation and whole cell and perforated-patch recording to examine the response of magnocellular neurons in hypothalamic paraventricular nucleus (PVN) to bath applications of vasopressin (VP; 100-500 nM). In 22/38 cells, responses were characterized by an increase in the frequency of bicuculline-sensitive inhibitory postsynaptic potentials or currents with no detectable influence on excitatory postsynaptic events. Perforated-patch recordings confirmed that VP did not have an effect on intrinsic membrane properties of magnocellular PVN neurons (n = 17). Analysis of intrinsic membrane properties obtained with perforated-patch recording (n = 23) demonstrated that all of nine VP-sensitive neurons showed a rebound depolarization after transient membrane hyperpolarization from rest. By contrast, 12/14 nonresponding neurons displayed a delayed return to resting membrane potentials. Recordings of reversed inhibitory postsynaptic currents with chloride-loaded electrodes showed that responses to VP persisted in media containing glutamate receptor antagonists but were abolished in the presence of tetrodotoxin. In addition, responses were mimicked by vasotocin [Phe(2), Orn(8)], a selective V(1a) receptor agonist, and blocked by [beta-Mercapto-beta, beta-cyclopentamethylenepropionyl(1),O-Me-Tyr(2), Arg(8)]-VP (Manning compound), a V(1a)/OT receptor antagonist. Neither [deamino-Cys(1),Val(4),D-Arg(8)]-VP, a selective V(2) receptor agonist, nor oxytocin were effective. Collectively, the results imply that VP acts at V(1a) receptors to excite GABAergic neurons that are presynaptic to a population of magnocellular PVN neurons the identity of which features a unique rebound depolarization. Endogenous sources of VP may be VP-synthesizing neurons in suprachiasmatic nucleus, known to project toward the perinuclear regions of PVN, and/or the magnocellular neurons within PVN.     

去除窦弓神经引起下丘脑室旁核小细胞部氮能神经元持续激活(英文)

目的:旨在研究去除窦弓神经是否导致下丘脑室旁核(PVN)氮能神经元处于持续激活状态。方法:成年大鼠行窦弓神经去除术,1周后制备下丘脑脑片,进行还原型尼克酰胺腺嘌呤二核苷酸脱氢酶(NADPH-d)组织化学结合Fos免疫组织化学染色。结果:在PVN的内侧、背侧和外侧小细胞部有大量Fos阳性神经元分布,并与NADPH-d部分共存,但在PVN的室周和前小细胞部以及大细胞仅观察到弱阳性的Fos信号,偶尔观察到双标记神经元。结论:去窦弓神经大鼠下丘脑室旁核小细胞部氮能神经元处于持续激活状态,可能起代偿性抑制中枢交感活性的作用。     

Pregnancy decreases GABAergic inhibition of the hypothalamic paraventricular nucleus

Depressor responses to peripheral or central infusion of Angiotensin II type 1 (AT₁) receptor antagonists (AT₁X) are greater in pregnant (P) compared to nonpregnant (NP) animals. AT₁ and ionotropic excitatory amino acid (EAA) receptors contribute to pressor responses to GABA_A receptor blockade with bicuculline (Bic) in the paraventricular nucleus (PVN) of male rats. Therefore, we hypothesized that GABAergic inhibition is decreased and AT₁ receptors play a greater excitatory role in the PVN of P versus NP rats. Unilateral microinjection of Bic was performed before (Bic₁), after AT₁X (Bic₂), and after AT₁X + EAA blockade (kynurenate, Kyn) (Bic₃) in the PVN. Increases in mean arterial pressure (MAP: NP = 20 ± 2; P = 12 ± 2 mmHg), heart rate (HR: NP = 57 ± 6; P = 19 ± 6 beats/min) and renal sympathetic nerve activity (RSNA: NP = 70 ± 9; P = 33 ± 7%) due to Bic (Bic₁) were attenuated in P rats. Responses to AT₁X and Kyn alone were insignificant in both groups. In NP rats, AT₁X attenuated (+ 12 ± 4 mmHg), and AT₁X + Kyn further decreased the pressor response to Bic in the PVN (+ 6 ± 2 mmHg). In P rats AT₁X reduced the pressor response to Bic (+ 5 ± 1 mm Hg), and Kyn had no additional effect (+ 3 ± 1 mmHg). Effects of PVN Bic to alter the autospectra of RSNA were suppressed by prior AT₁X and Kyn in both groups. Thus, tonic GABAergic inhibition is decreased and the contribution of AT₁ receptors in the PVN may be greater in P rats.     

A slow transient potassium current expressed in a subset of neurosecretory neurons of the hypothalamic paraventricular nucleus

Type I putative magnocellular neurosecretory cells of the hypothalamic paraventricular nucleus (PVN) express a prominent transient outward rectification generated by an A-type potassium current. Described here is a slow transient outward current that alters cell excitability and firing frequency in a subset of type I PVN neurons (38%). Unlike most of the type I neurons (62%), the transient outward current in these cells was composed of two kinetically separable current components, a fast activating, fast inactivating component, resembling an A-type potassium current, and a slowly activating [10-90% rise time: 20.4 +/- 12.8 (SE) ms], slowly inactivating component (time constant of inactivation: tau = 239.0 +/- 66.1 ms). The voltage dependence of activation and inactivation and the sensitivity to block by 4-aminopyridine (5 mM) and tetraethylammonium chloride (10 mM) of the fast and slow components were similar. Compared to the other type I neurons, the neurons that expressed the slow transient outward current were less excitable when hyperpolarized, requiring larger current injections to elicit an action potential (58.5 +/- 13.2 vs. 15.4 +/- 2.4 pA; 250-ms duration; P < 0.01), displaying a longer delay to the first spike (184.9 +/- 15.7 vs. 89.7 +/- 8.8 ms with 250- to 1,000-ms, 50-pA current pulses; P < 0.01), and firing at a lower frequency (18. 7 +/- 4.6 vs. 37.0 +/- 5.5 Hz with 100-pA current injections; P < 0. 05). These data suggest that a distinct subset of type I PVN neurons express a novel slow transient outward current that leads to a lower excitability. Based on double labeling following retrograde transport of systemically administered fluoro-gold and intracellular injection of biocytin, these cells are neurosecretory and are similar morphologically to magnocellular neurosecretory cells, although it remains to be determined whether they are magnocellular neurons.     

Influence of noradrenergic input into the hypothalamic paraventricular nucleus on fever in the guinea-pig

The febrile response of guinea-pigs to a bacterial pyrogen was tested under different experimental conditions: (1) during electrical stimulation of the hypothalamic paraventricular nucleus (PVN), (2) after destruction of noradrenergic afferents into the PVN by 6-hydroxydopamine (6-OHDA), (3) during a microinfusion of noradrenaline (NA) into the PVN. Electrical stimulation of the PVN neurons by implanted microelectrodes reduced the febrile response to 45% of the control values. This confirmed the proposed antipyretic function of these neurons. Chronic destruction of noradrenergic afferents to the PVN by microinjected 6-OHDA also resulted in a significant reduction of febrile responses to 38% of the control values. A microinfusion of NA into the PVN enhanced the febrile responses to bacterial endotoxin by 39% in comparison to animals microinfused with the solvent (0.9% NaCl). Immunoreactivity to an antiserum against arginine vasopressin (AVP) was compared in PVN neurons of 6-OHDA-treated and of control animals. The number of AVP-immunoreactive perikarya and the intensity of immunoreactivity were increased in the animals treated with 6-OHDA, especially in the medial part of the PVN. Since fever was increased by microinfused NA and decreased by 6-OHDA treatment, we assume an inhibitory influence of noradrenergic brain stem afferents on the proposed antipyretic vasopressinergic system of the PVN.     

Nicotinic cholinergic activation of magnocellular neurons of the hypothalamic paraventricular nucleus

The aim of the present work was to determine whether paraventricular neurons possess functional acetylcholine nicotinic receptors. Using infrared videomicroscopy and differential interference contrast optics, we performed whole-cell recordings in hypothalamic slices containing the paraventricular nucleus. Acetylcholine, locally applied by pressure microejection in the presence of the muscarinic antagonist atropine, evoked a rapidly rising inward current in paraventricular magnocellular endocrine neurons. This current persisted in the presence of blockers of synaptic transmission. It could be reversibly suppressed by nanomolar concentrations of methyllycaconitine, a selective antagonist of alpha 7-containing nicotinic receptors, but was insensitive to micromolar concentrations of dihydro-beta-erythroidine, an antagonist acting preferentially on non-alpha 7 nicotinic receptors. In addition, the effect of acetylcholine could be mimicked by exo-2-(2-pyridyl)-7-azabicyclo[2.2.1]heptane, a recently synthesized nicotinic agonist specific for alpha 7 receptors. Acetylcholine also desensitized paraventricular nicotinic receptors. Desensitization was pronounced and recovery from desensitization was rapid, consistent with the notion that paraventricular nicotinic receptors contain the alpha 7 subunit. Nicotinic currents could not be evoked in paraventricular parvocellular neurons, suggesting that these neurons are devoid of functional nicotinic receptors. The electrophysiological data were corroborated by light microscopic autoradiography, showing that [(125)I]alpha-bungarotoxin binding sites are present in all the magnocellular divisions of the paraventricular nucleus but are undetectable in other areas of this nucleus. Immunohistochemistry, performed using antibodies directed against vasopressin and oxytocin, indicated that responsiveness to nicotinic agonists was a property of vasopressin as well as of oxytocin magnocellular endocrine neurons, in both the paraventricular and the supraoptic nucleus. We conclude that nicotinic agonists can influence the magnocellular neurosecretory system by directly increasing the excitability of magnocellular neurons. By contrast, they are probably without direct effects on paraventricular parvocellular neurons.     

Serotonin inhibits GABA synaptic transmission in presympathetic paraventricular nucleus neurons

Activation of serotonin (5-hydroxytryptamine, 5-HT) receptors produces various autonomic and neuroendocrine responses in the hypothalamic paraventricular nucleus (PVN), including increased blood pressure and heart rate. However, the role(s) of 5-HT on the local GABA synaptic circuit have not been well understood in the PVN, where the inhibitory neurotransmitter GABA plays a key role in the modulation of sympathoexcitatory outflow. In the present study, we examined the effects of 5-HT on GABA synaptic transmission in presympathetic PVN neurons projecting to spinal cord using patch-clamp electrophysiology combined with tract-tracing techniques. Bath application of 5-HT (0.01-100 microM) reversibly decreased the frequency of spontaneous GABAergic inhibitory postsynaptic currents (sIPSC) in a concentration dependent manner (IC50, 0.07 microM), with no significant changes in the amplitudes and decay kinetics of sIPSC. The sIPSC inhibition of 5-HT was mimicked by 5-HT1A agonist, 8-OH-DPAT (8-hydroxy-2(di-n-propylamino)tetralin, 10 microM), and blocked by 5-HT1A antagonist WAY-100635 but not by 5-HT1B antagonist SB224289. 5-HT also reduced the frequency of miniature IPSC (mIPSC) (2.59+/-0.51 Hz, control vs. 1.25+/-0.31 Hz, 5-HT, n=16) in similar extent with 5-HT induced reduction of sIPSC frequency (sIPSCs, 55.8+/-6.2%, n=11 vs. mIPSCs, 52.30+/-5.85%, n=16; p>0.5). All together, our results indicate that 5-HT can inhibit presynaptic GABA release via presynaptic 5-HT1A receptors in presympathetic PVN neurons projecting to spinal cord.     

An activation of parvocellular oxytocinergic neurons in the paraventricular nucleus in oxytocin-induced yawning and penile erection

Intracerebroventricular (ICV) or PVN local injections of oxytocin induce yawning and penile erection, for which a positive feedback mechanism for the PVN oxytocinergic activation is suggested, but this had not been directly substantiated in vivo. We have assessed the behavioral effects and activity of oxytocinergic neurons with double-staining for c-Fos and oxytocin in the PVN after ICV administration of oxytocin in adult male rats. ICV oxytocin injections (50 and 200 ng) dose-dependently induced yawning and penile erection and significantly increased the percentage of c-Fos positive oxytocin neurons in the medial, dorsal and lateral parvocellular subdivision of the PVN. However, increases in the magnocellular portion were not significant. We also found that lithium chloride (LiCl, 0.5 and l.0 mEq), a compound known to activate oxytocinergic neurons, also significantly increased the percentage of c-Fos positive oxytocin neurons in all PVN portions. However, LiCl did not induce yawning and penile erection, but counteracted the oxytocin-induced yawning and penile erection. These results suggest that if the activation of oxytocinergic neurons in the PVN is important for mediating oxytocin-induced yawning and penile erection, a selective activation of parvocellular oxytocinergic neurons in the PVN is likely to be involved.     

gamma-Aminobutyric acid antagonist blocks baroreceptor-activated inhibition of neurosecretory cells in the hypothalamic paraventricular nucleus of rats

The effects of gamma-aminobutyric acid (GABA) antagonists on baroreceptor-activated inhibition of neurosecretory cells in the paraventricular nucleus (PVN) were examined in urethane-chloralose anesthetized rats. In 11 neurosecretory cells which were inhibited by baroreceptor activation induced by intravenous application of phenylephrine, microiontophoretically applied bicuculline and/or picrotoxin blocked the inhibition (n = 9) completely or partially, whereas strychnine (n = 4) did not. The results suggest that GABA is, at least in part, involved in the baroreceptor-activated inhibition of PVN neurosecretory cells.     

Effect of hypertonic saline on rat hypothalamic paraventricular nucleus magnocellular neurons in vitro

The effect of hypertonic saline on rat hypothalamic paraventricular nucleus (PVN) magnocellular neurons was examined using a whole-cell patch-clamp technique. Under a current-clamp, 58/68 of magnocellular neurons were depolarized by hypertonic stimulation. Under a voltage-clamp, hypertonic saline produced an inward current via increased non-selective cationic conductance and shifting of the reversal potential to more positive values. Furthermore, hypertonic saline even without a change in osmolality increased spontaneous excitatory postsynaptic currents (sEPSCs). A bath application of CNQX almost completely blocked EPSCs. Extracellular application of gadolinium blocked the hypertonic saline- and mannitol-induced response. These results suggest that PVN magnocellular neurons are responsive to osmolality and Na+ concentrations. Hypertonic saline excited PVN magnocellular neurons via osmo-reception, Na+ -detection, and excitatory glutamatergic synaptic input.     

Influence of ascending noradrenergic fibers on the neurotensin-like immunoreactive neurons in the rat paraventricular nucleus

The topographic organization of cells containing choline-acetyltransferase (CAT) and located within the magnocellular nuclei of the basal forebrain was studied by correlating maximum CAT decrease in one or another cortical region with a given localization of the cell lesions. Lesions were made by using ibotenic acid. Lesions affecting the ventral pallidum decreased CAT activity in the antero-medial prefrontal cortex and lesions of the internal and ventral borders of the pallidum decreased CAT activity in sensori-motor and parieto-temporal cortices. None of these lesions produced a decrease of CAT activity in the hippocampus. These results suggest that it is possible to show the presence of a specific cholinergic projection from the basal forebrain to the medial-associative prefrontal cortex of the rat.     

Descending input from the hypothalamic paraventricular nucleus to sympathetic preganglionic neurons in the rat

Summary The descending projection of the hypothalamic paraventricular nucleus (PVN) to the sympathetic preganglionic neurons (SPNs) in the upper thoracic cord of the rat was studied. PVN-fibers were labeled by anterograde transport of Phaseolus vulgaris leucoagglutinin (PHA-L), while SPNs were retrogradely labeled with cholera toxin subunit B (CTb) which was injected into the superior cervical ganglion. SPNs labeled with CTb were mainly observed in the nucleus intermediolateralis (IML) pars principalis and pars funicularis, and a small number of them were in the nucleus intercalatus (IC) and central autonomic nucleus (CA). SPNs found in the IML had dendrites that projected in various directions. Five types of dendritic projections were noted: medial, rostral, caudal, lateral (including dorsolateral) and ventral. Longitudinal dendritic bundles interconnected each cell cluster in the IML. Medial dendrites of the IML, together with dendrites of the IC and CA, formed transverse dendritic bundles extending from the IML to the central canal. The transverse dendritic bundles disentangled near the midline and formed a loose dendritic plexus in the region just dorsal to the central canal. PVN-fibers labeled with PHA-L were observed primarily in lamina I and intermediate gray (lamina VII). Although varicose PVN-fibers and SPNs coexisted in the IML, the tight packing of the dendritic bundles prevented any clear demonstration of direct contacts between them. On the other hand, PVN-fibers were occasionally found to appose and wind around the primary or secondary dendrites of some SPNs of the CA and IC. These dendrites were studded with varicosities of PVN-fibers for a short length, and terminal boutons of PVN-fibers were also seen to make contact directly with the dendrites. The results of this study substantiated a direct connection between the PVN and SPNs, using a combination of immunohistochemical techniques for PHA-L and CTb. The possible involvement of a direct pathway from the PVN to SPNs in cardiovascular regulation is discussed.Abbreviations AF anterior funiculus - CA central autonomic nucleus - CC central canal - CTb cholera toxin subunit B - HRP horseradish peroxidase - IC nucleus intercalatus - IMf nucleus intermediolateralis pars funicularis - IML nucleus intermediolateralis - IMp nucleus intermediolateralis pars principalis - LDB longitudinal dendritic bundle - LF lateral funiculus - PF posterior funiculus - PHA-L Phaseolus vulgaris leucoagglutinin - PVN hypothalamic paraventricular nucleus - SPNs sympathetic preganglionic neurons - TDB transverse dendritic bundle     

Adrenalectomy abolishes fasting-induced down-regulation of NADPH-diaphorase in the rat paraventricular nucleus

This study was conducted to define the molecular mechanism of fasting-induced down-regulation of neuronal nitric oxide synthase (nNOS) expression in the hypothalamic paraventricular nucleus (PVN). Rats were adrenalectomized (ADX), and then either underwent food deprivation or received varying doses of dexamethasone for 48 h. The brain tissues were processed for NADPH-diaphorase (NADPH-d) staining, a histochemical marker of nNOS enzyme activity. Both the ADX and the sham operated rats showed a significant weight loss after 48 h of food deprivation. Food deprivation decreased the number of NADPH-d containing cells in the PVN of sham rats, however, not in the ADX rats. Dexamethasone dose- dependently decreased NADPH-d cells in the PVN of ADX rats. The effect of ADX or dexamethasone was limited to the parvocellular subdivision of PVN. These results suggest that the adrenal glucocorticoids may down-regulate nNOS expression in the PVN during food deprivation.     

Endogenous mGluR activity suppresses GABAergic transmission in avian cochlear nucleus magnocellularis neurons

GABAergic transmission in the avian cochlear nucleus magnocellularis (NM) of the chick is subject to modulation by gamma-aminobutyric acid type B (GABA(B)) autoreceptors. Here, I investigated modulation of GABAergic transmission in NM by metabotropic glutamate receptors (mGluRs) with whole cell recordings in brain slice preparations. I found that tACPD, a nonspecific mGluR agonist, exerted dose-dependent suppression on evoked inhibitory postsynaptic currents (eIPSCs) in NM neurons. At concentrations of 100 or 200 microM, tACPD increased the failure rate of GABAergic transmission. Agonists for group I (3,5-DHPG, 200 microM), group II (DCG-IV, 2 microM), and group III (L-AP4, 10 microM) mGluRs produced a significant reduction in the amplitude of eIPSCs and a significant increase in failure rate, indicating the involvement of multiple mGluRs in this modulation. The frequency, but not the amplitude, of miniature IPSCs (mIPSCs) was decreased significantly by 3,5-DHPG or DCG-IV. Neither frequency nor amplitude of mIPSCs was affected by L-AP4. mGluR antagonists LY341495 (20 microM) plus CPPG (10 microM) significantly increased the amplitude of eIPSCs, indicating that endogenous mGluR activity suppresses GABA release to NM neurons. Furthermore, blockage of mGluRs increased GABA-evoked discharges recorded under physiological Cl(-) concentrations, whereas tACPD (100 microM) eliminated them. The results indicate that mGluRs play important roles in achieving balanced excitation and inhibition in NM and preserving fidelity of temporal information encoded by NM neurons.