Activity-dependent matching of excitatory and inhibitory inputs during refinement of visual receptive fields

The receptive field (RF) of single visual neurons undergoes progressive refinement during development. It remains largely unknown how the excitatory and inhibitory inputs on single developing neurons are refined in a coordinated manner to allow the formation of functionally correct circuits. Using whole-cell voltage-clamp recording from Xenopus tectal neurons, we found that RFs determined by excitatory and inhibitory inputs in more mature tectal neurons are spatially matched, with each spot stimulus evoking balanced synaptic excitation and inhibition. This emerges during development through a gradual reduction in the RF size and a transition from disparate to matched topography of excitatory and inhibitory inputs to the tectal neurons. Altering normal spiking activity of tectal neurons by either blocking or elevating GABA(A) receptor activity significantly impeded the developmental reduction and topographic matching of RFs. Thus, appropriate inhibitory activity is essential for the coordinated refinement of excitatory and inhibitory connections.     

A neuron model with learning capability and its relation to mechanisms of association

A neuron model with the ability of learning has been examined by means of mathematical and statistical methods. By use of the established anatomical concepts the main features of the model can be described as follows.The synapses are randomly distributed on the dendrites in a way that can be described by poisson processes. The afferent connections to the synapses are also random.The input signals are divided into excitatory, inhibitory and unspecified signals. The latter, whose detailed action is not specified, may involve excitatory as well as inhibitory action on the cell. Signals are described in terms of impulse frequencies.Learning takes place through facilitation of excitatory synapses. The condition for facilitation is the occurrence of simultaneous presynaptic and postsynaptic activity. The synaptical changes occurring during repeated learning are superimposed. Inhibitory synapses are capable of influencing learning by blocking the dendritic transmission.It is shown that, under certain conditions, a collection of model cells is able to work as an associative memory. This means that a pattern of output signals that once occurred through the combined action of the excitatory, the inhibitory, and the unspecified signals may later be recalled by applying just the two former signal patterns. It is shown that excitatory and inhibitory signals are similar in their ability to evoke associations.However there is also a difference between excitation and inhibition due to the fact that the pattern of inhibitory signals is subject to a non-linear transformation. This implies that great similarity is required between the inhibitory pattern once present during learning and the inhibitory pattern that is fed in later in order to obtain an associative recall. This phenomenon is called pattern separation and is supposed to be of importance when discriminating between patterns.     

Changes in the electrical activity of the rabbit proximal colon in vivo by stimulation of the vagus and splanchnic nerves]

1. Using extracellular electrodes placed on the serosa, we recorded the modifications of the electrical activity of the colonic muslce fibers caused by the stimulation of vagal and splanchnic nerve fibers. 2. Vagal stimulation produces two types of junction potentials: excitatory junction potentials (EJPs) and inhibitory junction potentials (IJPs). The IJPs are elicited by stimulation of vagal fibers which innervate intramural non-adrenergic inhibitory neurons. 3. The conduction velocity of the nerve impulse along the vagal pre-ganglionic fibers is 1.01 m/sec for excitatory fibers and 0.5. m/sec for inhibitory fibers. 4. Splanchnic fiber stimulation causes EJP disappearance, blocking transmission between preganglionic fibers and intramural excitatory neurons, and a decrease in IJP amplitude that most likely indicates a previous hyperpolarization of the smooth muscle. 5. IJP persistence during splanchnic stimulation proves that sympathetic inhibition does not modify the transmission of the vagal influx onto the non-adrenergic inhibitory neurons of the intramural plexuses. 6. Through a comparative study of proximal and distal colonic innervation, we are able to show that there is a similar organization of both regions, that is a double inhibitory innervation: an adrenergic one of a sympathetic origin, and a non adrenergic one of a parasympathetic origin.     

Mechanisms of epileptogenic effects of some convulsants on the neuronal activity in the neocortex

The data obtained in the studies of neurophysiological aspects of epileptogenesis in the brain cortex, which have been carried out in our laboratory for many years, are used for the analysis of epileptogenic effects of a few convulsants (penicillin, strychnine, and d-tubocurarine) on the activity of neocortical neurons. It has been demonstrated that the development of the epileptiform activity in the cortex is accompanied by suppression of IPSP, and the above convulsants directly influence the mechanisms of postsynaptic inhibition. Epileptogenic effects of strychine and penicillin are based on blocking of chloride ion channels and depend on the direction of chloride currents. The role of excitatory and inhibitory synaptic interactions among neurons in generation of the epileptiform activity is discussed.     

Excitatory and inhibitory responses of the ongoing sympathetic discharge in single renal neurons to liminal stimulation of aortic C-fibres in the rabbit

Excitatory and inhibitory responses of sympathetic discharge were recorded in single renal postganglionic neurons of rabbits anaesthetized with urethane and chloralose. The animals were vagotomized and had transected aortic nerves. Responses were elicited by single volleys in the aortic C-fibres. Excitatory responses consisted in short-lasting increase in the rate of ongoing sympathetic discharge and were followed by inhibitory responses. Excitatory effects together with inhibitory responses were seen in 68% of units (19/28). Only excitatory effects appeared in 2 neurons (7.1%) and only inhibitory effects in 7 neurons (25%). In renal neurons exhibiting both effects, the excitatory responses appeared after latency of 172 +/- 8 ms (x +/- S.D.) and had duration of 64 +/- 11 ms. Inhibitory effects had latency o f 257 +/- 10 ms and their duration amounted to 265 +/- 22 ms. In more than half of recordings the excitatory responses were separated from the inhibitory effects by discharge lasting 33 +/- 4 ms. Significant correlations between latencies of excitatory and inhibitory responses and between duration of excitatory and latency of inhibitory responses suggest interaction between both effects. Increase in the number of afferent volleys (1 through 5) evoked relatively small changes in duration of the excitatory effect indicating that temporal facilitation is of minor importance in generating this response. Temporal facilitation was found to play an important role in determining duration of the inhibitory response. Comparison of effects of unilateral and bilateral stimulation of the aortic C-fibres showed larger occlusion of durations of the excitatory than inhibitory responses.     

Selective block of AMPA/kainate receptors of hippocampal interneurons as a new approach to the investigation of inhibitory system

Effects of open channel blockers of AMPA/kainate receptors have been examined using whole cell recordings and kainate application in the neurons freshly isolated by vibrodissociation from the rat hippocampal slice preparation. Although the hippocampal neurons differed little in the voltage-current relations and sensitivity to kainate, a prominent difference was found in their susceptibility to the blocking action of adamantane derivatives studied. The pyramidal neurons had low sensitivity to the open channel blockers but the neurons which might be assigned most probably to the group of inhibitory interneurons proved to be highly sensitive. A group of neurons of intermediate sensitivity have also been found. The ability of the same blocking drugs to depress the excitatory inputs in the inhibitory interneurons has been demonstrated in the experiments on the hippocampal slice preparation. Enhancement of the field spike and excitatory postsynaptic potential amplitude was observed in the presence of adamantane derivatives. An additional treatment of the preparation with a GABA receptor antagonist, bicuculline, did not potentiate this effect. In conclusion, the observed difference in the pharmacological properties of inhibitory interneurons may be effectively used for detailed analysis of the brain synaptic transmission.     

Synchronization and sensitivity enhancement of the Hodgkin-Huxley neurons due to inhibitory inputs

Recent experimental results imply that inhibitory postsynaptic potentials can play a functional role in realizing synchronization of neuronal firing in the brain. In order to examine the relation between inhibition and synchronous firing of neurons theoretically, we analyze possible effects of synchronization and sensitivity enhancement caused by inhibitory inputs to neurons with a biologically realistic model of the Hodgkin-Huxley equations. The result shows that, after an inhibitory spike, the firing probability of a single postsynaptic neuron exposed to random excitatory background activity oscillates with time. The oscillation of the firing probability can be related to synchronous firing of neurons receiving an inhibitory spike simultaneously. Further, we show that when an inhibitory spike input precedes an excitatory spike input, the presence of such preceding inhibition raises the firing probability peak of the neuron after the excitatory input. The result indicates that an inhibitory spike input can enhance the sensitivity of the postsynaptic neuron to the following excitatory spike input. Two neural network models based on these effects on postsynaptic neurons caused by inhibitory inputs are proposed to demonstrate possible mechanisms of detecting particular spatiotemporal spike patterns. Received: 15 April 1999 /Accepted in revised form: 25 November 1999     

Nitric oxide inhibits nociceptive transmission by differentially regulating glutamate and glycine release to spinal dorsal horn neurons

Nitric oxide (NO) is involved in many physiological functions, but its role in pain signaling remains uncertain. Surprisingly, little is known about how endogenous NO affects excitatory and inhibitory synaptic transmission at the spinal level. Here we determined how NO affects excitatory and inhibitory synaptic inputs to dorsal horn neurons using whole-cell recordings in rat spinal cord slices. The NO precursor L-arginine or the NO donor SNAP significantly increased the frequency of glycinergic spontaneous and miniature inhibitory postsynaptic currents (IPSCs) of lamina II neurons. However, neither L-arginine nor SNAP had any effect on GABAergic IPSCs. L-arginine and SNAP significantly reduced the amplitude of monosynaptic excitatory postsynaptic currents (EPSCs) evoked from the dorsal root with an increase in paired-pulse ratio. Inhibition of the soluble guanylyl cyclase abolished the effect of L-arginine on glycinergic IPSCs but not on evoked monosynaptic EPSCs. Also, inhibition of protein kinase G blocked the increase in glycinergic sIPSCs by the cGMP analog 8-bromo-cGMP. The inhibitory effects of L-arginine on evoked EPSCs and high voltage-activated Ca(2+) channels expressed in HEK293 cells and dorsal root ganglion neurons were abolished by blocking the S-nitrosylation reaction with N-ethylmaleimide. Intrathecal injection of L-arginine and SNAP significantly increased mechanical nociceptive thresholds. Our findings suggest that spinal endogenous NO enhances inhibitory glycinergic input to dorsal horn neurons through sGC-cGMP-protein kinase G. Furthermore, NO reduces glutamate release from primary afferent terminals through S-nitrosylation of voltage-activated Ca(2+) channels. Both of these actions probably contribute to inhibition of nociceptive transmission by NO at the spinal level.     

Pigeon oesophageal EMG activity: analysis of intramural neural control

The effects of agonist and antagonist cholinergic and adrenergic drugs on spontaneous electrical activity of transverse muscular strips of pigeon cervical oesophagus were examined. Tetrodotoxin failed to affect EMG activity. Cholinomimetics produced excitatory effects. The response to carbachol was enhanced by hexamethonium and reversed into an inhibitory effect by atropine. Noradrenaline evoked a concentration-dependent, biphasic effect (inhibition at low and excitation at high concentrations). Isoproterenol induced inhibitory response unaffected by tetrodotoxin. Phenylephrine induced excitatory response completely antagonized by tetrodotoxin and partially opposed by atropine. It is concluded that: i) the oesophageal spontaneous EMG activity is myogenic; ii) the intramural neurons have no tonic influence on the spontaneous EMG activity; iii) in the intramural plexuses there are cholinergic excitatory-, non-cholinergic excitatory- and inhibitory neurons, with unknown neurotransmitter; iv) excitatory alpha-adrenoceptors, located on the nervous elements and inhibitory beta-adrenoceptors, located on the smooth-muscle cells, are present.     

A synergetic theory of environmentally-specified and learned patterns of movement coordination

By combining neuropharmacology and electrophysiology, we tried to determine whether the main neuronal mechanism responsible for direction-selective motion detection in the fly is based on an excitatory or an inhibitory synaptic interaction. By blocking inhibitory interactions with picrotoxinin, an antagonist of the inhibitory neurotransmitter GABA, we could abolish most of the directional selectivity of a large-field movement-sensitive neuron (H1-cell) in the lobula plate of the blowfly Calliphora erythrocephala. These modifications are similar to changes observed in the optomotor response of the fruitfly Drosophila melanogaster after application of picrotoxinin (Bülthoff and Bülthoff 1987a, b). Assuming a simplified logical model, these results are compatible with inhibitory synaptic interactions at the level of the elementary movement detectors. The picrotoxinin-induced changes in direction selectivity are not due to modifications of the peripheral visual processing in the retina and lamina. This was shown by simultaneous recordings of the electroretinogram and the H1-cell. The latencies between drug injections into various parts of the brain and their first effects on the H1-cell suggest that the inhibitory mechanism for motion detection is located in the medulla rather than in the lobula plate.     

Neuroligins mediate excitatory and inhibitory synapse formation: involvement of PSD-95 and neurexin-1beta in neuroligin-induced synaptic specificity

The balance between excitatory and inhibitory synapses is a tightly regulated process that requires differential recruitment of proteins that dictate the specificity of newly formed contacts. However, factors that control this process remain unidentified. Here we show that members of the neuroligin (NLG) family, including NLG1, NLG2, and NLG3, drive the formation of both excitatory and inhibitory presynaptic contacts. The enrichment of endogenous NLG1 at excitatory contacts and NLG2 at inhibitory synapses supports an important in vivo role for these proteins in the development of both types of contacts. Immunocytochemical and electrophysiological analysis showed that the effects on excitatory and inhibitory synapses can be blocked by treatment with a fusion protein containing the extracellular domain of neurexin-1beta. We also found that overexpression of PSD-95, a postsynaptic binding partner of NLGs, resulted in a shift in the distribution of NLG2 from inhibitory to excitatory synapses. These findings reveal a critical role for NLGs and their synaptic partners in controlling the number of inhibitory and excitatory synapses. Furthermore, relative levels of PSD-95 alter the ratio of excitatory to inhibitory synaptic contacts by sequestering members of the NLG family to excitatory synapses.     

Kainate receptors differentially regulate release at two parallel fiber synapses

Presynaptic kainate receptors (KARs) facilitate or depress transmitter release at several synapses in the CNS. Here, we report that synaptically activated KARs presynaptically facilitate and depress transmission at parallel fiber synapses in the cerebellar cortex. Low-frequency stimulation of parallel fibers facilitates synapses onto both stellate cells and Purkinje cells, whereas high-frequency stimulation depresses stellate cell synapses but continues to facilitate Purkinje cell synapses. These effects are mimicked by exogenous KAR agonists and eliminated by blocking KARs. This differential frequency-dependent sensitivity of these two synapses regulates the balance of excitatory and inhibitory input to Purkinje cells and therefore their excitability.     

Electrical stimulation of glossopharyngeal nerve and oesophageal EMG response in the pigeon

The effects of the efferent glossopharyngeal nerve stimulation, on EMG activity of the pigeon cervical oesophagus, were studied. In control animals, stimulation caused a biphasic response characterized by an intra-stimulus excitatory component followed by a post-stimulus inhibitory one. The EMG response to glossopharyngeal stimulation appeared simultaneously throughout the cervical oesophagus. A bell-shaped mechanical wave was detected relating to the electrical excitatory component. Atropine administration antagonized the excitatory component, while the inhibitory one persisted. It occurs intra-stimulus, and its duration is increased, compared to control ones. A reduction in the oesophageal resting pressure was observed relating to the electrical inhibitory component. Hexamethonium caused complete disappearance of any EMG response to glossopharyngeal stimulation, as well as suppression of mechanical responses. The comparison between the EMG responses to swallow and to efferent glossopharyngeal stimulation suggests that in pigeon cervical oesophagus: primary peristalsis is central in origin; a dual system of glossopharyngeal fibres, excitatory and inhibitory, carries the central control for oesophageal motility; these excitatory and inhibitory fibres supply the oesophageal muscle via intramural neurons; the synaptic arrangement of the inhibitory pathway is more complex than the excitatory one.     

Effects of cold and heat on behavior and cerebellar function in goldfish

Summary A similar sequence of behavioral effects was observed for either cooling or heating; most effects occurred on changing temperature of entire fish or of only the cerebellum. On moderate heating or cooling, fish are hyperexcitable, spontaneously hyperactive; on further heating or cooling swimming is uncoordinated; when the subcerebellar structures are heated or cooled, equilibrium is disturbed; on further heating or cooling coma and respiratory failure ensue. Critical temperatures are modifiable by acclimation. The behavioral effects of cerebellectomy are additive with temperature effects on motor centers.Electrical activity of Purkinje neurons changes in the same thermal ranges as behavior. Inhibition via cerebellar interneurons is most sensitive and can be modified by acclimation. Ongoing activity increases with warming up to a blocking temperature; interspike interval histograms show pattern changes during warming. Activation via mossy fibers-granule cells is more sensitive than that via climbing fibers, and antidromic impulses are most resistant.A neuronal model based on inhibitory actions of Purkinje neurons on motor centers and parallel feedback excitatory pathways can explain both behavioral and electrical observations.     

Multiple neural oscillators and muscle feedback are required for the intestinal fed state motor program

After a meal, the gastrointestinal tract exhibits a set of behaviours known as the fed state. A major feature of the fed state is a little understood motor pattern known as segmentation, which is essential for digestion and nutrient absorption. Segmentation manifests as rhythmic local constrictions that do not propagate along the intestine. In guinea-pig jejunum in vitro segmentation constrictions occur in short bursts together with other motor patterns in episodes of activity lasting 40-60 s and separated by quiescent episodes lasting 40-200 s. This activity is induced by luminal nutrients and abolished by blocking activity in the enteric nervous system (ENS). We investigated the enteric circuits that regulate segmentation focusing on a central feature of the ENS: a recurrent excitatory network of intrinsic sensory neurons (ISNs) which are characterized by prolonged after-hyperpolarizing potentials (AHPs) following their action potentials. We first examined the effects of depressing AHPs with blockers of the underlying channels (TRAM-34 and clotrimazole) on motor patterns induced in guinea-pig jejunum, in vitro, by luminal decanoic acid. Contractile episode durations increased markedly, but the frequency and number of constrictions within segmenting bursts and quiescent period durations were unaffected. We used these observations to develop a computational model of activity in ISNs, excitatory and inhibitory motor neurons and the muscle. The model predicted that: i) feedback to ISNs from contractions in the circular muscle is required to produce alternating activity and quiescence with the right durations; ii) transmission from ISNs to excitatory motor neurons is via fast excitatory synaptic potentials (EPSPs) and to inhibitory motor neurons via slow EPSPs. We conclude that two rhythm generators regulate segmentation: one drives contractions within segmentation bursts, the other the occurrence of bursts. The latter depends on AHPs in ISNs and feedback to these neurons from contraction of the circular muscle.     

Inhibition and facilitation in parasympathetic ganglia of the urinary bladder

Neurons in vesical parasympathetic ganglia receive excitatory and inhibitory inputs from both divisions of the autonomic nervous system. Sacral parasympathetic pathways (cholinergic) provide the major excitatory input to these ganglia via activation of nicotinic receptors. Parasympathetic pathways also activate muscarinic inhibitory and excitatory receptors, which may exert a modulatory influence on transmission. Cholinergic transmission is relatively inefficient when preganglionic nerves are stimulated at low frequencies (< 1 Hz). However, excitatory postsynaptic potentials (EPSPs) and postganglionic firing markedly increase during repetitive stimulation at frequencies of 1-10 Hz. It is concluded that enhanced transmitter release accounts for the temporal facilitation and that vesical ganglia function as "high pass filters" that amplify the parasympathetic excitatory input to the detrusor muscle during micturition. Transmission in vesical ganglia is also sensitive to adrenergic inhibitory and facilitatory synaptic mechanisms elicited by efferent pathways in the hypogastric nerves. The effects of exogenous norepinephrine indicate that adrenergic inhibition is mediated by alpha receptors and reflects primarily a presynaptic depression of transmitter release although postsynaptic adrenergic hyperpolarizing and depolarizing effects have also been noted. Adrenergic facilitation is mediated by beta receptors as well as unidentified receptors. Norepinephrine also can inhibit or excite spontaneously active neurons in vesical ganglia. The existence of inhibitory and facilitatory synaptic mechanisms in vesical ganglia provides the basis for a complex ganglionic modulation of the central autonomic outflow to the bladder.     

Effects of barbiturates on the inhibitory action of GABA on excitatory response of the stomach to stimulation of vagal afferent fibers in cat

Effects of barbiturates on the inhibitory action of GABA to the hexamethonium-resistant excitatory response of the stomach to stimulation of the vagal afferent fibers were studied in cats. Inhibition of the hexamethonium-resistant excitatory response by GABA were compared under alpha-chloralose, alpha-chloralose-phenobarbital (PhB), and alpha-chloralose-pentobarbital (PB)-anesthesia in cats. The ID50 of GABA on the hexamethonium-resistant excitatory response was not significantly affected by PhB, but reduced by PB. Both picrotoxin and bicuculline antagonized the effects of GABA. The present experiments demonstrated that PB potentiated the inhibitory effect of GABA on the hexamethonium-resistant excitatory response of the stomach, and suggested that the potentiation by PB may be due to activation of GABA-receptor-ionophore complex.     

Fasciola hepatica: the effects of neuropharmacological agents upon in vitro motility

The effects of a wide range of neuropharmacological agents on the motility in vitro of Fasciola hepatica have been determined using an isometric transducer system. The neuromuscular blocking agents tubocurarine and decamethonium cause a long-term stimulation of the basal activity of the fluke. Acetylcholine causes an inhibition of activity. This effect is mimicked by the cholinergic agonists carbachol and nicotine, antagonised by the cholinergic blocking agents atropine and mecamylamine, and potentiated by eserine, a cholinesterase inhibitor. With nicotine and atropine the effects are accompanied by an increase in muscle tone at a concentration of 1 X 10(-2) M. Noradrenaline and adrenaline also cause some inhibition of activity, an effect antagonised by guanethidine, which blocks the release of noradrenaline. In contrast, dopamine stimulates fluke motility, whilst its antagonist dihydroergotamine causes an inhibition of activity. The monoamine oxidase inhibitors iproniazid and p-chloromercuribenzoic acid induce a stimulation of activity; with the latter there is an increase in muscle tone at a concentration of 1 X 10(-3) M. The amine depleting agents chloroamphetamine and reserpine, and the monoamine uptake inhibitors desipramine and nortriptyline produce an inhibition of fluke activity, as does the serotonin uptake inhibitor fluoxetine. High concentrations of chloroamphetamine (1 X 10(-2) M) and the uptake inhibitors (1 X 10(-3) M and above) also induce an increase in muscle tone. Serotonin causes a marked stimulation of motility. The pharmacological evidence is consistent with a neurotransmitter role of acetylcholine (inhibitory), dopamine (excitatory), and noradrenaline (inhibitory). The status of serotonin is discussed.     

Unit study in cat claustrum of the effects of iontophoretic neurotransmitters and correlations with the effects of activation of some afferent pathways

Glutamate (Glut), acetylcholine (ACh) and dopamine (DA) were iontophoretically applied on cat claustral neurons. Glut did not affect all the neurons; ACh had both excitatory and inhibitory effects, while DA was prevalently inhibitory. An analysis was made of the time-course of excitatory and inhibitory responses on the basis of the mean firing rate variations during and after ACh and DA release. Three types of responses are described for each drug: short lasting inhibition, long lasting inhibition and long lasting excitation. The experimental data were statistically elaborated. The effects of ACh and of DA were compared with those of activation obtained by sensorial peripheric and thalamic stimulations. ACh could be supposed to be the transmitter of most of the inhibitory terminals of these sensitive afferences to the claustrum.     

Imperfect space clamp permits electrotonic interactions between inhibitory and excitatory synaptic conductances, distorting voltage clamp recordings

The voltage clamp technique is frequently used to examine the strength and composition of synaptic input to neurons. Even accounting for imperfect voltage control of the entire cell membrane ("space clamp"), it is often assumed that currents measured at the soma are a proportional indicator of the postsynaptic conductance. Here, using NEURON simulation software to model somatic recordings from morphologically realistic neurons, we show that excitatory conductances recorded in voltage clamp mode are distorted significantly by neighboring inhibitory conductances, even when the postsynaptic membrane potential starts at the reversal potential of the inhibitory conductance. Analogous effects are observed when inhibitory postsynaptic currents are recorded at the reversal potential of the excitatory conductance. Escape potentials in poorly clamped dendrites reduce the amplitude of excitatory or inhibitory postsynaptic currents recorded at the reversal potential of the other conductance. In addition, unclamped postsynaptic inhibitory conductances linearize the recorded current-voltage relationship of excitatory inputs comprising AMPAR and NMDAR-mediated components, leading to significant underestimation of the relative contribution by NMDARs, which are particularly sensitive to small perturbations in membrane potential. Voltage clamp accuracy varies substantially between neurons and dendritic arbors of different morphology; as expected, more reliable recordings are obtained from dendrites near the soma, but up to 80% of the synaptic signal on thin, distant dendrites may be lost when postsynaptic interactions are present. These limitations of the voltage clamp technique may explain how postsynaptic effects on synaptic transmission could, in some cases, be attributed incorrectly to presynaptic mechanisms.