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At least 469 records · Page 26Linked to original sources
PubMed2004

Reduced GABAergic transmission and number of hippocampal perisomatic inhibitory synapses in juvenile mice deficient in the neural cell adhesion molecule L1.

Cell adhesion molecules have been implicated in neural development and hippocampal synaptic plasticity. Here, we investigated the role of the neural cell adhesion molecule L1 in regulation of basal synaptic transmission and plasticity in the CA1 area of the hippocampus of juvenile mice. We show that theta-burst stimulation (TBS) and pairing of low-frequency presynaptic stimulation with depolarization of postsynaptic CA1 pyramidal cells induced similar levels of LTP in L1-deficient and wild-type mice. The basal excitatory synaptic transmission and density of asymmetric excitatory synapses in the stratum radiatum were also normal in L1-deficient mice. Since L1 is expressed not only by principal cells but also by inhibitory interneurons, we recorded inhibitory postsynaptic currents (IPSCs) evoked in CA1 pyramidal cells by minimal stimulation of perisomatic interneurons. L1-deficient mice showed a reduction in the mean amplitude of putative unitary IPSCs, higher values of the coefficient of amplitude variation, higher number of failures in transmitter release, and a reduction in frequency but not amplitude of miniature IPSCs. The use-dependent modulation of inhibitory transmission by paired-pulse or short tetanic stimulation was, however, normal in L1-deficient mice. The physiological abnormalities correlated with a strong reduction in the density of inhibitory active zones, indicating that L1 is involved in establishing inhibitory perisomatic synapses in the hippocampus.

Animals↗
PubMed2006

Calcium-dependent changes of paired-pulse modulation at single GABAergic synapses.

Whole-cell patch-clamp and local electrical stimulation were used for measuring of monosynaptic GABAergic currents from rat hippocampal neurons in culture. Under control conditions (normal extracellular calcium, 2 mM) paired-pulse depression with 150 ms interpulse interval was observed. The mean current amplitude for both 1st and 2nd IPSCs displayed bell-shaped dependency from the stimulus amplitude. When extracellular Ca was either decreased to 0.5 mM or increased to 5 mM both mean amplitude of IPSCs and mean release probability decreased/increased correspondingly yet their dependences from the stimulus strength remained bell-shaped. Mean paired-pulse ratio was also affected--we observed facilitation of second IPSC in low-calcium whereas the latter was depressed in high-calcium solution. Our results suggest that calcium concentrations not only regulate the strength of paired-pulse plasticity but also can invert its direction.

Animals↗
PubMed2006

Bilirubin potentiates inhibitory synaptic transmission in lateral superior olive neurons of the rat.

Bilirubin is a well-known neurotoxin that can result in multiple neurologic deficits. Previous studies have suggested that bilirubin affects aspects of synaptic transmission; however the acute effects of bilirubin on synaptic transmission have not been examined in real-time. In this study, using whole-cell voltage-clamp recordings, we observed the effect of bilirubin on inhibitory postsynaptic currents (IPSC) in postnatal 13-15-day-old neurons dissociated from lateral superior olive nuclei (LSO), one of the brainstem auditory nucleus that are highly vulnerable to bilirubin. The results showed that 10(-5)M bilirubin increased the frequency of spontaneous IPSC without causing change in their amplitudes or in the response to bath applied glycine, suggesting a presynaptic locus for the action. In the presence of tetrodotoxin, the frequency of miniature IPSC was also potentiated by 10(-5)M bilirubin. The facilitation by bilirubin was concentration dependent and increased with an increase in exposure time. Bicuculline only partially reduced the action of bilirubin. The action of bilirubin was observed in extracellular Ca(2+)-free ([Ca(2+)](o) free) solution but was fully occluded by pretreatment with BAPTA-AM in [Ca(2+)](o) free solution. Thus, in LSO neurons, bilirubin facilitates inhibitory synaptic transmission, in a manner independent of voltage-activated Na(+) and Ca(2+) channels but dependent on presynaptic [Ca(2+)](i). The increase of inhibitory synaptic transmission in response to acute bilirubin is a novel effect of bilirubin on the central nervous system and may have implications for neurotoxicity and the impairment of auditory transduction seen in hyperbilirubinemia.

Animals↗
PubMed2005

Timing and specificity of feed-forward inhibition within the LGN.

Local interneurons provide feed-forward inhibition from retinal ganglion cells (RGCs) to thalamocortical (TC) neurons, but questions remain regarding the timing, magnitude, and functions of this inhibition. Here, we identify two types of inhibition that are suited to play distinctive roles. We recorded excitatory and inhibitory postsynaptic currents (EPSCs/IPSCs) in TC neurons in mouse brain slices and activated individual RGC inputs. In 34% of TC neurons, we identified EPSCs and IPSCs with identical thresholds that were tightly correlated, indicating activation by the same RGC. Such "locked" IPSCs occurred 1 ms after EPSC onset. The remaining neurons had only "nonlocked" inhibition, in which EPSCs and IPSCs had different thresholds, indicating activation by different RGCs. Nonlocked inhibition may refine receptive fields within the LGN by providing surround inhibition. In contrast, dynamic-clamp recordings suggest that locked inhibition improves the precision of synaptically evoked responses in individual TC neurons by eliminating secondary spikes.

Action Potentials↗
PubMed2004

Adenosine A2A receptor-induced inhibition of NMDA and GABAA receptor-mediated synaptic currents in a subpopulation of rat striatal neurons.

The function of adenosine A(2A) receptors, localized at the enkephalin-containing GABAergic medium spiny neurons of the striatum, has been discussed controversially. Here we show that, in the absence of external Mg(2+), the adenosine A(2A) receptor agonist CGS 21680 postsynaptically depressed the NMDA, but not the non-NMDA (AMPA/kainate) receptor-mediated fraction of the electrically evoked EPSCs in a subpopulation of striatal neurons. Current responses to locally applied NMDA but not AMPA were also inhibited by CGS 21680. However, in the presence of external Mg(2+), the inhibition by CGS 21680 of the GABA(A) receptor-mediated IPSCs led to a depression of the EPSC/IPSC complexes. The current response to the locally applied GABA(A) receptor agonist muscimol was unaltered by CGS 21680. Whereas, the frequency of spontaneous (s)IPSCs was inhibited by CGS 21680, their amplitude was not changed. Hence, it is suggested that under these conditions the release rather than the postsynaptic effect of GABA was affected by CGS 21680. In conclusion, under Mg(2+)-free conditions, CGS 21680 appeared to postsynaptically inhibit the NMDA receptor-mediated component of the EPSC, while in the presence of external Mg(2+) this effect turned into a presynaptic inhibition of the GABA(A) receptor-mediated IPSC.

Adenosine↗
PubMed2005

Galanin receptor-1 knockout mice exhibit spontaneous epilepsy, abnormal EEGs and altered inhibition in the hippocampus.

Galanin is a widely-distributed neuropeptide that acts as an endogenous anticonvulsant. We have recently generated a galanin receptor type 1 knockout mouse (Galr1(-/-)) that develops spontaneous seizures. Our aim here was to characterize the seizures by making electroencephalogram (EEG) recordings from this animal, and also to elucidate the cellular basis of its epileptic phenotype by studying the neurophysiology of CA1 pyramidal neurons in acute hippocampal slices. EEGs showed that major seizures had a partial onset with secondary generalization, and that paroxysms of spike-and-slow waves occurred and were associated with hypoactivity. The interictal EEG was also abnormal, with a marked excess of spike-and-slow waves. Slice experiments showed that resting potential, input resistance, intrinsic excitability, paired-pulse facilitation of excitatory and inhibitory postsynaptic currents (EPSCs and IPSCs), stimulus--response plots for EPSCs, and several properties of spontaneous miniature EPSCs and IPSCs were all unchanged in the mutant mouse compared with wildtype. However, the frequency of miniature IPSCs was significantly reduced in the mutants. These results suggest that impaired synaptic inhibition in the hippocampus may contribute to the local onset of seizures in the Galr1(-/-) mouse.

Animals↗
PubMed2005

Modulation of available vesicles and release kinetics at the inhibitor of the crayfish neuromuscular junction.

We have investigated the effect of serotonin (5-HT) and okadaic acid (OA) on presynaptic processes at the crayfish inhibitory neuromuscular junction. Two different physiological parameters of transmitter release were examined: release kinetics and the size of the readily releasable pool of vesicles (RRP). Using a paired pulse stimulus and high frequency trains, we established that a single broad action potential, recorded in 20 mM tetraethylammonium and 1 mM 4-amino-pyridine, released the RRP in its entirety. Thus, by measuring the amplitude of inhibitory postsynaptic potential (IPSC) we were able to directly assess the effects of 5-HT and OA on the RRP. Serotonin at 200 nM and OA at 2.5 microM each significantly increased IPSC above control levels and the effects of these two modulators were comparable. Both modulators also induced a leftward shift in the rising phase of IPSC, i.e. an apparent acceleration in release kinetics. The shift caused by OA was significantly more pronounced than that induced by 5-HT. This apparent acceleration in release was not associated with a corresponding change in the presynaptic Ca2+ transient measured at a 2 kHz resolution, suggesting that modulation was not due to an acceleration in Ca2+ channel kinetics. In view of the comparable increase in the size of the RRP by the modulators, the differential modulation of release kinetics suggests that these two parameters may be modulated by separate biochemical processes.

4-Aminopyridine↗
PubMed2006

Contribution of brainstem GABA(A) synaptic transmission to morphine analgesic tolerance.

Chronic opioid-induced analgesic tolerance remains a major obstacle to improving clinical management of moderate to severe chronic pain. Our understanding of the underlying mechanisms for opioid tolerance is only partially understood at present. In this study, we investigated the effects of chronic morphine on GABA(A) receptor-mediated synaptic transmission, a major opioid target for pain inhibition, and the behavioral role of GABA synaptic transmission in the development of morphine tolerance. In the nucleus raphe magnus (NRM), a critical brainstem site for opioid analgesia, the GABA(A) receptor-mediated inhibitory postsynaptic current (IPSC) was significantly increased in NRM neurons kept in a morphine-tolerant state from chronic morphine-treated rats. The potency of cAMP analogs for enhancing the GABA IPSC was also enhanced. The protein kinase A (PKA) inhibitor H89 reversed the chronic morphine-induced synaptic adaptation in GABA IPSCs. Behaviorally, a low dose of GABA(A) receptor antagonist bicuculline microinjected into the NRM, ineffective alone, blocked morphine antinociception in control rats, but failed to do so in morphine-tolerant rats. With chronic treatment through daily NRM microinjections, bicuculline augmented the development of morphine tolerance, whereas the GABA(A) receptor agonist muscimol or H89 significantly attenuated the development of morphine tolerance. These results suggest that chronic morphine increases GABA synaptic activity through upregulation of the AMP system in morphine-tolerant NRM neurons and that while chronic GABA(A) receptor antagonism in the NRM augments morphine tolerance, chronic activation of NRM GABA(A) receptors or PKA inhibition reduces morphine tolerance with increased analgesic efficacy of chronic morphine.

Analgesics, Opioid↗
PubMed2026

Generation of two induced pluripotent stem cell lines from hereditary hemorrhagic telangiectasia patients harboring ACVRL1 mutations.

Hereditary hemorrhagic telangiectasia (HHT) is an autosomal dominant vascular disorder in which dysregulated endothelial signaling drives telangiectasias and arteriovenous malformations across multiple organs. Loss-of-function variants in ACVRL1 (ALK1), a core receptor in BMP9/10 signaling, are a major genetic cause. Here we report two patient-derived induced pluripotent stem cell (iPSC) lines generated from clinically diagnosed HHT donors carrying heterozygous ACVRL1 mutations: c.129dup (p.Pro44Alafs*125) and c.430C > T (p.Arg144*). Both lines showed expected iPSC morphology, robust expression of markers of the undifferentiated iPSC state, genomic stability by LP-WGS, and tri-lineage differentiation capacity. These resources enable human cell-based studies of ACVRL1 haploinsufficiency and provide a starting point for mechanistic and therapeutic work focused on HHT vascular pathobiology.

Journal Article↗
PubMed2006

Cholinergic modulation of periaqueductal grey neurons: does it contribute to epileptogenesis after organophosphorus nerve agent intoxication?

Previous work has shown that a single focal microinjection of the unselective cholinergic agonist, carbachol, into the periaqueductal grey (PAG) of the midbrain is sufficient to induce forebrain seizures in rats. In order to determine the cholinergic mechanisms underlying epileptogenesis at the cellular and network level of the PAG, we performed whole-cell recordings from rat PAG neurons in vitro and examined how the activation of muscarinic and nicotinic receptors modulates cellular excitability and synaptic responses. Stimulation of muscarinic receptors produced either a pirenzepine-sensitive depolarization (40% of PAG neurons), or a gallamine-sensitive hyperpolarization (20%), suggesting the involvement of M1 and M2 receptors, respectively. In the remaining neurons (40%), no change was observed. Voltage-clamp recordings showed that muscarinic depolarization resulted from the inhibition of a resting K(+) current, in part accompanied by simultaneous activation of a presumed non-selective cation current. Muscarinic hyperpolarization was caused by the activation of a G protein-coupled, inwardly rectifying K(+) current. Stimulation of muscarinic receptors enhanced the frequency of spontaneous inhibitory postsynaptic currents (IPSCs), but strongly suppressed evoked IPSCs. In addition, nicotine almost doubled the frequency of miniature IPSCs. Based on our findings and the network properties of the PAG, we advance a scenario in which excessive stimulation of cholinergic receptors would substantially contribute to generalized seizures after organophosphorus nerve agent poisoning.

Animals↗
PubMed2000

Tetanus-induced asynchronous GABA release in cultured hippocampal neurons.

Asynchronous GABA release was studied in cultured hippocampal neurons using paired whole-cell recordings. Tetanization of the presynaptic GABAergic neuron was accompanied by a train of IPSCs which showed tetanic depression. Asynchronous IPSCs (asIPSCs) also developed during the train and continued for 1.85+/-0.3 s after the stimulation. The threshold frequency for evoking asIPSCs was 10 Hz, while maximal asynchronous activity was achieved at 40 Hz. Perfusion with EGTA-AM blocked asIPSCs. The elevation of [Ca(2+)](i) that accompanies presynaptic action potential firing triggers asynchronous release of GABA vesicles, thereby counteracting tetanic depression of synchronous IPSCs.

2-Amino-5-phosphonovalerate↗
PubMed2000

Presynaptic modulation of synaptic gamma-aminobutyric acid transmission by tandospirone in rat basolateral amygdala.

Nystatin-perforated patch recordings were made from mechanically dissociated neurons (in which functional native presynaptic nerve terminals are preserved), isolated from the basolateral amygdala regions to investigate the effects of tandospirone on gamma-aminobutyric acidergic (GABAergic) inhibition. Two types of neurons, ovoid-shaped and pyramidal-shaped neurons, were obtained from the basolateral amygdala nuclei and the electrophysiological characteristics of these two types of neurons supported the morphological classification of these isolated neurons. From the ovoid-shaped neurons, bicuculline-sensitive GABA(A)ergic miniature inhibitory postsynaptic currents (miniature IPSC) were recorded in the presence of tetrodotoxin, 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX) and DL-2-amino-5-phosphovaleric acid (DL-AP5). Tandospirone (10 microM) reversibly and continuously inhibited the GABAergic miniature synaptic events to 66.3+/-2.1% of control (P<0.01, n=17) without affecting the miniature IPSC amplitude (104.0+/-3.1% of control, n=17). The similar inhibition of miniature IPSC frequency was mimicked by a specific 5-HT1A receptor agonist 8-hydroxy-2-(di-n-propylamino) tetralin (8-OH-DPAT, 1 microM), and the effects of tandospirone were prevented in the presence of a specific 5-HT1A receptor antagonist 1-(2-methoxyphenyl)-4-[4-(2-phthalimido)butyl] piperazine hydrobromide (NAN-190, 1 microM). Activation of 5-HT1A receptors by 8-OH-DPAT (1 microM) evoked no direct postsynaptic effects in enzyme-treated isolated basolateral amygdala neurons, suggesting that tandospirone acts at presynaptic 5-HT1A receptors. Furthermore, this presynaptic inhibition by tandospirone was prevented after treatment with a pertussis toxin-sensitive GTP-binding protein (G-protein) inhibitor, N-ethylmaleimide (at 3 microM for 5 min). In conclusion, in the basolateral amygdala nuclei, tandospirone activated presynaptic 5-HT1A receptors on the GABAergic nerve terminals projecting to ovoid-shaped neurons and inhibited synaptic GABA transmission via G-proteins.

8-Hydroxy-2-(di-n-propylamino)tetralin↗
PubMed2001

Cannabinoids inhibit GABAergic synaptic transmission in mice nucleus accumbens.

In mice nucleus accumbens slices, whole-cell patch clamp recording of medium-spiny neurons revealed that cannabimimetics ((R)-(+)-[2,3-dihydro-5-methyl-3-(4-morpholinylmethyl)pyrrolo[1,2,3-de]-1,4-benzoxazin-6-yl]-1-naphtalenylmethanone) (WIN-2) and ((-)-cis-3-[2-hydroxy-4-(1,1-dimethylheptyl)-phenyl]-trans-4-(3-hydroxypropyl)cyclohexanol) inhibit stimulus-evoked gamma-aminobutyric acid mediated inhibitory post-synaptic currents (IPSC). The actions of WIN-2 were reversed by the selective cannabinoid CB(1) receptor antagonist [N-piperidin-1-yl)-5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-carboximide hydrochloride] (SR141716A). WIN-2 modified paired-pulse ratio of evoked IPSCs and decreased miniature IPSC frequency indicating a presynaptic localization of cannabinoid CB(1) receptors.

Analgesics↗
PubMed2000

The anticonvulsant, lamotrigine decreases spontaneous glutamate release but increases spontaneous GABA release in the rat entorhinal cortex in vitro.

It has been suggested that the anticonvulsant effect of lamotrigine resides with it's ability to block voltage gated Na-channels at presynaptic sites, thus stabilizing the presynapse, and, consequently, reducing the release of synaptic transmitters. Neurochemical studies have shown that it can inhibit the veratrine-stimulated release of the excitatory transmitter, glutamate from cortical tissue, but that at slightly higher concentrations it also reduces the release of the inhibitory transmitter, GABA. In the present study we examined the effect of the drug on the release of these transmitters at synapses in the rat entorhinal cortex, using the whole-cell patch clamp technique to record spontaneous excitatory (EPSCs) and inhibitory postsynaptic currents (IPSCs). Lamotrigine reduced the frequency, but not the amplitude of spontaneous EPSCs. This clearly indicated a presynaptic effect to reduce the release of glutamate. However, the same effect was observed when we tested the drug on miniature EPSCs, recorded in the presence of TTX and Cd, showing that blockade of Na-channels or Ca-channels was not a prerequisite for inhibition of glutamate release. In contrast to it's effects on EPSCs, lamotrigine increased both the frequency and amplitude of spontaneous IPSCs, suggesting that the drug was acting presynaptically to enhance GABA release. Again, similar effects were seen with miniature IPSCs recorded in TTX. These opposite effects of lamotrigine on glutamate and GABA release are similar to those we have reported previously with phenytoin, and suggest that reciprocal modulation of the background release of the major excitatory and inhibitory transmitters may be a significant factor in dampening excitability in pathologically hyperexcitable cortical networks.

Animals↗
PubMed2002

Lamotrigine reduces spontaneous and evoked GABAA receptor-mediated synaptic transmission in the basolateral amygdala: implications for its effects in seizure and affective disorders.

Lamotrigine (LTG) is an antiepileptic drug that is also effective in the treatment of certain psychiatric disorders. Its anticonvulsant action has been attributed to its ability to block voltage-gated Na(+) channels and reduce glutamate release. LTG also affects GABA-mediated synaptic transmission, but there are conflicting reports as to whether inhibitory transmission is enhanced or suppressed by LTG. We examined the effects of LTG on GABA(A) receptor-mediated synaptic transmission in slices from rat amygdala, a brain area that is particularly important in epileptogenesis and affective disorders. In intracellular recordings, LTG (100 microM) reduced GABA(A) receptor-mediated IPSPs evoked by electrical stimulation in neurons of the basolateral nucleus. In whole-cell recordings, LTG (10, 50 and 100 microM) decreased the frequency and amplitude of spontaneous IPSCs, as well as the amplitude of evoked IPSCs, but had no effect on the kinetics of these currents. LTG also had no effects on the frequency, amplitude or kinetics of miniature IPSCs recorded in the presence of TTX. These results suggest that in the basolateral amygdala, LTG suppresses GABA(A) receptor-mediated synaptic transmission by a direct and/or indirect effect on presynaptic Ca(++) influx. The modulation of inhibitory synaptic transmission may be an important mechanism underlying the psychotropic effects of LTG.

Amygdala↗
PubMed2003

Competitive GABA(A) receptor antagonists increase the proportion of functional high-affinity alpha6 subunit-containing receptors in granule cells of adult rat cerebellum.

To investigate the properties of alpha6 subunit-containing GABA(A) receptors, whole-cell patch-clamp recordings were made from granule cells in adult rat cerebellar slices. In control, only currents evoked by low concentrations of GABA were significantly reduced in amplitude by furosemide, the alpha6 subunit-containing receptor antagonist. However, in the presence of competitive GABA(A) receptor antagonists, the furosemide block of currents evoked by higher GABA concentrations was markedly increased. Zinc, which preferentially blocks alpha6 subunit-containing receptors, also produced an increased block in the presence of bicuculline. To investigate whether similar effects occurred at synaptic receptors, inhibitory postsynaptic currents (IPSCs) were recorded. In most cells, furosemide produced little or no reduction in evoked IPSC amplitude. However in the presence of SR95531, a competitive antagonist, furosemide markedly reduced IPSC amplitude. One hypothesis, which could account for these observations, is that competitive antagonists prevent the continual activation of alpha6beta2/3gamma2 receptors by endogenous GABA and thus prevent their desensitisation. This hypothesis appears feasible as prolonged applications of low concentrations of GABA to recombinant alpha6beta2gamma2s receptors resulted in their desensitisation.

Animals↗
PubMed2003

Cannabinoid receptor-1 activation suppresses inhibitory synaptic activity in human dentate gyrus.

In spite of their popular uses as recreational drugs and their potential therapeutic uses, little direct information has been obtained about the synaptic effects of cannabinoids in the human brain. In the present study, patch-clamp recordings were performed on granule cells of the human dentate gyrus and the effects of cannabinoid receptor-1 (CB1) activation on inhibitory synaptic activity were examined. Activation of CB1 receptors by WIN55212-2 significantly suppressed both frequency and amplitude of spontaneous inhibitory synaptic currents (IPSCs) to about 50% of control. The suppressive effects were completely abolished in the presence of the CB1 receptor antagonist, AM251. WIN55212-2 also suppressed evoked IPSCs. However, neither frequency nor amplitude of miniature IPSCs were affected by WIN55212-2. These results provide electrophysiological evidence for the role of CB1 receptors in modulating inhibitory activity in human dentate gyrus.

Adolescent↗
PubMed2003

Chronic treatment with ionotropic glutamate receptor antagonist kynurenate affects GABAergic synaptic transmission in rat hippocampal cell cultures.

It is well documented that prolonged treatment with antagonists of ionotropic glutamate receptors activates a number of homeostatic mechanisms including alteration of glutamatergic transmission. We studied whether this treatment can also affect GABAergic transmission. Using whole-cell voltage clamp recording and local extracellular stimulation we investigated evoked inhibitory postsynaptic currents (IPSCs) in cultured rat hippocampal neurons grown in the presence of ionotropic glutamate receptor antagonist kynurenate (1 mM) and in control conditions. Chronic kynurenate treatment did not significantly affect the amplitude of evoked IPSCs and IPSC reversal potentials. In contrast we found that the paired-pulse depression was increased by 67% in cultures treated with kynurenic acid. We conclude that additional mechanism(s), alteration of GABAergic synaptic transmission, may contribute to homeostatic plasticity induced by chronic block of ionotropic glutamate receptors.

Animals↗