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gamma-Aminobutyrate, alpha-carboxy-2-nitrobenzyl ester selectively blocks inhibitory synaptic transmission in rat dentate gyrus.

gamma-Aminobutyrate, alpha-carboxy-2-nitrobenzyl ester (cGABA) is a stable photoactivatable probe used to study gamma-aminobutyrate (GABA) receptors. GABA is released from this compound when it is exposed to ultraviolet light, but little is known about the electrophysiological effects of the compound itself. Whole cell patch clamp recordings on rat hippocampal slices demonstrated that cGABA blocked polysynaptic inhibitory postsynaptic currents (IPSCs) evoked in dentate granule cells by antidromic stimulation of the mossy fibers. It also reduced monosynaptically evoked IPSCs with an IC(50) of 28 microM. In contrast, cGABA had no effect on excitatory postsynaptic currents (EPSCs) evoked by perforant path stimulation. The effect of cGABA was not mediated by depression of GABA release through activation of presynaptic GABA(B) receptors. cGABA inhibited muscimol-evoked currents by only 15% at a concentration of 40 microM. At this same concentration, it reduced the mean frequency of miniature inhibitory postsynaptic potentials by 71%, their mean peak amplitude by 44%, their mean decay time constant by 26% and the mean charge transfer per event by 52%. These effects may be explained by a phenothiazine-like modification of GABA(A) receptor kinetics and/or a selective block of somatic GABA synapses.

Animals↗

Comparative in vivo and in vitro studies with the potent GABAB receptor antagonist, CGP 56999A.

CGP 56999A ([3-[1-(R)-[(3-cyclohexylmethyl)hydroxyphosphinyl]-2-(S)- hydroxy-propyl] amino]ethyl]-benzoic acid) is a potent GABAB receptor antagonist showing much more pronounced convulsant features in mice than do other previously studied GABAB receptor antagonists. The goal of this study was to elucidate the physiological mechanisms underlying this effect. In mice a dose of 0.6 mg/kg intraperitoneal (i.p.) CGP 56999A elicited behavioral activation and stereotypy with periods of intensive scratching and grooming. At 1 mg/kg i.p. most mice displayed myoclonic seizure-like episodes lasting several min. Pretreatment with the lower dose of 0.6 mg/kg i.p. also induced seizures after treatment with a subthreshold dose of pentylenetetrazole (40 mg/kg i.p.). In rats a dose of 3 mg/kg CGP 56999A (i.p.) induced convulsions of tonic-clonic nature. Intracellular sharp microelectrode recordings from rat cortical neurons in slices revealed no paroxysmal actions of CGP 56999A (10 microM). Similar to other GABAB receptor antagonists, CGP 56999A suppressed the late inhibitory postsynaptic potential (i.p.s.p.), but had no effect on the excitatory postsynaptic potential (e.p.s.p.) in the cortex. In cortical slices exposed to picrotoxin (10 microM), the compound evoked pronounced, spontaneous and intense epileptiform discharges. In conclusion, these findings demonstrated that the convulsive feature of the potent GABAB receptor antagonist, CGP 56999A, may be due to suppression of the late i.p.s.p., which becomes apparent in the intact brain only, whereas this action remains undetected in untreated brain slices. This remarkable discrepancy between in vitro and in vivo may be a consequence either of disruption of neuronal circuits during slice preparation or of the pronounced hyperpolarization of pyramidal neurons, at least in the case of cortical slice preparations.

Animals↗

The effects of general anaesthetics on carbachol-evoked gamma oscillations in the rat hippocampus in vitro.

The effects of general anaesthetics and temperature on carbachol-evoked gamma oscillations in the rat hippocampal brain slice preparation were investigated. The frequency of the oscillations was found to be dependent on temperature in the range 32-25 degrees C, with a linear reduction in frequency from 40-17 Hz over this temperature range. The volatile anaesthetics isoflurane and halothane, and the intravenous anaesthetics thiopental, propofol and R(+)-etomidate caused a reduction in the frequency of the oscillations, in a concentration-dependent manner, over a range of clinically relevant concentrations. On the other hand, the intravenous agent ketamine and the "inactive" S(-)-isomer of etomidate had no significant effect on the oscillation frequency. The oscillations were markedly asymmetric over one cycle with a relatively rapid "rising" phase followed by a slower "decaying" phase. The decrease in oscillation frequency was due to an increase in the time-course of the "decaying phase" of the oscillation with little effect on the "rising" phase, consistent with the idea that carbachol-evoked gamma oscillations are trains of GABAergic inhibitory postsynaptic potentials and that the anaesthetics are acting postsynaptically at the GABA(A) receptor.

Anesthetics, General↗

Valproic acid inhibits the depolarizing rectification in neurons of rat amygdala.

The actions of valproic acid (VPA) on neuronal membrane properties and synaptic transmission were studied using intracellular recording techniques in rat basolateral neurons of the amygdala slices. In therapeutically attainable concentrations (10-100 microM), VPA decreased synaptically-induced epileptiform bursting in the presence of bicuculline. Additionally, the frequency of repetitive discharge induced by direct superthreshold depolarizing current pulses was decreased by VPA. However, evoked excitatory and inhibitory postsynaptic potentials were not affected at this level of drug concentration. The current-voltage relationship of untreated neurons revealed rectification of membrane potential when neuronal membrane was depolarized with cathodal current pulses. This depolarizing rectification was blocked by VPA. High medium calcium or addition of the sodium channel blocker tetrodotoxin (TTX) also blocked the depolarizing rectification, whereas the calcium channel antagonist diltiazem had no effect on the rectification. Elevation of medium calcium concentration also blocked the bicuculline-induced bursting. These results indicate that the inhibition by VPA of subthreshold slow sodium current and membrane depolarizing rectification results in suppression of neuronal membrane excitability which is probably a major mechanism for its anticonvulsant action.

Amygdala↗

Drivers and modulators from push-pull and balanced synaptic input.

In 1998, Sherman and Guillery proposed that there are two types of inputs to cortical neurons; drivers and modulators. These two forms of input are required to explain how, for example, sensory driven responses are controlled and modified by attention and other internally generated gating signals. One might imagine that driver signals are carried by fast ionotropic receptors, whereas modulators correspond to slower metabotropic receptors. Instead, we have proposed a novel mechanism by which both driver and modulator inputs could be carried by transmission through the same types of ionotropic receptors. In this scheme, the distinction between driver and modulator inputs is functional and changeable rather than anatomical and fixed. Driver inputs are carried by excitation and inhibition acting in a push-pull manner. This means that increases in excitation are accompanied by decreases in inhibition and vice versa. Modulators correspond to excitation and inhibition that covary so that they increase or decrease together. Theoretical and experimental work has shown that such an arrangement modulates the gain of a neuron, rather than driving it to respond. Constructing drivers and modulators in this manner allows individual excitatory synaptic inputs to play either role, and indeed to switch between roles, depending on how they are linked with inhibition.

Afferent Pathways↗

Effects of replacing extracellular chloride with formate on the inhibitory neuromuscular junction of the crayfish opener muscle.

The effect of partially replacing extracellular chloride by formate on the inhibitory junction of the crayfish opener muscle is investigated. Inhibitory postsynaptic potential (IPSP) amplitude, recorded in muscle fibers and presynaptic axons, increases significantly in the formate saline whereas input resistance and resting membrane potential of muscle fibers are not affected. The increase in IPSP amplitude is mainly due to an increase in IPSP driving force while the GABA mediated conductance change underlying IPSP is not altered. The waveform of presynaptic action potential is slightly altered by formate substitution where an after-depolarizing potential is decreased. This change does not seem to affect the probability of transmitter release because the magnitude of synaptic facilitation is unchanged. In conclusion, formate substitution significantly increases IPSP amplitudes by increasing its driving force without affecting presynaptic release mechanisms.

Animals↗

Synaptic mechanisms of inspiratory off-switching evoked by pontine pneumotaxic stimulation in cats.

To elucidate synaptic mechanisms and the involvement of N-methyl-D-aspartate (NMDA) receptors in inspiratory off-switching (IOS) evoked by the stimulation of the nucleus parabrachialis medialis (NPBM), excitatory and inhibitory postsynaptic potentials (EPSPs and IPSPs) were recorded from bulbar augmenting inspiratory (aug-I) and postinspiratory (PI) neurons in vagotomized cats. Stimulation of NPBM produced either transient inhibition or premature termination of inspiration (reversible or irreversible IOS), depending on the stimulus intensity. Each neuron displayed four-phasic postsynaptic responses during the reversible IOS, i.e. Phase 1 EPSPs, Phase 2 IPSPs, Phase 3 EPSPs and Phase 4 IPSPs in aug-I neurons, and Phase 1 plus 2 EPSPs, Phase 3 IPSPs and Phase 4 EPSPs in PI neurons. During the irreversible IOS, Phase 4 responses were replaced by sustained hyperpolarization in aug-I neurons and decrementing depolarization in PI neurons. Blockade of NMDA receptors by dizocilpine (0.3 mg kg(-1) i.v.) selectively increased Phase 4 potentials in both types of neurons and decreased the thresholds for evoking the irreversible IOS. The NPBM-induced responses had a pattern and time-course similar to those induced by vagal stimulation. The present results suggest that pneumotaxic and vagal inputs converge on the common IOS circuit, and the effectiveness of both inputs is modulated by NMDA receptors.

Animals↗

GABA(B(1)) mRNA expression in hippocampal sclerosis associated with human temporal lobe epilepsy.

GABA(B) receptors act to inhibit neurotransmitter release from presynaptic terminals, and mediate the late inhibitory postsynaptic potential. Studies of GABA(B) receptor function in rodent models of temporal lobe epilepsy (TLE) suggest that GABA(B) receptor expression and/or function may be perturbed. GABA(B(1)) mRNA levels were investigated in 10 hippocampal resection samples obtained at surgery from intractable hippocampal sclerosis (HS) associated TLE patients and five neurologically normal post-mortem (PM) control samples. In situ hybridisation with a 35S-dATP-labelled oligonucleotide was carried out to measure mRNA levels, along with three-dimensional cell counting, for assessment of neuronal density in hippocampal subregions. GABA(B(1)) mRNA was significantly up-regulated in the subiculum of HS samples as compared with PM controls. When adjusted for the characteristic neuronal density changes observed in HS, GABA(B(1)) mRNA was significantly up-regulated in CA1, hilus and dentate gyrus granule cell layer of HS samples as compared with PM controls. The possibility of increased GABA(B(1)) expression suggests that changes in GABA(B) receptor mechanisms may be involved in the pathogenesis of human HS-associated TLE.

Adult↗

Effects of the neuropeptide thyrotropin-releasing hormone on GABAergic synaptic transmission of CA1 neurons of the rat hippocampal slice during hypoxia.

Because thyrotropin-releasing hormone (TRH) has been suggested to improve recovery of brain neurons from hypoxia, which strongly impairs GABAergic synaptic transmission, the present electrophysiological study used intracellular recording from CA1 neurons of the rat hippocampal slice to examine the cellular mechanisms underlying this phenomenon. Hypoxia induced by superfusion with a medium devoid of oxygen evoked typical membrane hyperpolarization, fall in input resistance, and strong depression of monosynaptic, GABAA receptor-mediated fast inhibitory postsynaptic potentials (IPSPs). The depression of fast IPSPs during hypoxia was found to be due to a combination of factors such as shift in the IPSP reversal potential and membrane hyperpolarization. GABAB receptor-mediated slow IPSPs were comparatively less sensitive to hypoxia. TRH (10 microM), applied 1 min prior to hypoxia, selectively accelerated recovery of membrane potential and delayed return of fast IPSPs to control amplitude without changing the mechanisms responsible for depression of GABAergic transmission. In conclusion, despite a slower recovery of IPSPs, TRH facilitated earlier return of neuronal excitability after the hypoxic period.

Animals↗

GABA-ergic transmission in deep cerebellar nuclei.

gamma-Aminobutyric acid (GABA) is the inhibitory transmitter released at Purkinje cell axon terminals in deep cerebellar nuclei (DCN). Neurons in DCN also receive excitatory glutamatergic inputs from the inferior olive. The output of DCN neurons, which depends on the balance between excitation and inhibition on these cells, is involved in cerebellar control of motor coordination. Plasticity of synaptic transmission observed in other areas of the mammalian central nervous system (CNS) has received wide attention. If GABA-ergic and/or glutamatergic synapses in DCN also undergo plasticity, it would have major implications for cerebellar function. In this review, literature evidence for GABA-ergic synaptic transmission in DCN as well as its plasticity are discussed. Studies indicate that fast inhibitory postsynaptic potentials (IPSPs) and currents (IPSCs) in neurons of DCN are mediated by GABAA receptors. While GABAB receptors are present in DCN, they do not appear to be activated by Purkinje cell axons. The IPSPs undergo paired-pulse, as well as frequency-dependent, depressions. In addition, tetanic stimulation of inputs can induce a long-term depression (LTD) of the IPSPs and IPSCs. Excitatory synapses do not appear to undergo long-term potentiation or LTD. The LTD of the IPSP is not input-specific, as it can be induced heterosynaptically and is associated with a reduced response of DCN neurons to a GABAA receptor agonist. Postsynaptic Ca2+ and protein phosphatases appear to contribute to the LTD. The N-methyl-D-aspartate receptor-gated, as well as the voltage-gated Ca2+ channels are proposed to be sources of the Ca2+. It is suggested that LTD of GABA-ergic transmission, by regulating DCN output, can modulate cerebellar function.

Animals↗

Effect of temperature on synaptic transmission between identified neurones of the mollusc Lymnaea stagnalis.

The mollusc, Lymnaea stagnalis, has been used as a model to study the mechanisms of temperature-dependent processes in the central nervous system. Effects of temperature changes on transmission in monosynaptic connections, made by the FMRFamide-containing neurone VD4 and the giant dopaminergic neurone RPeD1 with follower neurones, were recorded with intracellular microelectrodes. In the temperature range of 4-6 degrees C, inhibitory postsynaptic potentials (IPSP) in response to VD4 stimulation were not observed in postsynaptic cells while the IPSPs persisted in the RPeD1 followers. A temperature rise resulted in a sharp increase in the IPSP amplitude in followers of both VD4 and RPeD1. In isolated nervous systems taken from molluscs which have been kept at 4-6 degrees C for 2 weeks and more, no coupling between VD4, RPeD1 and synaptically connected cells was seen in the full experimental temperature range. The synaptic coupling recovered only after maintaining the molluscs at a water temperature of 14-16 degrees C for at least 2 days. The changes observed in synaptic responses to temperature alterations correspond to the behaviour of the molluscs.

Animals↗

Postsynaptic firing produces long-term depression at inhibitory synapses of rat visual cortex.

High-frequency activation of excitatory synapses produces long-term depression (LTD) at inhibitory synapses in rat visual cortex. The LTD generation mechanism was studied by recording inhibitory postsynaptic potentials from layer V cells in response to layer IV stimulation under pharmacological blockade of excitatory synaptic transmission. LTD occurred after depolarizing current pulses applied to postsynaptic cells elicited repetitive firing. LTD induction was facilitated by a bath application of an L-type Ca(2+) channel activator, 1,4-Dihydro-2,6-dimethyl-5-nitro-4-[2-(trifluoromethyl) phenyl]-3-pyridinecarboxylic acid, methyl ester (BAY K 8644), while it was prevented by either the bath application of L-type Ca(2+) channel blocker nifedipine or postsynaptic loading of Ca(2+) chelator 1,2-bis-(o-aminophenoxy)ethane-N,N,N',N',-tetraaceticacid (BAPTA). These results suggest that LTD induction is at least partly mediated by Ca(2+) entry through L-type Ca(2+) channels in association with postsynaptic action potentials.

3-Pyridinecarboxylic acid, 1,4-dihydro-2,6-dimethy↗

Identification of a GABA-containing cerebral-buccal interneuron-11 in Aplysia californica.

The cerebral-buccal interneurons (CBIs) in Aplysia are a group of inter-ganglionic projection neurons that regulate feeding motor programs. In this study, electrophysiological and immunocytological methods were used to identify a previously uncharacterized CBI, designated CBI-11. CBI-11 is a gamma-aminobutyric acid (GABA)-immunoreactive neuron located in the G cluster of the cerebral ganglion. Firing CBI-11 produced fast picrotoxin-sensitive inhibitory postsynaptic potentials (IPSPs) in buccal motor neuron B3. Local application of GABA to B3 produced a picrotoxin-sensitive hyperpolarization that reversed at the same membrane potential as the IPSPs elicited by stimulation of CBI-11. Together, these observations indicate that CBI-11 utilizes GABA as its transmitter. Finally, stimulation of CBI-11 elicited rhythmic motor programs in quiescent buccal ganglia. Thus, CBI-11 is a GABAergic CBI that can function as a motor program initiator.

Animals↗

Enhancement of an inhibitory input to the feeding central pattern generator in Lymnaea stagnalis during conditioned taste-aversion learning.

To study the neuronal mechanism of a conditioned taste-aversion (CTA) learning in the pond snail Lymnaea stagnalis, we examined the synaptic connection between the neuron 1 medial (N1M) cell and the cerebral giant cell (CGC), the former is an interneuron in central pattern generator for the feeding response and the latter is a regulatory neuron to the central pattern generator. Inhibitory postsynaptic potential (IPSP) which was evoked in the N1M cell by activation of the CGC was larger and lasted longer in the conditioned animal than that in the control animal. The electrical properties of the cell body of CGC and the responses of the CGC to the chemosensory inputs were not changed during the CTA learning. These results, together with the previous report indicating the existence of excitatory projection from the N1M cell to the feeding motoneuron, suggest that enhanced IPSP in the N1M cell may underlie the suppression of feeding responses in the Lymnaea CTA learning.

Animals↗

Alpha-pompilidotoxin (alpha-PMTX), a novel neurotoxin from the venom of a solitary wasp, facilitates transmission in the crustacean neuromuscular synapse.

A new neurotoxin, named alpha-pompilidotoxin (alpha-PMTX) has been found in the venom of the solitary wasp Anoplius safnariensis. In the neuromuscular synapse of the lobster walking leg preparation, alpha-PMTX (10-100 micro/M) caused great enhancement of both the excitatory and inhibitory postsynaptic potentials. Recordings of the excitatory post synaptic currents (EPSCs) at the synaptic sites showed that alpha-PMTX reversibly and dose-dependently potentiates EPSCs. Alpha-PMTX may act primarily on the presynaptic membrane but the mode of action of the toxin is clearly different from other known facilitatory neurotoxins, such as alpha-latrotoxin, apamin or charybdotoxin. This novel toxin will serve as a useful tool in the research field of neuroscience.

Animals↗

Neuronal organization of the utricular macula concerned with innervation of single vestibular neurons in the cat.

We investigated whether cross-striolar inhibition, which may increase sensitivity to linear acceleration, contributed to utricular (UT) afferent innervation of single vestibular neurons (VNs). Excitatory and inhibitory postsynaptic potentials (EPSPs, IPSPs, respectively) were recorded from VNs after focal stimulation of the UT macula (M). From a total of 83 VNs, 25 (30%) neurons received inputs from both sides of the UTM, and the response patterns were opposite, i.e. cross-striolar inhibition was observed. In roughly 2/3 of these neurons, stimulation of the medial side of the UTM evoked EPSPs, while stimulation of the lateral side evoked IPSPs. In the remaining 1/3 neurons, the response patterns were opposite. Thirty-two (39%) of the 83 neurons received the identical pattern of inputs from both sides of the UTM: EPSPs in 26 neurons and IPSPs in six neurons. Twenty-six (31%) of the 83 neurons received inputs from either the medial or the lateral side of the UTM. These findings suggest that cross-striolar inhibition existed in the UT system, although it was not a dominant circuit that increased the sensitivity as in the saccular system [15].

Acoustic Maculae↗

Electrophysiological studies of rat substantia nigra neurons in an in vitro slice preparation after middle cerebral artery occlusion.

We studied sequential changes in electrophysiological profiles of the ipsilateral substantia nigra neurons in an in vitro slice preparation obtained from the middle cerebral artery-occluded rats. Histological examination revealed marked atrophy and neurodegeneration in the ipsilateral substantia nigra pars reticulata at 14 days after middle cerebral artery occlusion. Compared with the control group, there was no significant change in electrical membrane properties and synaptic responses of substantia nigra pars reticulata neurons examined at one to two weeks after middle cerebral artery occlusion. On the other hand, there was a significant increase in the input resistance and spontaneous firing rate of substantia nigra pars compacta neurons at 13-16 days after middle cerebral artery occlusion. Furthermore, inhibitory postsynaptic potentials evoked by stimulation of the subthalamus in substantia nigra pars compacta neurons was suppressed at five to eight days after middle cerebral artery occlusion. At the same time excitatory postsynaptic potentials evoked by the subthalamic stimulation was increased. Bath application of bicuculline methiodide (50 microM), a GABA(A) receptor antagonist, significantly increased the firing rate of substantia nigra pars compacta neurons from intact rats. These results strongly suggest that changes in electrophysiological responses observed in substantia nigra pars compacta neurons is caused by degeneration of GABAergic afferents from the substantia nigra pars reticulata following middle cerebral artery occlusion. While previous studies indirectly suggested that hyperexcitation due to deafferentation from the neostriatum may be a major underlying mechanism in delayed degeneration of substantia nigra pars reticulata neurons after middle cerebral artery occlusion, the present electrophysiological experiments provide evidence of hyperexcitation in substantia nigra pars compacta neurons but not in pars reticulata neurons at the chronic phase of striatal infarction.

Animals↗

Periodically-modulated inhibition of living pacemaker neurons--III. The heterogeneity of the postsynaptic spike trains, and how control parameters affect it.

Codings involving spike trains at synapses with inhibitory postsynaptic potentials on pacemakers were examined in crayfish stretch receptor organs by modulating presynaptic instantaneous rates periodically (triangles or sines; frequencies, slopes and depths under, respectively, 5.0 Hz, 40.0/s/s and 25.0/s). Timings were described by interspike and cross-intervals ("phases"); patterns (dispersions, sequences) and forms (timing classes) were identified using pooled graphs (instant along the cycle when a spike occurs vs preceding interval) and return maps (plots of successive intervals). A remarkable heterogeneity of postsynaptic intervals and phases characterizes each modulation. All cycles separate into the same portions: each contains a particular form and switches abruptly to the next. Forms differ in irregularity and predictability: they are (see text) "p:q alternations", "intermittent", "phase walk-throughs", "messy erratic" and "messy stammering". Postsynaptic cycles are asymmetric (hysteresis). This contrasts with the presynaptic homogeneity, smoothness and symmetry. All control parameters are, individually and jointly, strongly influential. Presynaptic slopes, say, act through a postsynaptic sensitivity to their magnitude and sign; when increasing, hysteresis augments and forms change or disappear. Appropriate noise attenuates between-train contrasts, providing modulations are under 0.5 Hz. Postsynaptic natural intervals impose critical time bases, separating presynaptic intervals (around, above or below them) with dissimilar consequences. Coding rules are numerous and have restricted domains; generalizations are misleading. Modulation-driven forms are trendy pacemaker-driven forms. However, dissimilarities, slight when patterns are almost pacemaker, increase as inhibition departs from pacemaker and incorporate unpredictable features. Physiological significance-(1) Pacemaker-driven forms, simple and ubiquitous, appear to be elementary building blocks of synaptic codings, present always but in each case distorted typically. (2) Synapses are prototype: similar behaviours should be widespread, and networks simulations benefit by nonlinear units generating all forms. (3) Relevant to periodic functions are that few variables need be involved in form selection, that distortions are susceptible to noise levels and, if periods are heterogeneous, that simple input cycles impose heterogeneous outputs. (4) Slow Na inactivations are necessary for obtaining complex forms and hysteresis. Formal significance--(1) Pacemaker-driven forms and presumably their modulation-driven counterparts, pertain to universal periodic, intermittent, quasiperiodic and chaotic categories whose formal properties carry physiological connotations. (2) Only relatively elaborate, nonlinear geometric models show all forms; simpler ones, show only alternations and walk-throughs. (3) Bifurcations resemble those of simple maps that can provide useful guidelines. (4) Heterogeneity poses the unanswered question of whether or not the entire cycle and all portions have the same behaviours: therefore, whether trajectories are continuous or have discontinuities and/or singular points.

Action Potentials↗