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Low-dimensional maps encoding dynamics in entorhinal cortex and hippocampus.

Cells that produce intrinsic theta oscillations often contain the hyperpolarization-activated current I(h). In this article, we use models and dynamic clamp experiments to investigate the synchronization properties of two such cells (stellate cells of the entorhinal cortex and O-LM cells of the hippocampus) in networks with fast-spiking (FS) interneurons. The model we use for stellate cells and O-LM cells is the same, but the stellate cells are excitatory and the O-LM cells are inhibitory, with inhibitory postsynaptic potential considerably longer than those from FS interneurons. We use spike time response curve methods (STRC), expanding that technique to three-cell networks and giving two different ways in which the analysis of the three-cell network reduces to that of a two-cell network. We show that adding FS cells to a network of stellate cells can desynchronize the stellate cells, while adding them to a network of O-LM cells can synchronize the O-LM cells. These synchronization and desynchronization properties critically depend on I(h). The analysis of the deterministic system allows us to understand some effects of noise on the phase relationships in the stellate networks. The dynamic clamp experiments use biophysical stellate cells and in silico FS cells, with connections that mimic excitation or inhibition, the latter with decay times associated with FS cells or O-LM cells. The results obtained in the dynamic clamp experiments are in a good agreement with the analytical framework.

Action Potentials↗

The versatile synapse.

'Typically' chemical synaptic transmission takes place when an influx of calcium ions during a presynaptic nerve impulse triggers exocytosis of neurotransmitter substance from synaptic vesicles. The neurotransmitter diffuses across the synaptic cleft and occupies receptors embedded in the subsynaptic membrane. This interaction (directly or via a second messenger) operates characteristic ion channels and produces an increase in the postsynaptic membrane permeability to particular ions. Depending on the ionic species to which the postsynaptic membrane becomes more permeable, the physiological response will be an excitatory or an inhibitory postsynaptic potential. The action of neurotransmitters may be terminated either by enzymic inactivation or by cellular uptake mechanisms. Over the last decade it has become clear that a neurotransmitter substance may exert a number of different actions on a single postsynaptic neurone. These may involve opening or closure of either voltage-independent or voltage-dependent ion channels. It is also possible that in some instances transmitters may act on neuronal biochemical systems to modify the physiology of postsynaptic cells without directly altering their electrical characteristics. Analysis of the postsynaptic actions of neurotransmitter substances has become further complicated by the increasing body of evidence which indicates that more than one transmitter substance (one of which may be a peptide) can be released from a single presynaptic neurone. The significance of such dual transmitter systems has yet to be fully elucidated. The efficacy of transmission across many synapses may be modified by either presynaptic or postsynaptic mechanisms; both transmitter release and postsynaptic responsiveness may depend on the recent history of a single synapse, on synaptic inputs from other neurones or on circulating neuroactive substances.

Animals↗

The stopping response of Xenopus laevis embryos: pharmacology and intracellular physiology of rhythmic spinal neurones and hindbrain neurones.

1. Xenopus laevis embryos stop swimming in response to pressure on the cement gland. This behaviour and 'fictive' stopping are blocked by bicuculline (10 mumol 1(-1)), tubocurarine (110 mumol 1(-1)) and kynurenic acid (0.5 mmol 1(-1)). 2. Intracellular recordings from spinal neurones active during swimming have shown that pressure on the cement gland evokes compound, chloride-dependent inhibitory postsynaptic potentials (IPSPs). These are blocked by bicuculline, tubocurarine and kynurenic acid, but are unaffected by strychnine (2 mumol 1(-1)). 3. When the cement gland is pressed, trigeminal ganglion activity precedes both the IPSPs and the termination of 'fictive' swimming activity recorded in rhythmic spinal neurones. The trigeminal discharge is unaffected by the antagonists bicuculline, tubocurarine, kynurenic acid and strychnine. 4. Intracellular recordings from the hindbrain have revealed neurones that are normally silent, but rhythmically inhibited during 'fictive' swimming. In these neurones pressure on the cement gland evokes depolarising potentials, often with one or more spikes. 5. We propose that the stopping response depends on the excitation of pressure-sensitive trigeminal receptors which innervate the cement gland. These release an excitatory amino acid to excite brainstem GABAergic reticulospinal neurones, which inhibit spinal neurones to turn off the central pattern generator for swimming. There may also be a less direct pathway.

Animals↗

An interneurone of unusual morphology is tuned to the female song frequency in the bushcricket Ancistrura nigrovittata (Orthoptera, Phaneropteridae).

The interneurone AN5-AG7 of the duetting bushcricket Ancistrura nigrovittata has its soma in the seventh (penultimate) abdominal ganglion. Its major postsynaptic arborizations with dense thin branches of smooth appearance are found in the prothoracic ganglion. The branches terminate in the auditory neuropile, predominantly at the same location as those auditory receptors that respond best to the female song frequency. Correspondingly, AN5-AG7 responds preferentially to frequencies between 24 and 28 kHz, thereby matching the carrier frequency of the female response song quite well. At frequencies below 24 kHz, AN5-AG7 receives inhibition, which is sometimes seen as clear inhibitory postsynaptic potentials. At these frequencies, thresholds of excitatory postsynaptic potentials are considerably lower than spike thresholds. In contrast, above 20 kHz, the two thresholds match and they correspond to the behavioural threshold. The AN5-AG7 interneurone is more sensitive to soma-contralateral stimuli and it receives predominantly inhibition, but also some excitation, from the soma-ipsilateral ear. Response strength is not greatly affected by stimulus duration but shows prominent habituation. This habituation depends only weakly on intensity and frequency. Some AN5-AG7 interneurones show very small graded potentials and no spiking responses to any acoustic stimuli.

Animals↗

[Molecular pharmacology of GABAA and GABAB receptors].

The receptor for gamma-aminobutyric acid (GABA), a major inhibitory neurotransmitter in the mammalian brain, has been classified into GABAA and GABAB subtypes. The GABAA receptor forms a Cl- channel and is consisted of several subunits. These subunits in the brain are known to be multiple and heterogeneous in their molecular structure. Therefore, it is suggested that these multiple GABAA receptors generate various inhibitory functions in the brain. In contrast, the GABAB receptor is known to be one of the metabotropic type of receptors which generate slow inhibitory postsynaptic potentials and functionally couple with Gi/Go types of GTP-binding proteins. The GABAB receptor in the brain has been purified to homogeneity using immunoaffinity purification procedures and found to be an 80-kDa protein. The possible existence of multiplicity in the cerebral GABAB receptor has also been suggested.

Animals↗

Intracortical spread of neuronal activities induced by stimulation of recurrent and thalamic afferent pathways compared with epicortical activation.

In the encéphale isolé cat preparation the cerebral peduncle (CP) and the nucleus ventralis lateralis (VL) of the thalamus were stimulated. Short-latency responses recorded from precruciate cortical neurons consisted of excitatory (EPSP) and inhibitory postsynaptic potentials (IPSP). Laminar distributions of these responses and their latencies wee viewed as the spatiotemporal pattern of spread of excitation and inhibition within the cortex in comparison with those obtained by epicortical stimulation (EPICS). In contrast with activities by EPICS spreading downwards from superficial to deep layers, CP recurrent activities spread upwards from deep to middle or superficial layers, and those by VL afferents spread from middle to both superficial and deep layers bidirectionally. These three intracortical routes shared common cell assemblies in that they received convergent EPSPs or IPSPs to various extents from different inputs. The routes for EPICS and VL inputs were overlapped particularly with abundant supply of convergence in spite of their functional difference. Relevant potentiality of the cerebral network in forming plural patterns was discussed.

Afferent Pathways↗

Effects of K-7259 on neuronal activity and synaptic transmission in the rat dorsolateral septal nucleus.

K-7259 is a dilazep dihydrochloride derivative that minimizes the damaged area from middle cerebral artery hemiocclusion in the rat (Yamauchi et al. 1992a, b). The effects of K-7259 on the electrophysiological properties of neurons in the rat dorsolateral septal nuclei (DLSN) were examined. K-7259 (100 microM-3 mM) depolarized the membrane with a decrease in input resistance in 36% of the DLSN cells. K-7259 (100 microM) depressed the inhibitory postsynaptic potential (IPSP) and the late hyperpolarizing potential (LHP). The magnitudes of the depressions of the IPSP and LHP with 100 microM K-7259 were 50 +/- 25% (n = 5) and 52 +/- 15% (n = 4), respectively. The amplitudes of the excitatory postsynaptic potentials (EPSPs) were augmented during the inhibition of the IPSP and LHP. However, a voltage-clamp analysis showed that K-7259 did not affect the isolated excitatory postsynaptic current (EPSC). The outward current produced by pressure application of gamma-aminobutyric acid (GABA) to the recording cell was not inhibited by K-7259. These results indicate that K-7259 presynaptically inhibits the IPSP and LHP through a GABAergic pathway.

Animals↗

Heterosynaptic transformation of GABAergic gating in the hippocampus and effects of carbonic anhydrase inhibition.

Recordings from CA1 pyramidal cells were made in rat hippocampal slices (in vitro). Activation of cholinergic receptors associated with tetanization of GABAergic inputs from stratum pyramidale transformed the hyperpolarizing GABA-mediated inhibitory postsynaptic potentials into depolarizing responses of rat hippocampal CA1 pyramidal neurons. The synaptic transformation was characterized by a significant shift of reversal potential of postsynaptic responses toward positive membrane potentials. This effect lasted more than 1 h and changed the function of the GABAergic synapses from excitation filter to amplifier. This long-term synaptic transformation was prevented by carbonic anhydrase inhibitors or the presence of HEPES buffer, indicating a dependence on HCO(3-). The presence or absence of an associated activation of cholinergic with GABAergic inputs thus gates the information processing through the pyramidal cells and network, forming an amplified "center" of attention and a filtered "surround". Information flow through the neural circuit is thereby directed according to temporal association of the relevant signals.

Acetazolamide↗

Pharmacological enhancement of synaptic efficacy, spatial learning, and memory through carbonic anhydrase activation in rats.

CA1 pyramidal cells were recorded in rat hippocampal slices. In the presence of carbonic anhydrase activators, comicrostimulation of cholinergic inputs from stratum oriens and gamma-aminobutyric acid (GABA)ergic inputs from stratum pyramidale at low intensities switched the hyperpolarizing GABA-mediated inhibitory postsynaptic potentials to depolarizing responses. In the absence of the activators, however, the same stimuli were insufficient to trigger the synaptic switch. This synaptic switch changed the function of the GABAergic synapses from excitation filter to amplifier and was prevented by carbonic anhydrase inhibitors, indicating a dependence on HCO. Intralateral ventricular administration of these same carbonic anhydrase activators caused the rats to exhibit superior learning of the Morris water maze task, suggesting that the GABAergic synaptic switch is critical for gating the synaptic plasticity that underlies spatial memory formation. Increased carbonic anhydrase activity might, therefore, also enhance perception, processing, and storing of temporally associated relevant signals and represents an important therapeutic target in learning and memory pharmacology.

Acetazolamide↗

[Divergent and convergent mechanisms of the integrative activity of the mammalian brain].

Convergent intercellular synaptic interaction is actualized, mainly, by two neurotransmitter systems: glutamate- and GABA-ergic (excitatory and inhibitory postsynaptic potentials, respectively). Fast and slow postsynaptic receptors of glutamate- and GABA-ergic synapses are described. All other brain systems are divergent neuromodulators. Modulators are released into the intercellular space and simultaneously interact with a large population of neurons. A hypothesis of divergent modulatory integration is described: the divergently functioning neuromodulators actualize stable functional states of the brain via appropriate long-term modification-inducing receptors. These stable states are a biochemical basis of the motivational and emotional states. Mechanisms of the secondary nuclear signaling triggered by the long-term modification-inducing receptors consolidate the stable states. The hypothesis of divergent modulatory integration is substantiated in the paper on the basis of the evidence obtained by the author and his collaborates. The haloperidol catalepsy and pentile-netetrazole kindling are considered as a behavioral model of the divergent modulatory integration. The experimental data suggest that divergently functioning neuromodulators actualize and consolidate general motivational and emotional states via the appropriate long-term modification-inducing receptors. The consolidation is structurally-specific. The motivational and emotional states concomitant of learning and memory are a specific variation of the general motivational and emotional state depending on the learning situation.

Animals↗

The dentate gyrus as a regulated gate for the propagation of epileptiform activity.

Properties of the interaction between the entorhinal cortex (EC) and the dentate gyrus were studied in a combined EC hippocampal slice preparation in which most of the fiber connectivity within this structure is intact. Epileptiform activity was induced by lowering extracellular Mg2+ concentration. This caused short recurrent discharges in the hippocampus while seizure-like events (SLE) slowly spread from the site of initiation to neighboring areas. At the end of a SLE, the EC, the subiculum and the neocortical area Te2 discharged in synchrony. This activity could develop into a state of recurrent tonic discharges highly synchronized between the different areas. These discharges were insensitive to treatment with currently available antiepileptic drugs. Although the SLE increased neuronal firing and extracellular potassium concentration in the dentate gyrus, this activity had only moderate effects on the activity generated in areas CA3 and CA1. Removing GABAergic inhibition with baclofen and bicuculline caused the spread of SLE from the EC to the dentate gyrus. Slow inhibitory postsynaptic potentials and intrinsic properties of dentate gyrus granule cells appear to underlie the filtering function of the dentate gyrus.

Afferent Pathways↗

[The neuronal electrical responses of the superior cervical ganglion in the rabbit to nociceptive skin stimulation].

The patterns of tonic activity in the neurons of rabbit superior cervical ganglion at rest and during noxious stimulation of the skin were studied using intracellular recording. According to reflex changes in the activity patterns, all neurons studied were classified into three groups. Cardiac rhythmicity is more pronounced in the neurons of the second type than in those of the first type. The magnitude of the cardiac rhythmicity in both types of neurons was reduced after noxious stimulation of the skin. In the third type of neurons the cardiac rhythmicity was absent. In some neurons slow excitatory and inhibitory postsynaptic potentials appeared resulting from skin stimulation.

Animals↗

[Effects of milnacipran on neuronal excitability and synaptic transmission in neurons of the rat locus coeruleus].

Effects of milnacipran (MIL), a selective serotonin and noradrenaline (NA) reuptake inhibitor, on the neuronal excitability and synaptic transmission in the rat locus coeruleus (LC) were examined by intracellular and whole-cell patch-clamp recording techniques. We compared MIL and methylphenidate (MPH), a selective NA and dopamine reuptake inhibitor, as a therapeutic agent for attention deficit/hyperactivity disorder. Application of MPH (1-100 microM) and MIL (1-100 microM) to artificial cerebrospinal fluid (ACSF) produced a hyperpolarizing response in LC neurons in a concentration-dependent manner. Spontaneous firing of LC neurons was blocked during the hyperpolarization. The MIL-induced hyperpolarization was blocked by yohimbine (1 microM), an antagonist for alpha-adrenoceptors. These results suggest that the MIL-induced hyperpolarization is mediated by NA via alpha2-adrenoceptors in LC neurons. Under the whole-cell patch-clamp condition, prolonged application of MIL produced an outward current which lasted as long as MIL existed in the ACSF. The outward current induced by NA was enhanced by MIL in LC neurons. MIL enhanced the amplitude and duration of the inhibitory postsynaptic potential, while it depressed the excitatory postsynaptic potential. The results indicated that both MIL and MPH showed almost the same effects on neuronal activity and synaptic transmission in the rat LC. These results suggest that MIL increases the concentration of NA at synaptic clefts by inhibiting the NA reuptake system in the rat LC.

Animals↗

[Three types of miniature inhibitory potentiaes in the frog spinal cord motoneurons: the possibility of GABA and glycine co-release].

Miniature inhibitory postsynaptic potentials (mlPSPs) were recorded from motoneurons of the frog isolated spinal cord after blocking action potentials and ionotropic glutamate receptors (TTX 1 mcm: CNQX 25 mcm, D-AP5 50 mcm). Three types of mlPSPs were selected by their time characteristics) fast, slow and mlPSPs with two decay time constants. We classified 8.7% of mlPSPs as dual-component, 64.5% as fast mlPSPs, and 26.8% as slow mlPSPs. The GABA(A)R blocker bicuculline (20 mcm) diminished the number of the slow and dual-component events while the number of mlPSP with a fast kinetics was increased. The GlyR antagonist strychnine (1 mcm) reduced the frequency of fast mlPSPs and increased this parameter of slow mlPSPs. These data suggest existence of three different mlPSP groups distinguished by their kinetics and sensitivity to receptor antagonists: fast events mediated by glycine, slow events mediated by GABA and dual-component mlPSPs corresponding to glycine and GABA co-release.

Action Potentials↗

A functional assay to measure postsynaptic gamma-aminobutyric acidB responses in cultured spinal cord neurons: heterologous regulation of the same K+ channel.

The stimulation of postsynaptic gamma-aminobutyric acid (GABA)B receptors leads to slow inhibitory postsynaptic potentials due to the influx of K(+)-ions. This was studied biochemically, in vitro in mammalian cultured spinal cord neurons by using 86Rb as a substitute for K+. (-)-Baclofen, a GABAB receptor agonist, produced a concentration-dependent increase in the 86Rb-influx. This effect was stereospecific and blocked by GABAB receptor antagonists like CGP 35 348 (3-aminopropyl-diethoxymethyl-phosphonic acid) and phaclofen. Apart from the GABAB receptors, both adenosine via adenosine1 receptors and 5-hydroxytryptamine (5-HT) via 5-HT1 alpha agonists also increased the 86Rb-influx. These agonists failed to show any additivity between them when they were combined in their maximal concentration. In addition, their effect was antagonized specifically by their respective antagonists without influencing the others. These findings suggest the presence of GABAB, adenosine1 and 5-HT1 alpha receptors in the cultured spinal cord neurons, which exhibit a heterologous regulation of the same K(+)-channel. The effect of these agonists were antagonized by phorbol 12,13-didecanoate, an activator of protein kinase C, and pretreatment with pertussis toxin. This suggests that these agonists by acting on their own receptors converge on the same K(+)-channel through the Gi/Go proteins. In summary, we have developed a biochemical functional assay for studying and characterizing GABAB synaptic pharmacology in vitro, using spinal cord neurons.

Animals↗

[Effect of nucleus entopeduncularis stimulation on thalamic nuclei motor neurons under normal conditions and after injury of the nigrostriatal dopaminergic system produced by the neurotoxin MPTP].

Two groups of acute experiments were performed on cats anesthetized by ketamine and immobilized by myorelaxine to study reactions of neurons in ventral anterior (VA) and ventral lateral (VL) thalamic nuclei to stimulation of nucleus entopeduncularis (nEp) in normal animals and in those treated with chronic injections of neurotoxin--N-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP; 5 mg/kg, i.m., daily, for five days). It was established that in normal cats 28% of the neurons studied have responded to nEp stimulation by inhibition with the latency shorter than 7 ms. In a half of inhibiting neurons after the first phase of inhibition which lasted 18 +/- 2 ms, the second inhibitory phase was registered. The duration of the latter was 25 +/- 4 ms. In MPTP-treated cats the number of neurons inhibited after nEp stimulation was practically the same as in normal ones (24.5%). A tendency of the first phase shortening and a statistically significant increase of the second inhibition phase duration up to 50 +/- 11 ms were found. It was suggested that changes in the inhibitory processes in VA-VL neurons receiving afferents from nEp might be explained by hyperpolarization of the nerve cell membrane evoked by increasing pallidothalamic inhibitory influences. That hyperpolarization created conditions for a decrease in Cl(-)-dependent and an increase in Ca(2+)-dependent K(+)-related phases of inhibitory postsynaptic potentials.

1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine↗

[The central neurons that inhibit the work of the heart in the edible snail].

The neurones causing the inhibitory postsynaptic potentials (IPSP) with duration 150-200 ms in the myocardium have been identified in the visceral ganglion of Helix pomatia. The neurones are characterized by the high frequency of discharges (2-3 c/s) which changes modulate the heart frequency. IPSP is blocked by d-tubocurarine in the concentration 5.10(-5)-1.10(-4) M.

Animals↗

Actions of cocaine on central monoamine neurons: intracellular recordings in vitro.

Intracellular recordings from monoaminergic neurons in brain slice preparations have been used to study the action of cocaine. The firing rate of noradrenergic neurons in the locus coeruleus, serotonergic neurons of dorsal raphe and dopaminergic neurons from substantia nigra zona compacta is reduced or inhibited by the transmitter substance that they produce. This process, which can be brought about by release of the transmitter from either dendrites or axon collaterals in the vicinity of the cell bodies, has been referred to as 'autoinhibition'. In each case, the inhibition results from a membrane hyperpolarization caused by an increased conductance to potassium ions. In each of the nuclei, cocaine caused a decrease in spontaneous firing through a membrane hyperpolarization. This action of cocaine was blocked by the respective 'autoreceptor' antagonist. In the locus coeruleus and dorsal raphe cocaine prolonged an inhibitory postsynaptic potential caused by the release of noradrenaline and 5-HT respectively. The concentration-response curve for the exogenously applied agonist in each of the three nuclei was shifted to the left in the presence of cocaine. These observations indicate that the activity of these aminergic neurons was affected by cocaine through an inhibition of the reuptake of endogenously release transmitter. The blockade of reuptake increased the extracellular level of noradrenaline, 5-HT and dopamine in the respective nuclei to concentrations which caused electrophysiologically detectable effects. This suggests that the reuptake process is a primary mechanism for termination of the response. In addition, this action of cocaine occurs at behaviorally relevant concentrations. The fact that all monoaminergic transmission can be affected by cocaine may contribute to the complexity of its behavioral actions.

Action Potentials↗