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PubMed1993

Role of synaptic excitation in the generation of bursting-induced epileptiform potentials in the endopiriform nucleus and piriform cortex.

1. The mechanism of generation of epileptiform excitatory postsynaptic potentials (e-EPSPs) induced by bursting activity in vitro was examined in slices of piriform cortex. 2. Previous study revealed that e-EPSPs in piriform cortex are generated in the subjacent endopiriform nucleus, perhaps with a contribution from the claustrum and deep part of layer III of piriform cortex. A puzzling feature of these e-EPSPs was their abrupt origin at long latency with little sign of preceding abnormal activity. 3. Systematic mapping revealed that within spatially restricted regions of the endopiriform nucleus there is an irregular buildup in extracellularly recorded multiunit activity and intracellularly recorded depolarization that precedes the onset of e-EPSPs. Analysis of latency revealed that these "slow-onset" e-EPSPs precede the more widely distributed "abrupt-onset" e-EPSPs, suggesting that they occur at sites of initiation. 4. The hypothesis was tested that the buildup associated with slow-onset e-EPSPs is dependent on synaptically mediated excitation. According to this hypothesis, all-or-none e-EPSPs originate when mutually excitatory (positive feedback) interactions within a population of cells in the endopiriform nucleus become self-regenerative. 5. Predictions from the regenerative positive feedback hypothesis that were successfully verified include the presence of excitatory synaptic connections between cells in the endopiriform nucleus; the consistent prediction of a subsequent e-EPSP from the occurrence of the accelerating buildup in population activity; the occurrence of inhibitory postsynaptic potentials (IPSPs) together with EPSPs during the buildup period; and the blockage of the buildup and e-EPSP by a low concentration of a specific excitatory amino acid antagonist 6,7-dinitroquinoxaline-2,3-dione (DNQX). 6. Blockage of e-EPSPs by a concentration of DNQX that was much less than that required to block monosynaptic EPSPs in the endopiriform nucleus indicates that synaptic reverberation is mediated by alpha-amino-3-hydroxy-5-methylisoxazole-4-propionic acid (AMPA) type excitatory amino acid receptors. 7. D-2-amino-5-phosphonovaleric acid (D-APV) reduced the duration and amplitude of e-EPSPs but did not block their occurrence, indicating that N-methyl-D-aspartate (NMDA) receptors have a boosting effect on e-EPSPs but are not required for their generation. This is in contrast to the induction of e-EPSPs by bursting activity for which NMDA receptor activation is required. 8. Outside the region of initiation e-EPSPs propagated through the endopiriform nucleus at a velocity of 0.1 m/s.(ABSTRACT TRUNCATED AT 400 WORDS)

Animals↗

PubMed1984

Activity of commissural interneurons in spinal cord of Xenopus embryos.

Horseradish peroxidase- (HRP) filled microelectrodes have been used to examine the anatomy and physiology of "commissural interneurons," a morphologically defined class of spinal cord interneuron in Xenopus laevis embryos. Commissural interneurons have unipolar cell bodies in the dorsal half of the spinal cord. Their dendrites lie in the mid to ventral parts of the lateral tracts and their axons cross the cord ventrally, T branch, and ascend and descend on the opposite side of the cord. Recordings were made from animals immobilized in tubocurarine and responding to natural stimulation with three patterns of fictive motor activity. During episodes of fictive swimming, commissural interneurons are phasically excited to fire 1 spike/cycle in phase with motor discharge on the same side and receive a midcycle inhibitory postsynaptic potential (IPSP) in phase with motor discharge on the opposite side. Rhythmic activity is superimposed on a background depolarization. During periods of synchrony, phasic excitatory input doubles in frequency so that cells fire with half the swimming cycle period. The background depolarization is generally stronger than during swimming. During periods of fictive struggling, evoked by electrical stimulation of the skin, commissural interneurons fire a burst of spikes per cycle, cells being relatively hyperpolarized when motoneurons on the opposite side are active. In response to ipsilateral skin stimulation, some cells receive an IPSP at a latency of 12-20 ms. This precedes the onset of fictive locomotion. We discuss how anatomy and activity of commissural interneurons is suitable for a reciprocal inhibitory role.

Animals↗

PubMed1997

Synaptic interactions in neocortical local circuits: dual intracellular recordings in vitro.

Properties of local synaptic connections in neocortex, studied with dual intracellular recordings in vitro and correlated with cell and synaptic morphology are summarized. The different durations and sensitivities to somatic membrane potential of pyramid-pyramid excitatory postsynaptic potentials (EPSPs) apparently reflect the positions of the synapses on the postsynaptic dendrites. Their time-, frequency- and voltage-dependent properties enable supra-linear summation of several low-frequency inputs arising in the same dendritic region, even if only loosely coincident, but they depress during repetitive firing in any one input. Pyramidal input to classical fast spiking and low threshold spiking interneurones are strikingly different. Here low presynaptic firing rates results in many transmission failures. EPSPs are brief and inputs must be near coincident for summation. However, these synapses display pronounced. frequency-dependent, incrementing facilitation at higher presynaptic frequencies. Once initiated by a brief high-frequency burst, this facilitation is maintained at lower frequencies. GABAA receptor-mediated inhibitory postsynaptic potentials (IPSPs) arising proximally are of very different durations depending on the type of interneurone activated and can prevent and subsequently synchronize firing in their many postsynaptic partners with very different delays (eg. 10-100 ms). Low threshold spiking interneurones, in contrast, generate brief IPSPs only in more distal dendritic regions and have little effect on somatic excitability acting to shunt input distally.

Animals↗

PubMed1988

In vitro effects of substance P on neonatal rat sympathetic preganglionic neurones.

1. Intracellular recordings were made from antidromically identified sympathetic preganglionic neurones (SPNs) in thin transverse neonatal rat thoracolumbar spinal cord slices. 2. Applied either by pressure ejection or superfusion, substance P (SP) caused a slow, monophasic depolarization in 60% of sympathetic preganglionic neurones; a biphasic response consisting of an initial hyperpolarization followed by a depolarization was observed in a few neurones. In addition, SP induced the occurrence of repetitive inhibitory postsynaptic potentials (IPSPs) in about 20% SPNs. 3. Low-Ca2+ or tetrodotoxin (TTX)-containing Krebs solution abolished the hyperpolarizing phase of the biphasic response and the small IPSPs, thereby augmenting the depolarizing response of SP. 4. SP-induced depolarizations were often associated with a moderate increase in membrane resistance. Generally, the response was made smaller on hyperpolarization and reversed at the membrane potential between -90 and -100 mV. These findings suggest that a reduction of membrane K+ conductance may underlie the depolarizing action of SP. 5. Subthreshold fast, excitatory postsynaptic potentials (EPSPs) evoked by stimulation of dorsal rootlets were consistently augmented during SP-induced depolarization, leading to cell discharge. 6. Focal stimulations elicited, in addition to a fast EPSP, a slow EPSP in about 40% of SPNs. The slow EPSP was often associated with an increased membrane resistance and became smaller on hyperpolarization. 7. In 15% of SPNs that generated a slow EPSP, the latter was reversibly abolished during SP-induced depolarization; the blockade persisted when the membrane potential was restored to the resting level by hyperpolarizing current. 8. It is concluded that SP is excitatory to SPNs and that its synaptic release may initiate a slow EPSP which serves to augment impulse transmission through SPNs. Further, it appears that inhibitory interneurones may also be sensitive to SP and their activation may provide a negative feed-back mechanism which can limit excessive excitation of SPNs by the peptide.

Action Potentials↗

PubMed2004

Firing properties and connectivity of neurons in the rat lateral central nucleus of the amygdala.

Using whole cell recordings from acute slices of the rat amygdala, we have examined the physiological properties of and synaptic connectivity to neurons in the lateral sector of the central amygdala (CeA). Based on their response to depolarizing current injections, CeA neurons could be divided into three types. Adapting neurons fired action potentials at the start of the current injections at high frequency and then showed complete spike-frequency adaptation with only six to seven action potentials evoked with suprathreshold current injections. Late-firing neurons fired action potentials with a prolonged delay at threshold but then discharged continuously with larger current injections. Repetitive firers discharged at the start of the current injection at threshold and then discharged continuously with larger current injections. All three cells showed prolonged afterhyperpolarizations (AHPs) that followed trains of action potentials. The AHP was longer lasting with a larger slow component in adapting neurons. The AHP in all cell types contained a fast component that was inhibited by the SK channel blocker UCL1848. The slow component, not blocked by UCL1848, was blocked by isoprenaline and was significantly larger in adapting neurons. Blockade of SK channels increased the discharge frequency in late firers and regular-spiking neurons but had no effect on adapting neurons. Blockade of the slow AHP with isoprenaline had no effect on any cell type. All cells received a mixed glutamatergic and GABAergic input from a medial pathway. Electrical stimulation of the lateral (LA) and basolateral (BLA) nuclei evoked a large monosynaptic glutamatergic response followed by a disynaptic inhibitory postsynaptic potential. Activation of neurons in the LA and BLA by puffer application of glutamate evoked a small monosynaptic response in 13 of 55 CeA neurons. Local application of glutamate to the CeL evoked a GABAergic response in all cells. These results show that at least three types of neurons are present in the CeA that can be distinguished on their firing properties. The firing frequency of two of these cell types is determined by activation of SK channels. Cells receive a small input from the LA and BLA but may receive inputs that course through these nuclei en route to the CeA.

Action Potentials↗

PubMed1997

Dopamine inhibition: enhancement of GABA activity and potassium channel activation in hypothalamic and arcuate nucleus neurons.

Dopamine (DA) decreases activity in many hypothalamic neurons. To determine the mechanisms of DA's inhibitory effect, whole cell voltage- and current-clamp recordings were made from primary cultures of rat hypothalamic and arcuate nucleus neurons (n = 186; 15-39 days in vitro). In normal buffer, DA (usually 10 microM; n = 23) decreased activity in 56% of current-clamped cells and enhanced activity in 22% of the neurons. In neurons tested in the presence of glutamate receptor antagonists D,L-2-amino-5-phosphonovalerate (AP5; 100 microM) and 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX; 10 microM), DA application (10 microM) revealed heterogeneous effects on electrical activity of cells, either hyperpolarization and decrease in activity (53% of 125) or depolarization and increase in spontaneous activity (22% of 125). The DA-mediated hyperpolarization of membrane potential was associated with a decrease in the input resistance. The reversal potential for the DA-mediated hyperpolarization was -97 mV, and it shifted in a positive direction when the concentration of K+ in the incubating medium was increased, suggesting DA activation of K+ channels. Because DA did not have a significant effect on the amplitude of voltage-dependent K+ currents, activation of voltage-independent K+ currents may account for most of the hyperpolarizing actions of DA. DA-mediated hyperpolarization and depolarization of neurons were found during application of the Na+ channel blocker tetrodotoxin (1 microM). The hyperpolarization was blocked by the application of DA D2 receptor antagonist eticlopride (1-20 microM; n = 7). In the presence of AP5 and CNQX, DA (10 microM) increased (by 250%) the frequency of spontaneous inhibitory postsynaptic currents (IPSCs) in 11 of 19 neurons and evoked IPSCs in 7 of 9 cells that had not previously shown any IPSCs. DA also increased the regularity and the amplitude (by 240%) of spontaneous IPSCs in 9 and 4 of 19 cells, respectively. Spontaneous and DA-evoked IPSCs and inhibitory postsynaptic potentials were blocked by the gamma-aminobutyrate A (GABA(A)) antagonist bicuculline (50 microM), verifying their GABAergic origin. Pertussis toxin pretreatment (200 ng/ml; n = 15) blocked the DA-mediated hyperpolarizations, but did not prevent depolarizations (n = 3 of 15) or increases in IPSCs (n = 6 of 10) elicited by DA. Intracellular neurobiotin injections (n = 21) revealed no morphological differences between cells that showed depolarizing or hyperpolarizing responses to DA. Immunolabeling neurobiotin-filled neurons that responded to DA (n = 13) showed that GABA immunoreactive neurons (n = 4) showed depolarizing responses to DA, whereas nonimmunoreactive neurons (n = 9) showed both hyperpolarizing (n = 6) and depolarizing (n = 3) responses. DA-mediated hyperpolarization, depolarization, and increases in frequency of postsynaptic activity could be detected in embryonic hypothalamic or arcuate nucleus neurons after only 5 days in vitro, suggesting that DA could play a modulatory role in early development. These findings suggest that DA inhibition in hypothalamic and arcuate nucleus neurons is achieved in part through the direct inhibition of excitatory neurons, probably via DA D2 receptors acting through a Gi/Go protein on K+ channels, and in part through the enhancement of GABAergic neurotransmission.

2-Amino-5-phosphonovalerate↗

PubMed1991

Thalamocortical responses of mouse somatosensory (barrel) cortex in vitro.

We have developed a novel slice preparation of the mouse somatosensory forebrain. This preparation is unique in including both the ventrobasal nucleus of the thalamus and the sensorimotor "barrel" cortex in a 400-microns-thick slice with the functional connectivity between them preserved, and in allowing direct visualization of the various components of the barrel system in unstained living tissue. Thalamocortical connectivity was demonstrated by recording the laminar profile of cortical field potentials evoked electrically from the ventrobasal nucleus. Current-source density analysis of this profile showed that the largest and earliest sinks were coextensive with the two known sites of thalamocortical terminals, layer IV and the junction of layers V and VI. The sink in layer IV could be dissociated experimentally into a small, early sink of presynaptic origin (most probably a presynaptic spike volley in the thalamocortical terminals) and a later, larger sink generated postsynaptically. By mapping the subcortical stimulation sites that elicited a response at different layer IV recording sites we concluded that the thalamus-to-cortex projection preserves the general dorsoventral relationship of the afferents. Intracellularly recorded responses elicited by thalamic stimulation included (but were not limited to) monosynaptic excitatory and disynaptic inhibitory postsynaptic potentials. The thalamus-to-cortex connections were also mapped with the axonal fluorescent tracer dioctadecyl-tetramethylindocarbocyanine perchlorate. The thalamo-cortical slice is a very suitable system for studying the physiology and pharmacology of the thalamocortical synapse and for exploring the synaptic circuitry of the somatosensory cortex.

Animals↗

PubMed1997

Two types of cholinergic neurons in the rat tegmental pedunculopontine nucleus: electrophysiological and morphological characterization.

Two types of tegmental pedunculopontine nucleus neurons have been reported previously based on their electrophysiological characteristics: type I neurons were characterized by low-threshold Ca spikes and type II neurons displayed a transient outward current. This report describes the membrane properties, synaptic inputs, morphologies and axonal projections of two subgroups of type II neurons examined in an in vitro slice preparation. Type II neurons were divided into two groups based on their spike durations: short-duration neurons with an action potential duration of 0.7-1.5 ms and long-duration neurons with an action potential duration of 1.6- 2.9 ms. Choline acetyltransferase immunohistochemistry combined with biocytin labeling indicated that 56% of short-duration neurons and 61% of long-duration neurons were immunopositive for choline acetyltransferase. Short-duration neurons had a high input resistance and the capacity to discharge with high frequency. By contrast, long-duration neurons had a low input resistance and low firing frequency and upon current injection displayed an accommodation (spike-frequency adaptation) before reaching a steady firing frequency. Microstimulation of the substantia nigra pars compacta evoked antidromic responses in both short-duration neurons (n=5/14, 36%) and long-duration neurons (n=20/39. 51%). Stimulations of the subthalamic nucleus and the substantia nigra pars reticulata induced in these neurons excitatory and inhibitory postsynaptic potentials, respectively. Short-duration neurons were dispersed equally throughout the extent of the tegmental pedunculopontine nucleus area, while long-duration neurons were located more in the rostral tegmental pedunculopontine nucleus. Short-duration neurons were small with two to four thin primary dendrites. Long-duration neurons were medium to large with three to six thick primary dendrites. Cell size was positively correlated with spike duration and axonal conduction velocity, but negatively with input resistance and spontaneous firing frequency. Both groups of neurons had ascending (toward thalamus, pretectal areas and tectum) and descending (toward pontomedullary reticular formation) axons in addition to nigropetal axons. Ascending axons were observed in 75% (6/8) of short-duration neurons and in 45% (15/33) of long-duration neurons, while nigropetal axons were observed in 50% (4/8) of short-duration neurons and in 76% (25/33) of long-duration neurons. These results suggest that the tegmental pedunculopontine nucleus cholinergic projection system is composed of heterogeneous populations of neurons in terms of electrophysiological and morphological characteristics as well as their distribution patterns in the nucleus.

Action Potentials↗

PubMed1992

Activation of kappa-opioid receptors depresses electrically evoked excitatory postsynaptic potentials on 5-HT-sensitive neurones in the rat dorsal raphé nucleus in vitro.

Intracellular recordings from dorsal raphé neurones in slices from rat brains were used to study the actions of kappa-opioid receptor agonists on an excitatory postsynaptic potential (epsp) evoked by local electrical stimulation of afferent terminals. The epsp was observed on all 5-HT-sensitive neurones and was blocked by 1 microM TTX. The epsp was reduced in a dose-dependent manner by the specific kappa-opioid receptor agonist [5R-(5 alpha,7 alpha,8 beta)]-N-methyl-N-[7-(1-pyrrolidinyl)-1- oxaspiro[4.5]dec-8-yl]-4-benzofuranacetamide monohydrochloride (CI-977) (1-100 nM). The effects of CI-977 were blocked by the specific kappa-opioid receptor antagonist norbinaltorphimine (NorBNI) (0.1-1 microM). In the presence of the GABAA receptor antagonists picrotoxin and bicuculline (30 microM), CI-977 still had its depressant action on the epsp. Application of the excitatory amino acid receptor antagonists either kynurenic acid (0.5-1 mM) or 6-cyano-2,3-dihydro-7-nitro-quinoxaline-2,3-dione (CNQX) (30 microM) and DL-2-amino-5-phosphonovaleric acid (APV) reduced both the peak and area of the epsp suggesting that the main component of the epsp evoked by electrical stimulation was largely due to release of excitatory amino acids from afferent terminals. Using potassium chloride-filled recording electrodes an epsp which was only partially occluded by kynurenic acid or CNQX and APV was seen on some neurones, this residual epsp was insensitive to CI-977 but was blocked by 30 microM picrotoxin and bicuculline. The specific mu-opioid receptor agonist, DAGOL, had no consistent effect on the fast epsp. Longer duration electrical stimuli produced a slow inhibitory postsynaptic potential (ipsp) and a long duration increase in firing. CI-977 did not affect either the slow 5-HT-mediated ipsp which was blocked by spiperone or the slow noradrenaline-mediated increase in firing which was sensitive to prazosin. CI-977 did not change the depolarizing response to brief applications of either glutamic acid or N-methyl-D-aspartic acid (NMDA). CI-977, NorBNI, naloxone, DAGOL, picrotoxin, bicuculline and kynurenic acid had no consistent effects on the resting postsynaptic membrane potential or conductance. Under voltage-clamp conditions CI-977 had no effect on a membrane current resembling IA. These results suggest that kappa-opioid receptors are present on the terminals of afferents which release excitatory amino acids onto the 5-HT-sensitive neurones in the raphé.

2-Amino-5-phosphonovalerate↗

PubMed2001

Postnatal development of inhibitory synaptic transmission in the rostral nucleus of the solitary tract.

To explore the postnatal development of inhibitory synaptic activity in the rostral (gustatory) nucleus of the solitary tract (rNST), whole cell and gramicidin perforated patch-clamp recordings were made in five age groups of rats [postnatal day 0-7 (P0-7), P8-14, P15-21, P22-30, and P >55]. The passive membrane properties of the developing rNST neurons as well as the electrophysiological and pharmacological characteristics of single and tetanic stimulus-evoked inhibitory postsynaptic potentials (IPSPs) were studied in brain slices under glutamate receptor blockade. During the first postnatal weeks, significant changes in resting membrane potential, spontaneous activity, input resistance, and neuron membrane time constant of the rNST neurons occurred. Although all the IPSPs recorded were hyperpolarizing, the rise and decay time constants of the single stimulus shock-evoked IPSPs decreased, and the inhibition response-concentration function to the gamma-aminobutyric acid (GABA) receptor antagonist bicuculline methiodide (BMI) shifted to the left during development. In P0-7 and P8-14, but not in older animals, the IPSPs had a BMI-insensitive component that was sensitive to block by picrotoxin, suggesting a transient expression of GABA(C) receptors. Tetanic stimulation resulted in both short- and long-term changes of inhibitory synaptic transmission in the rNST. For P0-7 and P8-14 animals tetanic stimulation resulted in a sustained hyperpolarization that was maintained for some time after termination of the tetanic stimulation. In contrast, tetanic stimulation of neurons in P15-21 and older animals resulted in hyperpolarization that was not sustained but decayed back to a more positive level with an exponential time course. Tetanic stimulation resulted in potentiation of single stimulus shock-evoked IPSPs in ~50% of neurons in all age groups. These developmental changes in inhibitory synaptic transmission in the rNST may play an important role in shaping synaptic activity in early development of the rat gustatory system during a time of maturation of taste preferences and aversions.

Animals↗

PubMed1988

Stratum lacunosum-moleculare interneurons of hippocampal CA1 region. I. Intracellular response characteristics, synaptic responses, and morphology.

Stable intracellular recordings were obtained from nonpyramidal cells (interneurons) in stratum lacunosum-moleculare (L-M) of the CA1 region of guinea pig hippocampal slices. The intracellular response characteristics of these interneurons were distinctly different from responses of pyramidal cells and of other interneurons (basket cells and oriens-alveus interneurons). L-M interneurons had a high resting membrane potential (-58 mV), a high input resistance (64 M omega), and a large amplitude (60 mV), relatively long duration (2 msec) action potential. A large afterhyperpolarization (11 mV, 34 msec) followed a single action potential. Most L-M interneurons did not display any spontaneous firing. Lucifer yellow (LY)-filled L-M interneurons showed nonpyramidal morphology. Cells were generally fusiform or multipolar, with aspinous, beaded dendritic processes ramifying in stratum lacunosum-moleculare, radiatum, and (sometimes) oriens. The varicose axon originated from a primary dendrite, projected along stratum lacunosum-moleculare, branched profusely in stratum radiatum, and coursed toward and into stratum pyramidale and occasionally into oriens. Processes of cells with somata in the L-M region of CA1 were not restricted to the CA1 region. The dendritic and axonal processes of some L-M interneurons were seen ascending in stratum lacunosum-moleculare, crossing the hippocampal fissure, and coursing in stratum moleculare of the dentate gyrus. Excitatory and inhibitory postsynaptic potentials (EPSPs and IPSPs) were evoked in L-M interneurons from stimulation of major hippocampal afferents. EPSPs were most effectively elicited by stimulation of fiber pathways in transverse slices, whereas IPSPs were predominantly evoked when major pathways were stimulated in longitudinal slices. We have identified a population of interneurons with intracellular response characteristics and morphology distinctly different from previously described pyramidal and nonpyramidal neurons of CA1 region. The possible role of these interneurons in hippocampal circuitry is discussed.

Animals↗

PubMed1992

Effects of ethanol and other drugs on excitatory and inhibitory neurotransmission in the crayfish.

1. Crayfish exposed to 434 mM ethanol (EtOH) showed signs of hyperactivity within 0.5-2 h, at which times crayfish hemolymph EtOH concentration had reached 60-90 mM. 2. A 10-min exposure to 60-90 mM EtOH reduced presynaptic inhibition of excitatory postsynaptic currents (EPSCs) at the crayfish opener neuromuscular junction (NMJ) in vitro but did not significantly alter excitatory neurotransmission. The same concentrations of EtOH did not alter other potentials or currents associated with inhibition at this synapse, such as presynaptic inhibitory potentials (PIPs), inhibitory postsynaptic potentials (IPSPs), and inhibitory postsynaptic currents (IPSCs). 3. Intermediate EtOH concentrations (120-180 mM) applied for 10 min in vitro reduced the amplitude of excitatory postsynaptic potentials (EPSPs) by decreasing the membrane resistance of opener muscle fibers and by reducing the amplitude of EPSCs. 4. High EtOH concentrations (434 mM) applied for 10 min in vitro had yet greater depressive effects on measures of postsynaptic properties described above. The time course of EPSCs was also significantly reduced. In addition, presynaptic properties such as action-potential (AP) amplitude and frequency of spontaneous release of neurotransmitter were reduced by 434 mM EtOH. 5. Presynaptic inhibition, gamma-aminobutyric acid (GABA; 250-500 microM), muscimol (50 microM), and baclofen (75 microM) all reduced the depolarizing afterpotential of APs in the excitor axon and reduced EPSPs in opener muscle fibers. GABA (500 microM) and baclofen (75 microM) significantly reduced presynaptic AP amplitudes, whereas presynaptic inhibition, GABA (250 microM), and muscimol (50 microM) had no effect on AP amplitude. Bicuculline (250-500 microM), a GABAA antagonist, did not entirely eliminate presynaptic inhibition, whereas picrotoxin (50 microM), another GABAA antagonist, completely removed presynaptic inhibition. Thus presynaptic inhibitory mechanisms may involve both GABAA and GABAB receptors on the opener excitor axon. 6. Our data suggest that the behavioral hyperactivity seen at hemolymph EtOH concentrations of 60-90 mM is not accompanied by a change in excitatory synaptic transmission observed at the opener NMJ. Rather, crayfish hyperactivity may be due to depressive effects of EtOH on inhibitory synapses in the CNS similar to the disinhibition evoked by EtOH at the opener NMJ.

Animals↗

PubMed1975

Regulation of unit activity in nucleus reticularis thalami by the mesencephalic reticular formation and the frontal granular cortex.

Recruiting responses and related synchronous activities appear to be mediated by thalamic inhibition originating in nucleus reticularis thalami, a structure jointly regulated by an ascending projection from mesencephalic reticular formation and a descending influence from the frontal cortex. Extracellular unit activity was recorded in the anterior nucleus reticularis thalami (RVA) during recruiting responses, augmenting responses, stimulation of the mesencephalic reticular formation (MRF), and cryogenic blockade of the inferior thalamic peduncle (ITP). During recruiting responses, RVA units responded to medial thalamic (MT) stimulation with prolonged high frequency bursts. Analysis of the post-stimulus time histograms of these responses showed tham to have the same latency, duration, incrementing character, and envelope shape as the phasic thalamic inhibitory postsynaptic potentials (IPSPs) which appear to mediate recruiting responses. Brief stimulation of the MRF, which abolishes recruiting responses and thalamic IPSPs, prevented the response of RVA units to MT stimuli, and inhibited the spontaneous discharge of these units for 20 sec or more. We propose that the desynchronizing effect of MRF activation results from the abolition of thalamic inhibition originating in RVA. Cryogenic blockade of the ITP, which abolishes recruiting responses in the thalamus and cortex, also prevented R units from responding to MT stimuli. This result suggests that the MT activates R units via a thalamo-frontocortico-R pathway and explains the long latency of R bursts and thalamic IPSPs following MT stimulation. R cells that fired prolonged bursts during recruiting responses did not respond during augmenting responses. This result suggests that separate thalamic inhibitory mechanisms are involved in these two types of synchronization.

Animals↗

PubMed1995

IPSPs strongly inhibit climbing fiber-activated [Ca2+]i increases in the dendrites of cerebellar Purkinje neurons.

The interaction between the excitatory climbing fiber (CF) response and stellate cell inhibition was studied in guinea pig Purkinje cells in sagittal slices from the cerebellar vermis. Sharp microelectrode recordings from the soma or dendrites were combined with high-speed fluorescence imaging of intracellularly injected fura-2. In this way both the electrical responses and the associated [Ca2+]i changes could be monitored at the same time. Usually simultaneously activated inhibition caused almost no change to the somatically recorded CF response. However, the inhibition caused a strong reduction in the CF-associated [Ca2+]i increase which normally was widespread in the dendrites. This effect was graded; stronger inhibition caused a larger and more widespread reduction in the [Ca2+]i change that was greatest in the more distal dendrites. Sometimes the reduction was over 90% in the distal dendrites and occasionally it was localized to only a single dendritic branch. Both the inhibitory postsynaptic potential (IPSP) and the associated reduction in the CF-induced [Ca2+]i change were blocked by bicuculline, a GABAA receptor antagonist. Dendritic recordings showed that each CF response evoked a 2-3 msec wide action potential. The amplitude of this action potential was reduced in a graded manner by the IPSP in parallel with the reduction in the [Ca2+]i change. Varying the time between the activation of the IPSP and the CF response showed that both the reduction in the [Ca2+]i change and the action potential amplitude occurred in a narrow time window of about 8-10 msec, about the rise time of the IPSP. Together these results indicate that the CF response activates a fast dendritic Ca2+ spike that causes most of the [Ca2+]i increase, both of which can be blocked by an inhibitory shunting conductance. This interaction provides a means whereby Ca(2+)-dependent dendritic mechanisms can be modulated without affecting the immediate output of the Purkinje cell.

Action Potentials↗

PubMed2000

Histamine H3 receptor-mediated suppression of inhibitory synaptic transmission in the submucous plexus of guinea-pig small intestine.

Conventional intracellular microelectrodes and marker injection techniques were used to study the actions of histamine on inhibitory synaptic transmission in the submucous plexus of guinea-pig small intestine. Bath application of histamine (1-300 microM) reversibly suppressed both noradrenergic and non-adrenergic slow inhibitory postsynaptic potentials in a concentration-dependent manner. These effects of histamine were mimicked by the selective histamine H(3) receptor agonist R(-)-alpha-methylhistamine but not the selective histamine H(1) receptor agonist, 6-[2-(4-imidazolyl)ethylamino]-N-(4-trifluoromethylphenyl) heptanecarboxamide (HTMT dimaleate), or the selective histamine H(2) receptor agonist, dimaprit. The histamine H(3) receptor antagonist, thioperamide, blocked the effects of histamine. Histamine H(1) and H(2) receptor antagonists did not change the action of histamine. Hyperpolarizing responses to focal application of norepinephrine or somatostatin by pressure ejection from micropipettes were unaffected by histamine and R(-)-alpha-methylhistamine. The results suggest that histamine acts at presynaptic histamine H(3) receptors on the terminals of sympathetic postganglionic fibers and intrinsic somatostatinergic nerves in the small intestine to suppress the release of the inhibitory neurotransmitters, norepinephrine and somatostatin.

Animals↗

PubMed1999

Development and role of GABA(A) receptor-mediated synaptic potentials during swimming in postembryonic Xenopus laevis tadpoles.

We have investigated the contribution of GABA(A) receptor activation to swimming in Xenopus tadpoles during the first day of postembryonic development. Around the time of hatching stage (37/8), bicuculline (10-50 microM) causes a decrease in swim episode duration and cycle period, suggesting that GABA(A) receptor activation influences embryonic swimming. Twenty-four hours later, at stage 42, GABA(A) receptor activation plays a more pronounced role in modulating larval swimming activity. Bicuculline causes short, intense swim episodes with increased burst durations and decreased cycle periods and rostrocaudal delays. Conversely, the allosteric agonist, 5beta-pregnan-3alpha-ol-20-one (1-10 microM) or the uptake inhibitor, nipecotic acid (200 microM) cause slow swimming with reduced burst durations and increased cycle periods. These effects appear to be mainly the result of GABA release from the spinal terminals of midhindbrain reticulospinal neurons but may also involve spinal GABAergic neurons. Intracellular recordings were made using KCl electrodes to reverse the sign and enhance the amplitude of chloride-dependent inhibitory postsynaptic potentials (IPSPs). Recordings from larval motoneurons in the presence of strychnine (1-5 microM), to block glycinergic IPSPs, provided no evidence for any GABAergic component to midcycle inhibition. GABA potentials were observed during episodes, but they were not phase-locked to the swimming rhythm. Bicuculline (10-50 microM) abolished these sporadic potentials and caused an apparent decrease in the level of tonic depolarization during swimming activity and an increase in spike height. Finally, in most larval preparations, GABA potentials were observed at the termination of swimming. In combination with the other evidence, our data suggest that midhindbrain reticulospinal neurons become involved in an intrinsic pathway that can prematurely terminate swim episodes. Thus during the first day of larval development, endogenous activation of GABA(A) receptors plays an increasingly important role in modulating locomotion, and GABAergic neurons become involved in an intrinsic descending pathway for terminating swim episodes.

Animals↗

PubMed1996

Cortical modulation of spinal excitability: an F-wave study.

F-waves are known to be highly sensitive to changes in the excitatory state of the spinal cord. This paper describes the effects of subthreshold transcranial magnetic stimulation on the F-waves evoked in hand and foot muscles. In the abductor pollicis brevis muscle, the F-wave was significantly enhanced when the cortical stimulus was given with a delay corresponding approximately to the expected time of collision, i.e., the difference between the mean latency of the F-wave and the mean latency of the motor evoked potential. A second, usually larger facilitatory phase follows the first phase after 2-3 msec, and later peaks of enhancement often occurred. After the enhancement periods, a significant inhibition of the F-wave was usually observed. In the extensor digitorum brevis muscle, the first facilitatory phase was observed some milliseconds earlier than expected in 4 of 5 subjects, and the inhibitory phase was less pronounced. We argue that the sequential arrival of I-waves at the spinal segment could be responsible for the changes observed in the F-wave recorded from the small hand muscle. In the foot muscle, anatomical and technical factors could contribute to the generation of a D-wave. The strong inhibition observed in the F-wave recorded from the hand muscle is likely to be due to the arrival on alpha-motoneurons of inhibitory postsynaptic potentials (IPSPs) generated by the cortical stimulus. Our data show that the F-wave ia a probe for changes in the spinal cord excitatory state.

Adult↗

PubMed2003

Use-dependent shift from inhibitory to excitatory GABAA receptor action in SP-O interneurons in the rat hippocampal CA3 area.

Cortical inhibitory interneurons set the pace of synchronous neuronal oscillations implicated in synaptic plasticity and various cognitive functions. The hyperpolarizing nature of inhibitory postsynaptic potentials (IPSPs) in interneurons has been considered crucial for the generation of oscillations at beta (15-30 Hz) and gamma (30-100 Hz) frequency. Hippocampal basket cells and axo-axonic cells in stratum pyramidale-oriens (S-PO) play a central role in the synchronization of the local interneuronal network as well as in pacing of glutamatergic principal cell firing. A lack of conventional forms of plasticity in excitatory synapses onto interneurons facilitates their function as stable neuronal oscillators. We have used gramicidin-perforated and whole cell clamp recordings to study properties of GABAAR-mediated transmission in CA3 SP-O interneurons and in CA3 pyramidal cells in rat hippocampal slices during electrical 5- to 100-Hz stimulation and during spontaneous activity. We show that GABAergic synapses onto SP-O interneurons can easily switch their mode from inhibitory to excitatory during heightened activity. This is based on a depolarizing shift in the GABAA reversal potential (EGABA-A), which is much faster and more pronounced in interneurons than in pyramidal cells. We also found that the shift in interneuronal function was frequency dependent, being most prominent at 20- to 40-Hz activation of the GABAergic synapses. After 40-Hz tetanic stimulation (100 pulses), GABAA responses remained depolarizing for approximately 45 s in the interneurons, promoting bursting in the GABAergic network. Hyperpolarizing EGABA-A was restored >60 s after the stimulus train. Similar but spontaneous GABAergic bursting was induced by application of 4-aminopyridine (100 microM) to slices. A shift to depolarizing IPSPs by the GABAAR permeant weak acid anion formate provoked interneuronal population bursting, supporting the role of GABAergic excitation in burst generation. Furthermore, depolarizing GABAergic potentials and synchronous interneuronal bursting were enhanced by pentobarbital (100 microM), a positive allosteric modulator of GABAARs, and were blocked by picrotoxin (100 microM). Intriguingly, GABAergic bursts displayed short (<1 s) oscillations at 15-40 Hz, even though only depolarizing GABAA responses were seen in the SP-O interneurons. This beta-gamma rhythmicity in the interneuron network was dependent on electrotonic coupling, and was abolished by blockade of gap junctions with carbenoxolone (200 microM). Results here implicate the rapid activity-dependent degradation of hyperpolarizing IPSPs in SP-O interneurons in setting the temporal limits for a given interneuron to participate in beta-gamma oscillations synchronized by GABAergic synapses. Furthermore, they imply that mutual GABAergic excitation provided by interneurons may be an integral part in the function of neuronal networks. We suggest that the use-dependent change in EGABA-A could represent a form of short-term plasticity in interneurons promoting coherent and sustained activation of local GABAergic networks.

Animals↗