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PubMed1995

N-methyl-D-aspartate transmission modulates GABAB-mediated inhibition of rat hippocampal pyramidal neurons in vitro.

Slow inhibition was investigated by stimulating inhibitory neurons at the border of stratum radiatum and lacunosum-moleculare with focal microapplications of glutamate, while recording resultant slow inhibitory postsynaptic potentials in CA1 pyramidal neurons in rat hippocampal slices. The slow inhibitory postsynaptic potentials evoked had an average peak amplitude of -2.2 mV, measured at -60 mV. Their peak conductance was 2.5 nS. These events were characterized as slow GABAB inhibitory postsynaptic potentials because they reversed at -90 mV, and were blocked by CGP 35348 (500 microM). Exposure to magnesium-free solutions augmented glutamate-evoked slow inhibitory postsynaptic potentials. Mean peak amplitude and conductance were -3.1 mV and 4.0 nS. Exposure to the N-methyl-D-aspartate antagonist MK-801 (20 microM) allowed separation of the glutamate-triggered slow inhibitory postsynaptic potential into components induced by non-N-methyl-D-aspartate and N-methyl-D-aspartate receptor activation. The N-methyl-D-aspartate component dominated, even under control conditions, and could account for up to 60% of the control slow inhibitory postsynaptic potential. Thus, the activation and recruitment of GABAB-mediated inhibition depend on both non-N-methyl-D-aspartate and N-methyl-D-aspartate-mediated excitation of inhibitory interneurons. Under physiological conditions slow inhibition may act as an important synaptic filtering mechanism, but when N-methyl-D-aspartate-mediated excitation increases, slow inhibition is further recruited, providing an important means to offset excessive excitation.

6-Cyano-7-nitroquinoxaline-2,3-dione↗

PubMed1989

Postnatal development of GABA-mediated synaptic inhibition in rat hippocampus.

Developmental alterations in GABAergic synaptic transmission were examined physiologically and biochemically in hippocampus of rats from 3 days of age to adulthood. Neither antidromic nor orthodromic stimulation could elicit identifiable inhibitory postsynaptic potentials in CA1 neurons in slices from rats 5 or 6 days of age. In contrast, at this age these stimuli result in large inhibitory postsynaptic potentials in CA3 pyramidal cells. In the latter cells orthodromic stimulation produced a brief monosynaptic excitatory postsynaptic potential which was followed by a large prolonged biphasic hyperpolarization. These signals were strikingly similar to those recorded in 1-month-old rats. In addition, large recurrent inhibitory postsynaptic potentials were produced by antidromic stimulation. By postnatal day 9 similar inhibitory postsynaptic potentials could be elicited in a majority of neurons of the CA1 subfield. As in mature pyramidal cells, application of GABA antagonists, such as bicuculline, selectively eliminated the antidromic inhibitory postsynaptic potential and the first component of the biphasic inhibitory postsynaptic potential generated by stimulation of stratum radiatum. In the CA3 subfield, this blockade of GABA receptors resulted in prolonged afterdischarges in slices from immature but not month-old rats. Measurements of the equilibrium potential and the conductance of antidromic inhibitory postsynaptic potentials in CA3 neurons were very similar when made during the first postnatal week and at 1 month of age. While on days 10-11 the equilibrium potential was very similar to measurements made at these other ages, the conductance was 3-4 times greater. The activity of glutamate decarboxylase, the synthetic enzyme for GABA, was very low at 3 days in hippocampus, and increased until 30 days of age at which time adult values were obtained. By comparison, hippocampal GABA levels were high early in postnatal life. Glutamate decarboxylase activities in microdissected CA3 and CA1 subfields were similar in immature hippocampus. These results demonstrate dramatic differences in the ontogenesis of functional GABAergic inhibitory synaptic transmission in the CA1 and CA3 subfields of rat hippocampus. The late development of GABA-mediated synaptic inhibition in the CA1 subfield could play a role in the susceptibility of immature hippocampus to seizures. However, the large GABA-mediated inhibitory postsynaptic potentials present in the CA3 subfield at the same age have a critical role in dampening neuronal excitability.(ABSTRACT TRUNCATED AT 400 WORDS)

Action Potentials↗

PubMed1984

The electrical properties of neurones of the rat suprachiasmatic nucleus recorded intracellularly in vitro.

Stable intracellular recordings were obtained from 22 suprachiasmatic neurones in isolated brain slices. These cells were characterized by resting potentials of about -60 mV, high input resistances, relatively short time constants and action potentials of short duration. The action potentials were preceded by a slow depolarization and followed by a relatively brief afterhyperpolarization and long-lasting increase in membrane conductance. Current-voltage relations were usually linear between 0 and 80 mV negative to the resting potential. Postsynaptic potentials were evoked in these cells by electrical stimulation of the optic chiasm or contralateral suprachiasmatic nucleus. Both excitatory postsynaptic potentials, which evoked action potentials, and inhibitory postsynaptic potentials were recorded. Synaptic potentials were associated with an increase in membrane conductance. Action potentials evoked by synaptic activation were sometimes followed by up to three small, fast potentials. Small fast potentials were not seen to occur spontaneously, or to follow spontaneous, or current-evoked spikes, nor were they evoked by synaptic potentials that failed to evoke action potentials. The suprachiasmatic nucleus is essential for the generation of normal biological rhythms in mammals. The input it receives from the optic nerve is thought to be important in this role. It is hoped that these preliminary intracellular studies will form a basis for further work on the inherent properties of suprachiasmatic neurones and their responses to visual input.

Animals↗

PubMed1999

Potentiation of GABAergic synaptic transmission in the rostral nucleus of the solitary tract.

Whole-cell recordings were made from neurons in the rostral nucleus of the solitary tract in horizontal brainstem slices. Monosynaptic GABAA receptor-mediated inhibitory postsynaptic potentials were evoked by single stimulus shocks or by high-frequency tetanic stimulation in the presence of glutamate receptor blockers. While single stimulus-evoked inhibitory postsynaptic potentials had variable amplitudes, tetanic stimulation-induced, hyperpolarizing postsynaptic potentials were of a more constant amplitude. Furthermore, tetanic stimulation resulted in potentiation of the amplitude of single stimulus shock-evoked inhibitory postsynaptic potentials. Of 55 neurons that were tested, potentiation lasted over 30 min for 11, 10-30 min for 13, less than 10 min for 23 and no potentiation occurred in eight. Tetanic stimulation did not result in potentiation of the tetanic stimulus-evoked hyperpolarizing postsynaptic potentials. Both the single stimulus shock- and tetanic stimulus-evoked potentials had similar inhibition concentration-response curves to the GABAA antagonist, bicuculline methiodide (EC50 = 0.75 and 0.83, respectively), indicating that they were mediated by the same postsynaptic receptors. By comparing the effect of bicuculline methiodide on the amplitude of the single stimulus shock-evoked inhibitory postsynaptic potentials and the tetanic stimulus-evoked hyperpolarizing potentials, we concluded that a single stimulus shock does not activate all postsynaptic GABAA receptors. However, tetanic stimulation results in activation of all postsynaptic GABAA receptors and induces long-lasting changes in the presynaptic GABAergic neuron. These long-lasting changes of the presynaptic neuron facilitate the release of GABA during single stimulus shock and, as a consequence, more postsynaptic receptors are activated during single stimulus shock-evoked synaptic transmission. This conclusion is supported by the results of experiments in which the extracellular Ca2+ concentration was manipulated to change the amount of neurotransmitter released from the presynaptic GABAergic terminals. The single stimulus shock-evoked inhibitory postsynaptic potentials were sensitive to the extracellular Ca2+ concentration, whereas tetanic stimulus-evoked inhibitory post-synaptic potentials were essentially insensitive to extracellular Ca2+ concentration. The relationship between the single stimulus shock-evoked inhibitory postsynaptic potential amplitude and extracellular Ca2+ concentration indicates that, in control physiological saline containing 2.5 mM Ca2+, a single stimulus shock activates less than half the postsynaptic GABA receptors. The phenomenon of long-lasting potentiation of inhibitory transmission within the rostral nucleus of the solitary tract may be important in the processing of gustatory information and play a role in taste-guided behaviors.

Animals↗

PubMed1998

Morphological and electrical characteristics of postnatal hippocampal neurons in culture: the presence of bicuculline- and strychnine-sensitive IPSPs.

A modified method was developed for tissue-culturing postnatal hippocampal neurons using simple mechanical trituration for cell isolation and not including any hydrolysing enzymes, nerve growth factors or antiproliferating agents. The morphological properties of such neurons were characterized with light and interference polarizing microscopy, which revealed the appearance of growth cones from peripheral neurons and the presence of different types of neurons, including bipolar, stellate and pyramidal-like cells (i.e., pyramidal and dentate gyrus granule cells), which could be related to their putative counterparts in intact brain. The whole-cell configuration of the patch-clamp method was used for electrophysiological recordings of inhibitory synapses between these dissociated cultured neurons from the early postnatal rat hippocampus. This study indicated the presence of tetrodotoxin (TTX)-sensitive and TTX-resistant inhibitory postsynaptic potential (IPSPs) and inhibitory postsynaptic currents (IPSCs) in current-clamp and voltage clamp modes respectively. The coincident reversal potentials for IPSCs and for GABAA and glycine-evoked currents, and the sensitivity of the IPSCs to bicuculline or strychnine, indicated that these IPSCs were Cl-(-)dependent and mediated by either GABAA or glycine receptors. Inhibitory postsynaptic currents recorded under voltage-clamp conditions decayed with a time course that could be fitted by a single exponential with a value of 26 ms. An average quantal content of 2.5 was responsible for a typical GABA and glycine-activated IPSC and a single quantum for GABAergic input was inferred to activate about 160, and for glycinergic, about 200 Cl-, channels.

Action Potentials↗

PubMed1993

Cocaine actions on rat prefrontal cortical and hippocampal dentate granule neurons in vitro.

The electrophysiological actions of cocaine hydrochloride (COC) on medial prefrontal cortical (mpfc) and hippocampal dentate granule (DG) neurons were investigated in rat brain slices with intracellular recording techniques. The following parameters were measured: resting membrane potential (RMP), spike threshold, spike firing adaptation, postspike train afterhyperpolarization (AHP), excitatory postsynaptic potentials (EPSPs), and inhibitory postsynaptic potentials (IPSPs). In the mpfc, COC appeared to have both inhibitory and excitatory effects. In the majority of cells examined, the EPSP amplitude was attenuated by COC (200 nM-20 microM), whereas the amplitude of the postspike train afterhyperpolarization (AHP) was reduced (an excitatory effect). In DG neurons, 1 microM COC caused a small depolarization. COC potentiated the EPSPs at 1 microM but attenuated EPSPs and IPSPs at 10-100 microM. The amplitude of antidromically evoked EPSPs was also increased by 20 microM COC. At concentrations of 10 microM and greater, COC increased spike threshold. It is concluded that COC actions on mpfc and DG neurons are both excitatory and inhibitory and that these effects may be mediated by multiple neurotransmitters/modulators.

Adaptation, Physiological↗

PubMed2001

Medullary reticulospinal tract mediating the generalized motor inhibition in cats: parallel inhibitory mechanisms acting on motoneurons and on interneuronal transmission in reflex pathways.

The present study was designed to elucidate the spinal interneuronal mechanisms of motor inhibition evoked by stimulating the medullary reticular formation. Two questions were addressed. First, whether there is a parallel motor inhibition to motoneurons and to interneurons in reflex pathways. Second, whether the inhibition is mediated by interneurons interposed in known reflex pathways. We recorded the intracellular activity of hindlimb motoneurons in decerebrate cats and examined the effects of medullary stimulation on these neurons and on interneuronal transmission in reflex pathways to them. Stimuli (three pulses at 10-60microA and 1-10ms intervals) delivered to the nucleus reticularis gigantocellularis evoked inhibitory postsynaptic potentials in alpha-motoneurons (n=147) and gamma-motoneurons (n=5) with both early and late latencies. The early inhibitory postsynaptic potentials were observed in 66.4% of the motoneurons and had a latency of 4.0-5.5ms with a segmental delay of more than 1.4ms. The late inhibitory postsynaptic potentials were observed in 98.0% of the motoneurons and had a latency of 30-35ms, with a peak latency of 50-60ms. Both types of inhibitory postsynaptic potentials were evoked through fibers descending in the ventrolateral quadrant. The inhibitory postsynaptic potentials were not influenced by recurrent inhibitory pathways, but both types were greatly attenuated by volleys in flexor reflex afferents. Conditioning medullary stimulation, which was subthreshold to evoke inhibitory postsynaptic potentials in the motoneurons, neither evoked primary afferent depolarization of dorsal roots nor reduced the input resistance of the motoneurons. However, the conditioning stimulation often facilitated non-reciprocal group I inhibitory pathways (Ib inhibitory pathways) to the motoneurons in early (<20ms) and late (30-80ms) periods. In contrast, it attenuated test postsynaptic potentials evoked through reciprocal Ia inhibitory pathways, and excitatory and inhibitory pathways from flexor reflex afferent and recurrent inhibitory pathways. The inhibitory effects were observed in both early and late periods. The present results provide new information about a parallel inhibitory process from the medullary reticular formation that produces a generalized motor inhibition by acting on alpha- and gamma-motoneurons, and on interneurons in reflex pathways. Interneurons receiving inhibition from flexor reflex afferents and a group of Ib interneurons may mediate the inhibitory effects upon motoneurons.

Animals↗

PubMed1995

Adrenergic modulation of hilar neuron activity and granule cell inhibition in the guinea-pig hippocampal slice.

To study the effects of norepinephrine on synaptic inhibition in the dentate gyrus, intracellular recordings were made from hilar neurons in the guinea-pig hippocampal slice. The effects of norepinephrine on hilar neurons were compared with changes in the frequency of spontaneous inhibitory postsynaptic potentials recorded from granule cells. Hilar neurons comprised two electrophysiologically distinct groups: type I hilar neurons displayed a pronounced single spike afterhyperpolarization and little spike frequency accommodation, type II hilar neurons had small afterhyperpolarizations and pronounced spike frequency accommodation. The majority of recordings were from type I hilar neurons which are presumably inhibitory to granule cells. In most instances, effects of norepinephrine (2-10 microM) on hilar neurons could be mimicked by the beta-adrenergic agonist isoproterenol (0.1-1 microM). Isoproterenol induced a slight depolarization, blocked a slow afterhyperpolarization and, in type II neurons, reduced spike frequency accommodation. These effects were associated with an increase in the spontaneous discharge rate and an enhancement of spontaneous excitatory and inhibitory postsynaptic potentials. In accordance, isoproterenol and norepinephrine increased the frequency of inhibitory postsynaptic potentials in granule cells. In the presence of the non-N-methyl-D-aspartate receptor antagonist 6-cyano-7-nitroquinoxaline-2,3-dione and the N-methyl-D-aspartate receptor antagonist CGP 37849, isoproterenol and norepinephrine also increased the frequency of Cl- -dependent inhibitory postsynaptic potentials in granule cells. Under this experimental condition, however, norepinephrine reduced the discharge rate of type I hilar neurons through an effect on alpha-receptors. In the presence of GABAA receptor blockers, norepinephrine increased the frequency of spontaneously occurring K(+)-dependent inhibitory postsynaptic potentials in granule cells. Accordingly, the frequency of burst discharges in type I hilar neurons was increased. We suggest that the discrepancy in the effect of norepinephrine on the discharge rate of presumed inhibitory hilar neurons and the frequency of Cl- -dependent inhibitory postsynaptic potentials in granule cells results from a direct effect of norepinephrine on GABAergic terminals because norepinephrine also enhanced the frequency of tetrodotoxin-resistant inhibitory postsynaptic potentials in granule cells. Thus, the net effect of synaptically released norepinephrine on synaptic inhibition in the dentate gyrus will be determined by opposing actions of alpha- versus beta-receptor stimulation at the synapse on hilar neurons.

Animals↗

PubMed1998

Modulation of synaptic transmission by dopamine and norepinephrine in ventral but not dorsal striatum.

Although the ventral striatum (nucleus accumbens; NAc) and dorsal striatum are associated with different behaviors, these structures are anatomically and physiologically similar. In particular, dopaminergic afferents from the midbrain appear to be essential for the normal functioning of both nuclei. Although a number of studies have examined the effects of dopamine on the physiology of NAc or striatal cells, results have varied, and few studies have compared directly the actions of dopamine on both of these nuclei. Here we use slice preparations of the NAc and dorsal striatum to compare how synaptic transmission in these nuclei is modulated by catecholamines. As previously reported, dopamine depressed excitatory postsynaptic potentials (EPSPs) and inhibitory postsynaptic potentials (IPSPs) in the NAc. Surprisingly, however, neither EPSPs nor IPSPs in the dorsal striatum were affected by dopamine. Similarly, norepinephrine depressed excitatory synaptic transmission in the NAc by an alpha-adrenergic receptor-dependent mechanism but was without effect on excitatory transmission in the dorsal striatum. Inhibitory synaptic transmission was not affected by norepinephrine in either structure. These results suggest that the functional roles of dopamine and norepinephrine are not the same in the dorsal striatum and the NAc.

Animals↗

PubMed1993

An ascending spinal pathway transmitting a central rhythmic pattern to the magnocellular red nucleus in the cat.

The activity of cells in the magnocellular red nucleus (RNm) was recorded extra- and intracellularly in the curarized thalamic cat performing fictive locomotion. The locomotor episodes were detected from the rhythmic activity recorded in the motor nerves of the contralateral hindlimb. It was confirmed that, during fictive locomotion, a large proportion of the rubrospinal cells (56% in our sample) exhibit a rhythmic pattern of activity which is synchronized with the efferent spinal motor nerve activity. On the basis of the intracellular recordings it was established that phases of intense synaptic activity with mixed excitatory postsynaptic potentials (EPSPs) and inhibitory postsynaptic potentials (IPSPs) are involved in this rhythmicity. After eliminating the cerebellar input to the RNm, it was observed that the cells still received intense excitatory and inhibitory inputs, resulting in a continuous modulation of their membrane potential, due to the occurrence of EPSPs and IPSPs. During fictive locomotor-like activity and after elimination of the cerebellar afferents to the RNm, it was observed that the spontaneous PSPs in RNm cells (in the case of 45% of the cells) were organized in repetitive subthreshold bursts occurring in phase relationships with the activity recorded in the motor nerves. Some extracellularly recorded cells (12%) showed a rhythmic firing pattern. It is generally recognized that, in the thalamic cat preparation, the locomotor pattern observed in efferent nerves originates from the central pattern generator (CPG) of the spinal cord. It therefore seems likely that the rhythmicity observed here in the RNm may originate from the spinal CPG and be transmitted through the spino-rubral pathway ascending in the ventral part of the cord. It is concluded that the spino-rubral pathway may transmit both somatosensory information and corollary discharges relating to the activity of the spinal CPG for locomotion.

Animals↗

PubMed2004

Effects of adenosine and ATP on the membrane potential and synaptic transmission in neurons of the rat locus coeruleus.

Effects of adenosine (Ado) and adenosine 5'-triphosphate (ATP) on the membrane potential and synaptic transmission in neurons of the rat locus coeruleus (LC) were examined, in vitro. Ado (30-300 microM) produced a hyperpolarizing response and inhibited spontaneous firing activity in neurons of the rat LC. Ado decreased input resistance of LC neurons. The Ado-induced hyperpolarization reversed polarity near the equilibrium potential of K+ (EK). Ado (100-300 microM) depressed both excitatory postsynaptic potential (EPSP) and inhibitory postsynaptic potential (IPSP). Ado (300 microM) did not alter the hyperpolarization induced by norepinephrine (30 microM). N6-Cyclopentyladenosine (CPA, 100 microM), an A1 receptor agonist, also produced a hyperpolarizing response and depressed both the EPSP and IPSP. Another A1 receptor agonist, adenosine amine congener (ADAC, 30 microM) also produced a hyperpolarizing response and consistently depressed the EPSP and IPSP. Application of ATP (100 microM) to LC neurons caused a depolarizing response associated with an increase in the firing rate of spontaneous action potential in LC neurons. The ATP-induced depolarization was accompanied by an increased input resistance and reversed polarity at--91 mV. ATP (100 microM) consistently depressed the IPSP, while it did not change the amplitude of the EPSP in a majority of neurons. alpha, beta-Methylene ATP (alpha, beta-meATP, 30 micro/M), a P2 receptor agonist, mimicked these effects of ATP. Adenosine 5'-(beta, gamma-imido) triphosphate (AMP-PNP, 100 microM), a non-metabolizable analogue of ATP, produced a depolarizing response in LC neurons, but it produced no obvious depression of the EPSP and IPSP. These results suggest that Ado and ATP cause inhibitory and excitatory modulation, respectively, of neuronal activity and synaptic transmission in the rat LC.

Adenosine↗

PubMed1984

Effects of injectable anaesthetics on responses to L-glutamate and on spontaneous synaptic activity in lamprey reticulo-spinal neurones.

Intracellular recordings were made from reticulo-spinal cells in the medulla of lamprey ammocoetes; potential changes in response to iontophoretically applied L-glutamate were measured before, during and after the preparation was superfused with anaesthetic solutions. Of the anaesthetics pentobarbitone, ketamine, alphaxalone/alphadolone (Saffan) and metomidate, only pentobarbitone (greater than 10 microM) had a consistent dose-related depressant effect on glutamate responses. Spontaneous excitatory postsynaptic potentials (e.p.s.ps) and inhibitory postsynaptic potentials (i.p.s.ps) were diminished in frequency by high concentrations (1 mM) of all anaesthetics. Anaesthetic concentrations of all drugs also reduced i.p.s.ps; for e.p.s.ps this was true of pentobarbitone (100 microM) immediately, and of ketamine (370 microM) and alphaxalone (10-30 microM) after a transitory increase in activity. Consideration of the results in the light of previous observations on inhibitory responses suggests a basis for some of the excitatory side effects of these compounds, assuming that the equivalent mammalian cells are similarly affected.

Anesthetics↗

PubMed1990

5-Hydroxytryptamine responses in neonate rat motoneurones in vitro.

1. Current and voltage recordings were made from antidromically identified motoneurones (MNs) in transverse thoracolumbar spinal cord slices of neonatal rats. 2. Applied by superfusion (10-100 microM) or pressure ejection, 5-hydroxytryptamine (5-HT) elicited a slow depolarization (or inward current) in 81% and a hyperpolarization (or outward current) in 9% of responsive MNs; the responses persisted in a low-Ca2+, high-Mg2+ or tetrodotoxin (TTX)-containing solution. 3. 5-HT induced the occurrence in some MNs of excitatory postsynaptic potentials (EPSPs) or inhibitory postsynaptic potentials (IPSPs), which were reversibly eliminated by TTX, low-Ca2+, high-Mg2+ solution or by the 5-HT2 receptor antagonists ketanserin and spiperone. Also, kynurenic acid and strychnine abolished, respectively, the 5-HT-induced EPSPs and IPSPs. 4. The 5-HT depolarization was associated with increased membrane resistance, was reduced by hyperpolarization and nullified near -100 mV. The extrapolated reversal potential was shifted to a positive direction in elevated [K+]o. 5. The depolarizing response was mimicked by the 5-HT2 receptor agonist (+2-)-1(2,5-dimethyoxy-4-iodophenyl)-2-aminopropane hydrochloride (DOI) and blocked by 5-HT antagonists methysergide and cyproheptadine and by 5-HT2 antagonists ketanserin and spiperone; methiothepin and MDL 72222 were without effect. 6. The 5-HT hyperpolarization was associated with decreased membrane resistance. The 5-HT1A agonist 8-hydroxy-2-(di-N-propylamino) tetralin hydrobromide (8-OH-DPAT) mimicked the hyperpolarizing response. 7. Single or repetitive (10-30 Hz) electrical stimuli elicited in about 30% of MNs, in addition to a fast EPSP, a slow EPSP with electrophysiological characteristics similar to that of 5-HT induced depolarization. Methysergide and spiperone abolished the slow EPSPs evoked in some of these MNs. 8. It is suggested that 5-HT, acting on 5-HT2 and 5-HT1A receptors, depolarizes and hyperpolarizes the MNs by decreasing and increasing K+ conductance. Additionally, 5-HT activates, via 5-HT2 receptors, excitatory and inhibitory interneurones, thereby indirectly affecting the activity of MNs. More importantly, 5-HT released from intraspinal nerves appears to be the mediator of a slow EPSP in a population of MNs.

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

PubMed1996

Somatosensory cortical efferent neurons of the awake rabbit: latencies to activation via supra--and subthreshold receptive fields.

1. Latencies to peripheral sensory stimulation were examined in four classes of antidromically identified efferent neurons in the primary somatosensory cortex (S1) of awake rabbits. Both suprathreshold responses (action potentials) and subthreshold responses were examined. Subthreshold responses were examined by monitoring the thresholds of efferent neurons to juxtasomal current pulses (JSCPs) delivered through the recording microelectrode (usually 1-3 microA). Through the use of this method, excitatory postsynaptic potentials (EPSPs) and inhibitory postsynaptic potentials (IPSPs) were manifested as decreases and increases in threshold, respectively. Efferent populations examined included callosal (CC) neurons, ipsilateral corticocortical (C-IC) neurons, and descending corticofugal neurons of layer 5 (CF-5) and layer 6 (CF-6). Very brief air puffs (rise and fall times 0.6 ms) were delivered to the receptor periphery via a high-speed solenoid valve. 2. Whereas all CF-5 neurons had demonstrable suprathreshold excitatory and/or inhibitory responses to peripheral stimulation, most CC, C-IC, and CF-6 neurons did not. CC and CF-6 neurons that yielded no suprathreshold response to the stimulus had lower axonal conduction velocities than those that did respond (P < 0.0001 in both cases). However, subthreshold receptive fields could be demonstrated in many of the otherwise unresponsive CC (81%), C-IC (88%), and CF-6 (43%) neurons. The subthreshold responses usually consisted of an initial excitatory component (a decrease in the threshold to the JSCP) and a subsequent long-duration (> 80 ms) inhibitory component. A few neurons (1 CC, 1 C-IC, and 5 CF-6) showed an initial short latency inhibitory response in the absence of any excitatory component. 3. Some CC and C-IC neurons yielded supra- and/or subthreshold responses to peripheral stimulation at latencies of 6.1-7 ms. All such neurons were found at intermediate cortical depths (thought to correspond to deep layer 2-3 through layer 5). It is argued that such latencies are indicative of monosynaptic activation via thalamic afferents. Very superficial CC and C-IC neurons, and all CF-6 neurons responded to latencies of > 7 ms. All CF-5 neurons responded to latencies of > 8 ms, although many were found at the same depth as the deeper CC and C-IC neurons that responded at monosynaptic latencies. These results indicate that cortical cell type as well as laminar position are important factors that determine the sequence of intracortical neuronal activation after peripheral sensory stimulation.

Action Potentials↗

PubMed1991

Laminar distribution of neuronal membrane properties in neocortex of normal and reeler mouse.

1. Reeler is an autosomal recessive mutation of mice that alters neuronal migration during development, yielding a general inversion of the laminae in the neocortex. We recorded in vitro from slices of normal and reeler neocortex to study the influence of neuron position and shape on membrane properties and synaptic responses. 2. The intrinsic firing patterns, action-potential shapes, resting membrane potentials, input resistances, and evoked excitatory postsynaptic potentials (EPSPs) and inhibitory postsynaptic potentials (IPSPs) did not differ between reelers and controls when data were grouped. 3. The depth distribution of intrinsic firing patterns was inverted in the reeler: intrinsically bursting (IB) neurons were found only in layer 5 in the normal mouse, but they were found exclusively in supragranular layers of the reeler cortex. 4. The spatial distribution of synaptic responses in the reeler was also inverted: very prominent IPSPs were characteristic of upper layer neurons in the normal mouse, but in the reeler similar inhibitory responses were observed predominantly in deep infragranular layers. 5. Dye injections in reeler pyramidal neurons revealed atypical morphologies, including distorted apical dendrites and cell inversion. 6. The data imply that cortical neurons develop the membrane and synaptic properties appropriate to their function, despite being malformed and mispositioned.

Animals↗

PubMed1995

A review of the preclinical pharmacology of tiagabine: a potent and selective anticonvulsant GABA uptake inhibitor.

We review the neurochemical and behavioral profile of the selective gamma-aminobutyric acid (GABA) uptake inhibitor, (R)-N-(4,4-di-(3-methylthien-2-yl)but-3-enyl) nipecotic acid hydrochloride [tiagabine (TGB), previously termed NNC 05-0328, NO 05-0328, and NO-328], which is currently in phase III clinical trials for epilepsy. TGB is a potent, and specific GABA uptake inhibitor. TGB lacks significant affinity for other neurotransmitter receptor binding sites and/or uptake sites. In electrophysiological experiments in hippocampal slices in culture, TGB prolonged the inhibitory postsynaptic potentials (IPSP) and inhibitory postsynaptic currents (IPSC) in the CA1 and CA3 produced by the addition of exogenous GABA. In vivo microdialysis shows that TGB also increases extracellular GABA overflow in a dose-dependent manner. Together these biochemical data suggest that the in vitro and in vivo mechanism of action of TGB is to inhibit GABA uptake specifically, resulting in an increase in GABAergic mediated inhibition in the brain. TGB is a potent anticonvulsant agent against methyl-6,7-dimethyoxy-4-ethyl-B-carboline-3-carboxylate (DMCM)-induced clonic convulsions (mice), subcutaneous pentylenetetrazol (PTZ)-induced tonic convulsions (mice and rats), sound-induced convulsions in DBA/2 mice and genetically epilepsy-prone rats (GEPR), and electrically induced convulsions in kindled rats. TGB is partially efficacious, against subcutaneous PTZ-induced clonic convulsions, and photically induced myoclonus in Papio papio. TGB is weakly efficacious in the intravenous PTZ seizure threshold test and the maximal electroshock seizure (MES) test and produces only partial protection against bicuculline (BIC)-induced convulsions in rats. The overall biochemical and anticonvulsant profile of TGB suggests potential utility in the treatment of chronic seizure disorders such as generalized clonic-tonic epilepsy (GTCS), photomyoclonic seizures, myoclonic petit mal epilepsy, and complex partial epilepsy.

Animals↗

PubMed2005

Effects of pharmacological treatment and photoinactivation on the directional responses of an insect neuron.

Soma-ipsilateral branches of the large segmental omega neuron of the phaneropterid bush cricket Ancistrura nigrovittata have smooth endings, which extend through most of the auditory neuropile. Correspondingly, it shows a broad frequency tuning. Large excitatory postsynaptic potentials (EPSPs) and inhibitory postsynaptic potentials (IPSPs) are observed when recording from soma-ipsilateral branches. Stimulation from the soma-ipsilateral side leads to a strong excitation. Soma-contralateral branches have a strong, beaded appearance. IPSPs, which seem to be of soma-contralateral origin, can be recorded from these branches. Stimulation from the soma-contralateral side leads to a strong inhibition of the omega neuron. Soma-contralateral stimulation must be 30-40 dB more intense than soma-ipsilateral stimulation to evoke similar spike numbers in the omega neuron. The side-to-side difference is reduced to 10-15 dB after cutting the input from the soma-contralateral leg (tympanic nerve). The thresholds for eliciting IPSPs by soma-contralateral stimulation correspond roughly to excitatory thresholds of the mirror-image omega with the same stimuli. Pharmacological treatment with picrotoxin (PTX) or photoinactivation of the Lucifer Yellow filled mirror-image omega neuron reduces contralateral inhibition considerably and eliminates all visible IPSPs. Nevertheless, an additional contralateral inhibition survives both procedures and is only eliminated after cutting the soma-contralateral tympanic nerve. These results demonstrate that the mirror-image partners of the omega neuron mutually inhibit each other in bush crickets--as in crickets. This mutual inhibition is PTX-sensitive. At least one additional element exerts contralateral PTX-insensitive inhibition on the omega neuron.

Acoustic Stimulation↗

PubMed1991

Neurophysiological maturation of cat substantia nigra neurons: evidence from in vitro studies.

The membrane properties and synaptic physiology of developing cat substantia nigra (SN) neurons were studied in in vitro slice preparations. Stable intracellular recordings were obtained from 46 neurons in 20 kittens ranging in age from fetal day (F) 51 to postnatal day (P) 120. Only two of these properties changed with development. The percentage of cells displaying inward rectification and the percentage of cells that generated low-threshold Ca++ spikes increased with age. Properties that did not change included resting membrane potentials, action potential amplitudes and durations, and input resistances. At all ages locally evoked synaptic responses consisted of sequences of excitatory postsynaptic potentials followed by inhibitory postsynaptic potentials. Most of the cells recorded had the electrophysiological properties which have been attributed to SN dopamine-containing neurons. To identify neurons morphologically, and verify the recording site, cells were filled with Lucifer yellow at the end of each experiment. Somatic shapes varied widely from oval to fusiform to triangular. Somatic diameters and dendritic length increased with development. Filopodial processes and growth cones were present up to the first postnatal month. Dye-coupling occurred only in the fetal group. These results indicate that cat SN neurons have many mature physiological properties during late fetal and early postnatal development. This contrasts with the significant maturation that occurs in cat caudate neurons during the same developmental period.

Action Potentials↗