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At least 433 records · Page 24Linked to original sources
PubMed1991

Gamma-butyrolactone antagonism of the picrotoxin receptor: comparison of a pure antagonist and a mixed antagonist/inverse agonist.

Multiple receptors modulate the ion channel gated by the inhibitory neurotransmitter gamma-aminobutyric acid (GABA). gamma-Butyrolactones and gamma-thiobutyrolactones are compounds that act at the picrotoxin recognition site on the GABA receptor complex as either agonists or inverse agonists, depending on the nature of the alkyl substituents. Here we have compared the effects of two gamma-butyrolactones, alpha-ethyl-alpha-methyl-gamma-butyrolactone (alpha EMGBL) and alpha-isopropyl-alpha-methyl-gamma-butryolactone (alpha IMGBL), on GABA currents and inhibitory postsynaptic currents (IPSCs) in cultured, voltage-clamped, rat hippocampal neurons. alpha EMGBL also decreased the rate of IPSC decay without altering IPSC peak amplitude. At higher GABA concentrations (30 microM), alpha EMGBL has already been shown to block picrotoxin receptor agonists and inverse agonists. Thus, alpha EMGBL is a mixed antagonist/inverse agonist. In contrast to alpha EMGBL, alpha IMGBL had no effect on responses to either 0.5 or 30 microM GABA or on IPSCs, but it was able to block the effects of picrotoxin receptor agonists and inverse agonists. Therefore, alpha IMGBL is the first pure antagonist to be described for the picrotoxin receptor. The main conductance state of the GABA-gated channel probably has two or more open states, brief openings associated with binding of a single GABA molecule and longer openings due to the binding of two GABA molecules. We were able to simulate the results obtained with alpha EMGBL, using a computer model, by assuming that alpha EMGBL altered only the opening and closing rate constants for the monoliganded open channel of the GABA receptor. In addition to having site-selective actions, these results suggest that drugs modulating the GABA-linked chloride ionophore may be specific for the kinetic state of the GABA-gated channel.

4-Butyrolactone↗
PubMed1990

Physiological regulation of the picrotoxin receptor by gamma-butyrolactones and gamma-thiobutyrolactones in cultured hippocampal neurons.

We examined the effects of alkyl-substituted gamma-butyrolactones (GBLs), and gamma-thiobutyrolactones (TBLs) on GABA currents in cultured, voltage-clamped rat hippocampal neurons. Convulsant GBLs and TBLs reversiby diminished GABA responses in a concentration-dependent manner. beta-Ethyl-beta-methyl GBL (beta-EMGBL) completely abolished GABA responses at 3 mM (IC(50)390 microM), while TBL and beta-ethyl-beta-methyl TBL (beta-EMTBL)-induced inhibition of GABA currents was incomplete, saturating at about 50% of control at 300 microM and 10 mM for beta-EMTBL and TBL, respectively. beta-EMGBL and beta-EMTBL both increased the rate of decay of inhibitory post-synaptic currents (IPSCs) and beta-EMGBL also decreased IPSC peak amplitude. In contrast, the anticonvulsant alpha-ethyl-alpha-methyl TBL (alpha-EMTBL) potentiated GABA currents at all GABA concentrations tested; maximal potentiation was 190% of control at 1 mM alpha-EMTBL (EC50 102 microM). Another anticonvulsant alpha-ethyl-alpha-methyl GBL (alpha-EMGBL), potentiated responses to low (0.5 microM) but not high (greater than or equal to 10 microM) GABA. It also blocked the inhibitory effects of picrotoxin and beta-EMGBL and the facilitative effect of alpha-EMTBL on responses to 30 microM GABA. alpha-EMGBL did not interfere with other agents which augment GABA currents. Both alpha-EMTBL and alpha-EMGBL decreased the rate of IPSC decay without altering IPSC peak amplitude. None of these compounds had any direct membrane effects. We propose that beta-alkyl GBLs diminish GABA currents, and therefore, we hypothesize that these compounds are picrotoxin receptor agonists. beta-Alkyl TBLs partially diminish GABA currents and may be partial agonists.(ABSTRACT TRUNCATED AT 250 WORDS)

4-Butyrolactone↗
PubMed1995

The serotonergic inhibitory postsynaptic potential in prepositus hypoglossi is mediated by two potassium currents.

Synaptic inhibition mediated by the activation of potassium channels has been reported from several types of neurons. In each case, despite mediation by different neurotransmitters, the K+ conductance underlying the synaptic potential is activated by a G protein and inwardly rectifies. We report here a second K+ current that contributes to synaptic inhibition. Intracellular recordings were made from guinea pig nucleus prepositus hypoglossi in vitro, where we have described a 5-HT-mediated IPSP. Voltage-clamp analysis of the current induced by applied 5-HT revealed two separate conductances: an inwardly rectifying, rapidly activating K+ current (IIR) and an outwardly rectifying, slowly activating K+ current (IOR). IIR was blocked by extracellular Ba2+ (200 microM) and TEA+ (126 mM). IOR was insensitive to this concentration of Ba2+ and TEA+, but was inhibited by Cd2+ and intracellular BAPTA, indicating Ca dependence. Single focal electrical stimuli evoked a 5-HT-mediated IPSP, or under voltage clamp, an inhibitory postsynaptic current (IPSC). Ba2+ blocked only a component of this IPSC, which corresponded to the current caused by IIR. When multiple stimuli were applied (to prolong the release of transmitter), the time-dependent current IOR was more fully activated, resulting in an augmentation of the IPSC. We conclude that the IPSC is caused by both currents and that its amplitude can be modulated by the degree to which IOR is activated. This represents a mechanism by which synaptic responses can be potentiated.

Animals↗
PubMed1995

Endogenous opioids regulate long-term potentiation of synaptic inhibition in the dentate gyrus of rat hippocampus.

Long-term potentiation (LTP) of excitatory transmission in the hippocampus has been extensively studied as a synaptic model of learning and memory. Here we report a new form of LTP in which inhibitory synaptic signals are potentiated following tetanic stimulation of an opioid-containing excitatory pathway in the presence of opioid antagonists. The lateral perforant path (LPP) was stimulated at the dentate outer molecular layer of hippocampal slices. Evoked synaptic currents were recorded from dentate granule cells using whole-cell voltage-clamp techniques. A high-frequency stimulus train (100 Hz, 1 sec) delivered to the LPP in the presence of naloxone (1 microM) was found to induce a long-lasting potentiation (20 min to 2 hr) in the amplitude of gamma-aminobutyric acidA (GABAA) receptor-mediated inhibitory postsynaptic currents (IPSCs) of granule cells. Such a potentiation was not observed when tetanizing the LPP in control medium. Naloxone-revealed LTP of LPP-evoked IPSCs did not depend upon the presence of granule cell discharge, and was not accompanied by potentiation of mossy fiber-evoked IPSCs, indicating that feedforward, but not feedback, inhibitory circuits were involved. Induction of this LTP could be completely blocked by the N-methyl-D-aspartate (NMDA) receptor antagonist D-2-amino-5-phosphonopentanoic acid (D-APV). However, it was not significantly affected by hyperpolarization of granule cells. These results suggest that LTP may occur at the excitatory synapses between LPP terminals and GABAergic interneurons, rather than at the inhibitory synapses between interneurons and granule cells. Further examination using selective opioid antagonists demonstrated that blocking delta, but not mu and kappa, receptors is critical for inducing LTP of IPSCs in granule cells.

2-Amino-5-phosphonovalerate↗
PubMed1995

Presynaptic inhibition of gamma-aminobutyric acidB-mediated synaptic current by adenosine recorded in vitro in midbrain dopamine neurons.

Adenosine receptor antagonists such as caffeine cause dopamine-dependent behavioral arousal and hyperlocomotion in rodents. In the present study, we used the whole-cell recording technique in the rat brain slice to investigate effects of adenosine on dopamine neurons and their synaptic inputs in the substantia nigra zona compacta and ventral tegmental area. Adenosine was most potent for inhibiting the amplitude of the inhibitory postsynaptic current (IPSC) mediated by gamma-aminobutyric acid (GABA)B receptors (EC50 = 47 +/- 3 microM) compared with inhibition of the GABAA-mediated IPSC (117 +/- 51 microM) and the excitatory amino acid-mediated excitatory postsynaptic current (119 +/- 36 microM). Adenosine failed to inhibit current evoked by exogenous GABA or baclofen, suggesting that adenosine acted presynaptically to reduce GABA release from nerve terminals. Adenosine inhibited the GABAB-mediated IPSC by acting at the adenosine A1 receptor, because its effect was blocked by the selective adenosine A1 receptor antagonist 8-cyclopentyl-1,3-dipropylxanthine (100 nM), as well as by the methylxanthines caffeine (1 mM) and theophylline (300 microM). The rank-order of potency of adenosine agonists [N6-cyclohexyladenosine > R-(-)-N6-(2-phenylisopropyl)-adenosine = N6- cyclohexyladenosine > 5'-N-ethylcarboxamidoadenosine > 2-chloroadenosine] also was consistent with activation of the adenosine A1 receptor, whereas the selective adenosine A2A agonist CGS 21680 [2-p-(2-carboxyethyl)phenethylamino-5'-N-ethylcarboxamido adenosine] had no effect on the GABAB IPSC. None of the adenosine agonists or antagonists affected holding current or membrane conductance.(ABSTRACT TRUNCATED AT 250 WORDS)

Adenosine↗
PubMed1995

Presynaptic enhancement of inhibitory synaptic transmission by protein kinases A and C in the rat hippocampus in vitro.

The protein kinase C activator phorbol 12,13-dibutyrate (0.5 microM, PDBu) and the protein kinase A activator forskolin (20 microM) each increased evoked monosynaptic inhibitory postsynaptic current (IPSC) amplitude, without affecting its reversal potential, and increased the frequency of miniature IPSCs (mIPSCs), without affecting their amplitude or kinetics, as assessed with whole-cell recording form CA3 pyramidal cells in hippocampal slice cultures. The effects of forskolin and PDBu on both evoked IPSC amplitude and mIPSC frequency were additive and were antagonized by inhibitors of protein kinases A and C, respectively. The kinase activator-induced increases in mIPSC frequency were quantitatively comparable to the increases in evoked IPSC amplitude. The increases in mIPSC frequency were not attenuated by the voltage-dependent calcium channel blocker Cd2+ (100 microM). We conclude that stimulation of protein kinases A and C potentiates hippocampal inhibitory synaptic transmission through independent presynaptic mechanisms of action. Kinase-induced potentiation of spontaneous release does not require modulation of axon terminal Ca2+ channels. This mechanism may also contribute substantially to the potentiation of evoked release.

Animals↗
PubMed1994

Potentiation of GABAA-mediated synaptic current by ethanol in hippocampal CA1 neurons: possible role of protein kinase C.

Ethanol has been reported to interact with numerous voltage- and ligand-gated ion channels in central mammalian neurons. In particular, the type A gamma-aminobutyric acid (GABAA) receptor/chloride ionophore complex has received considerable attention as a cellular substrate for ethanol and other sedative-hypnotic drugs. Direct electrophysiological evidence that ethanol modulates GABAA receptor function has been controversial. In this study, we investigated the effects of ethanol on the GABAA receptors that mediate fast inhibitory synaptic transmission in the rat hippocampus. Using the whole-cell patch-clamp recording technique in brain slices, we found that clinically relevant concentrations of ethanol (10-50 mM) potentiate pharmacologically isolated GABAA-mediated inhibitory postsynaptic currents (IPSCs) recorded from rat hippocampal CA1 neurons. In addition, we demonstrate that ethanol- but not diazepam-mediated enhancement of GABAA IPSCs requires intracellular ATP and can be blocked by Ro-31-8220 or PKC19-31, specific inhibitors of protein kinase C. Furthermore, the active phorbol ester 4-beta-PDBu but not its inactive analog also interferes with ethanol enhancement of GABAA IPSCs. These results demonstrate that ethanol potentiation of pharmacologically isolated GABAA IPSCs can be modulated by protein kinase C.

Adenosine Triphosphate↗
PubMed1996

Differential actions of serotonin, mediated by 5-HT1B and 5-HT2C receptors, on GABA-mediated synaptic input to rat substantia nigra pars reticulata neurons in vitro.

The ability of serotonin to modulate GABA-mediated synaptic input to substantia nigra pars reticulata (SNr) neurons was investigated with the use of whole-cell patch-clamp recording from slices of rat midbrain. Fast evoked GABA(A) receptor-mediated synaptic currents (IPSCs) were attenuated reversibly approximately 60% by serotonin, which also caused an inward current with reversal potential of -25 mV. This inward current was blocked by the 5-HT2 receptor antagonist ritanserin, whereas the IPSC depression was blocked by the 5-HT1B receptor antagonist pindolol. The amplitude ratio of IPSC pairs (50 msec interpulse interval) was enhanced by serotonin (in ritanserin) and also by the GABA(B) receptor agonist baclofen (which also depressed the IPSC), consistent with a presynaptic site of action in both cases. In contrast, spontaneous tetrodotoxin-sensitive GABA(A) synaptic currents (sIPSCs) were increased in frequency by serotonin (an action that was sensitive to ritanserin, but not pindolol) but reduced in frequency by baclofen. SNr neurons therefore receive inhibitory synaptic input mediated by GABA(A) receptors from at least two distinct sources. One, probably originating from the striatum, may be depressed via presynaptic 5-HT1B and GABA(B) receptors. The second is likely to arise from axon collaterals of SNr neurons themselves and is facilitated by an increase in firing via postsynaptic, somatodendritic 5-HT2C receptor activation, but it is depressed by GABA(B) receptor activation. Thus, serotonin can both depolarize and disinhibit SNr neurons via 5-HT2C and 5-HT1B receptors, respectively, but excitation may be limited by GABA released from axon collaterals.

Animals↗
PubMed1997

Cholecystokinin increases GABA release by inhibiting a resting K+ conductance in hippocampal interneurons.

Cholecystokinin (CCK) is found co-localized with the inhibitory neurotransmitter GABA in interneurons of the hippocampus. Also, CCK receptors are found in abundance in this brain region. The possibility that CCK alters interneuron activity was examined using whole-cell current- and voltage-clamp recordings from visualized interneurons in the stratum radiatum of area CA1 in rat hippocampal slices. The effect of CCK on GABA-mediated IPSCs was also determined in pyramidal neurons. The sulfated octapeptide CCK-8S increased action potential frequency or generated inward currents in the majority of interneurons. These effects of CCK persisted in the presence of tetrodotoxin and cadmium, suggesting that they were direct. Current-voltage plots revealed that CCK-8S inhibited a conductance that was linear across command potentials and reversed near the equilibrium potential for K+ ions. The K+ channel blocker tetraethylammonium (10 mM) generated inward currents similar to those initiated by CCK, and it occluded the effect of the peptide. BaCl2 (1 mM) and 4-aminopyridine (2 mM) did not alter the effect of CCK. The CCKB receptor antagonist PD-135,158 completely blocked the inward currents generated by CCK-8S. CCK also resulted in an increase in spontaneous action potential-dependent IPSC frequency, but no changes in action potential-independent miniature IPSCs or evoked IPSCs in pyramidal neurons. These results provide evidence that CCK can depolarize hippocampal interneurons through the inhibition of a resting K+ conductance, leading to increased tonic inhibition of pyramidal neurons. This action of CCK may contribute to its anticonvulsant properties, as observed in limbic seizure models.

Animals↗
PubMed1996

[Opposite actions of ACh on excitatory and inhibitory synaptic transmission in cultured rat cortical neurons].

Effect of ACh on spontaneous EPSC and IPSC in cultured postnatal rat cortical neurons was studied using whole-cell voltage-clamp technique. EPSC was blocked by a non-NMDA glutamate receptor antagonist DNQX, while IPSC was blocked by a GABAA receptor antagonist bicuculline. When ACh (10-100 mumol/L) was applied by puff pipettes to the cells recorded, the frequency of EPSC was enhanced greatly, but the amplitude distribution was not changed significantly. However, the frequency of IPSC was attenuated by ACh even at a quite low concentration (1 mumol/L). The effect of ACh on EPSC and IPSC could be blocked by M type ACh receptor antagonist atropine (1 mumol/L). ACh had no significant effect on whole-cell currents activated by glutamate and GABA. The above results provide evidence that ACh has opposite effects on excitatory and inhibitory synaptic transmission in rat cortex by acting at presynaptic sites. It is also suggested that ACh plays an important role in the maintenance of excitability of cortical neurons.

Acetylcholine↗
PubMed1998

The synaptic basis of GABAA,slow.

Although two kinetically distinct evoked GABAA responses (GABAA,fast and GABAA,slow) have been observed in CA1 pyramidal neurons, studies of spontaneous IPSCs (sIPSCs) in these neurons have reported only a single population of events that resemble GABAA,fast in their rise and decay kinetics. The absence of slow sIPSCs calls into question the synaptic basis of GABAA,slow. We present evidence here that both evoked responses are synaptic in origin, because two classes of minimally evoked, spontaneous and miniature IPSCs exist that correspond to GABAA,fast and GABAA,slow. Slow sIPSCs occur infrequently, suggesting that the cells underlying these events have a low spontaneous firing rate, unlike the cells giving rise to fast sIPSCs. Like evoked GABAA,fast and GABAA,slow, fast and slow sIPSCs are modulated differentially by furosemide, a subtype-specific GABAA antagonist. Furosemide blocks fast IPSCs by acting directly on the postsynaptic receptors, because it reduces the amplitude of both miniature IPSCs and the responses of excised patches to applied GABA. Thus, in the hippocampus, parallel inhibitory circuits are composed of separate populations of interneurons that contact anatomically segregated and pharmacologically distinct postsynaptic receptors.

Animals↗
PubMed1998

Presynaptic GABAB autoreceptor modulation of P/Q-type calcium channels and GABA release in rat suprachiasmatic nucleus neurons.

GABA is the primary transmitter released by neurons of the suprachiasmatic nucleus (SCN), the circadian clock in the brain. Whereas GABAB receptor agonists exert a significant effect on circadian rhythms, the underlying mechanism by which GABAB receptors act in the SCN has remained a mystery. We found no GABAB receptor-mediated effect on slow potassium conductance, membrane potential, or input resistance in SCN neurons in vitro using whole-cell patch-clamp recording. In contrast, the GABAB receptor agonist baclofen (1-100 microM) exerted a large and dose-dependent inhibition (up to 100%) of evoked IPSCs. Baclofen reduced the frequency of spontaneous IPSCs but showed little effect on the frequency or amplitude of miniature IPSCs in the presence of tetrodotoxin. The activation of GABAB receptors did not modulate postsynaptic GABAA receptor responses. The depression of GABA release by GABAB autoreceptors appeared to be mediated primarily through a modulation of presynaptic calcium channels. The baclofen inhibition of both calcium currents and evoked IPSCs was greatly reduced (up to 100%) by the P/Q-type calcium channel blocker agatoxin IVB, suggesting that P/Q-type calcium channels are the major targets involved in the modulation of GABA release. To a lesser degree, N-type calcium channels were also involved. The inhibition of GABA release by baclofen was abolished by a pretreatment with pertussis toxin (PTX), whereas the inhibition of whole-cell calcium currents by baclofen was only partially depressed by PTX, suggesting that G-protein mechanisms involved in GABAB receptor modulation at the soma and axon terminal may not be identical. We conclude that GABAB receptor activation exerts a strong presynaptic inhibition of GABA release in SCN neurons, primarily by modulating P/Q-type calcium channels at axon terminals.

Animals↗
PubMed1998

Dendrodendritic inhibition in the olfactory bulb is driven by NMDA receptors.

At many central excitatory synapses, AMPA receptors relay the electrical signal, whereas activation of NMDA receptors is conditional and serves a modulatory function. We show here quite a different role for NMDA receptors at dendrodendritic synapses between mitral and granule cells in the rat olfactory bulb. In whole-cell patch-clamp recordings in bulb slices, stimulation of mitral cells elicited slowly decaying, GABAA receptor-mediated reciprocal IPSCs that reflected prolonged GABA release from granule cells. Although granule cells had a normal complement of AMPA and NMDA receptors, the IPSC was completely blocked by the NMDA receptor antagonist D,L-AP-5, suggesting that NMDA receptor activation is an absolute requirement for dendrodendritic inhibition. The AMPA receptor antagonist 1,2,3,4-tetrahydro-6-nitro-2, 3-dioxobenzo[f]quinoxaline-7-sulfonamide (NBQX) had no effect on IPSCs in the absence of extracellular magnesium but modestly reduced IPSCs in 1 mM magnesium, indicating that the primary effect of the AMPA receptor-mediated depolarization was to facilitate the unblocking of NMDA receptors. Granule cell voltage recordings indicated that effective spike stimulation in granule cells depended on the slow NMDA receptor kinetics. Granule cells also showed a pronounced delay between synaptic stimulation and action potential generation, suggesting that their intrinsic membrane properties underlie the ineffectiveness of brief AMPA receptor-mediated EPSPs. NMDA receptors also seem to have a central role in dendrodendritic inhibition in vivo, because intraperitoneal dizocilpine maleate (MK-801) injection in young adult rats resulted in disinhibition of mitral cells as measured by the generation of c-fos mRNA. The unique dependence of dendrodendritic inhibition on slow EPSPs generated by NMDA receptors suggests that olfactory information processing depends on long-lasting reciprocal and lateral inhibition.

2-Amino-5-phosphonovalerate↗
PubMed2003

Aging alters dendritic morphology, input resistance, and inhibitory signaling in dentate granule cells of the rhesus monkey.

The neural substrates of age-related hippocampal dysfunction in primates are poorly understood. This issue was addressed with combined intracellular biocytin filling and whole-cell patch clamp recordings of intrinsic membrane properties and inhibitory postsynaptic currents (IPSCs) in dentate granule cells in in vitro slices prepared from behaviorally characterized young (<11 years old) and aged (>24 years old) rhesus monkeys. Six of nine aged monkeys were significantly impaired in performance on the hippocampally mediated delayed nonmatch to sample (DNMS) task at a 2-minute delay. Morphometric analyses showed that cells from aged monkeys had significantly reduced vertical dendritic extents and distal dendritic branching but increased proximal dendritic branching. Intrinsic membrane and action potential properties did not differ between cells from young and aged monkeys with the exception of a small but significant increase in input resistance with age. The frequency, amplitude, and rise time of gamma-aminobutyric acid (GABA)(A) receptor-mediated miniature IPSCs were not significantly different in cells from young vs. aged monkeys. However, the miniature IPSC decay time constant and the benzodiazepine potentiation of this decay time constant were both significantly increased in cells from aged monkeys. These differences in the properties of dentate granule cells correlated positively with age but not specifically with impairment on the DNMS 2-minute delay task. Nevertheless, these changes in dendritic morphology, input resistance, and inhibitory signaling properties may be part of a constellation of subtle functional changes contributing to age-associated cognitive impairment.

Action Potentials↗
PubMed2004

Differential depression of inhibitory synaptic responses in feedforward and feedback circuits between different areas of mouse visual cortex.

Recordings of synaptic responses of pyramidal neurons to feedback (FB) inputs from higher to lower areas of visual cortex show that excitatory synaptic responses are only weakly opposed by disynaptic inhibition. Whether weak inhibition is preserved at high frequencies remains unknown. Whole-cell recordings were performed in pyramidal cells of mouse visual cortex to study the frequency dependence of excitatory and inhibitory postsynaptic currents (EPSCs, IPSCs) elicited by feedforward (FF) input from the primary visual cortex (V1) to the higher lateromedial area (LM) and by FB input from the LM to V1. EPSCs showed similar frequency dependencies in FF and FB pathways; the amplitudes decreased during stimulus trains, and the depression was larger at higher frequencies. IPSCs decreased during repetitive stimulation, and the depression increased at higher frequencies. At >20 Hz, the depression of IPSCs in the FB pathway was greater than in the FF pathway. Thus, unlike FF circuits, FB circuits provide balanced excitatory and inhibitory inputs across a wide range of frequencies. This property was shown to be critically important in cortical circuits that modulate the gain of pyramidal cell firing (Chance et al. [2002] Neuron 35:773-782).

6-Cyano-7-nitroquinoxaline-2,3-dione↗
PubMed2006

GABAergic signaling in young granule cells in the adult rat and mouse dentate gyrus.

Throughout most of the developing brain, including the hippocampus, GABAergic synapses are the first to become functional. Several features of GABAergic signaling change across development, suggesting that this signaling in the immature brain may play important roles in the growth of young neurons and the establishment of networks. To determine whether GABA(A) receptor (GABA(A)R)-containing synapses in new neurons born in the adult dentate gyrus have similar immature features, we examined spontaneous and evoked GABA(A)R-mediated synaptic currents in young (POMC-EGFP or doublecortin-immunostained) granule cells in acute slice preparations from adult mice and rats. Spontaneous inhibitory postsynaptic currents (IPSCs) were observed in nearly all immature granule cells, but their frequency was considerably lower and their decay time constant was nearly two times longer than in neighboring mature (doublecortin-non-immunoreactive or EGFP-non-expressing) granule cells within the sub-granular zone. Evoked IPSCs (eIPSCs) in mature granule cells, but not immature granule cells, were sensitive to zolpidem, suggesting a maturational increase in GABA(A)R alpha1-subunit expression. Perforated-patch recording revealed that eIPSCs depolarized young neurons, but hyperpolarized mature neurons. The early establishment of synaptic GABAergic inputs slow IPSC decay time, and depolarizing action of eIPSCs are remarkably similar to features previously seen in neurons during development, suggesting that they are intrinsic features of immature neurons and not functions of the surrounding circuitry. These developmental features in adult-born granule cells could play a role in maturational processes such as developmental cell death. However, treatment of adult mice with GABA(A)R agonists and an inverse agonist did not significantly alter the number of 4- to 14-day-old BrdU-labeled cells.

Aging↗
PubMed2003

Actions of the sodium channel inhibitor 202W92 on rat midbrain dopaminergic neurons.

Excessive glutamatergic activity is implicated in Parkinson's disease (PD) and sodium channel blockade, resulting in inhibition of glutamate release, is a potential therapeutic approach to PD therapy. Beneficial effects of riluzole and lamotrigine have been reported in animal models of PD, but these compounds have relatively low potency as sodium channel inhibitors and also inhibit N and P/Q-type calcium channels. 202W92, a structural analog of lamotrigine, is a potent sodium channel inhibitor, with no effect on N, P/Q-type channels. Here we present the effects of 202W92 on single patch-clamped dopaminergic neurons. 202W92 (> or =10 microM) inhibited spontaneous action potential firing and reduced amplitude and frequency of evoked action potentials. It also inhibited the frequency of 4-aminopyridine (4-AP)- and electrically evoked excitatory postsynaptic currents (EPSCs) and GABAergic inhibitory postsynaptic currents (IPSCs), with >80% inhibition at 10 microM (IC(50) 1.5 microM). EPSC and IPSC amplitudes were partially inhibited. 202W92 did not affect postsynaptic responses to locally applied glutamate and GABA, nor spontaneously occurring mini-IPSCs. These actions of 202W92 are compatible with sodium channel inhibition and depression of transmitter release.

Action Potentials↗
PubMed1991

Some pharmacological differences between hippocampal excitatory and inhibitory synapses in transmitter release: an in vitro study.

The effects of adenosine, carbachol, and baclofen on synaptic transmission between neurons in cultured rat hippocampal explants were studied using the tight-seal whole cell clamp technique. In the culture, stimulations of neurites cause postsynaptic currents (PSCs) in nearby neurons under voltage-clamp condition. In the presence of 20 microM bicuculline, most PSCs were considered as glutamatergic excitatory postsynaptic currents (EPSCs), because they were blocked by glutamate antagonist, kynurenate at 1 mM. In the presence of 1 mM kynurenate, PSCs seemed to be inhibitory postsynaptic currents mediated by gamma-aminobutyric acid (GABA), because they were blocked by GABA antagonist, bicuculline at 20 microM. Adenosine at 100 microM and carbachol at 10 microM suppressed these EPSCs to about 35% of control. However, adenosine and carbachol at the same concentration did not suppress the IPSCs. Baclofen at 10 microM suppressed both EPSCs and IPSCs significantly (EPSCs: to about 40% of control, IPSCs: to about 30% of control). In contrast, membrane currents elicited by ionophoretically applied glutamate and GABA were not suppressed by 100 microM adenosine, 10 microM carbachol, and 10 microM baclofen. From these results, it is suggested that the pharmacological sensitivities of transmitter release from presynaptic terminals are different between glutamatergic excitatory synapses and GABAergic inhibitory synapses in hippocampal cultures.

Adenosine↗