Effects of phase on homeostatic spike rates

Recent experimental results by Talathi et al. (Neurosci Lett 455:145–149, 2009) showed a divergence in the spike rates of two types of population spike events, representing the putative activity of the excitatory and inhibitory neurons in the CA1 area of an animal model for temporal lobe epilepsy. The divergence in the spike rate was accompanied by a shift in the phase of oscillations between these spike rates leading to a spontaneous epileptic seizure. In this study, we propose a model of homeostatic synaptic plasticity which assumes that the target spike rate of populations of excitatory and inhibitory neurons in the brain is a function of the phase difference between the excitatory and inhibitory spike rates. With this model of homeostatic synaptic plasticity, we are able to simulate the spike rate dynamics seen experimentally by Talathi et al. in a large network of interacting excitatory and inhibitory neurons using two different spiking neuron models. A drift analysis of the spike rates resulting from the homeostatic synaptic plasticity update rule allowed us to determine the type of synapse that may be primarily involved in the spike rate imbalance in the experimental observation by Talathi et al. We find excitatory neurons, particularly those in which the excitatory neuron is presynaptic, have the most influence in producing the diverging spike rates and causing the spike rates to be anti-phase. Our analysis suggests that the excitatory neuronal population, more specifically the excitatory to excitatory synaptic connections, could be implicated in a methodology designed to control epileptic seizures.     

Inhibitory Synapse Formation in a Co-culture Model Incorporating GABAergic Medium Spiny Neurons and HEK293 Cells Stably Expressing GABAA Receptors

Inhibitory neurons act in the central nervous system to regulate the dynamics and spatio-temporal co-ordination of neuronal networks. GABA (γ-aminobutyric acid) is the predominant inhibitory neurotransmitter in the brain. It is released from the presynaptic terminals of inhibitory neurons within highly specialized intercellular junctions known as synapses, where it binds to GABA_A receptors (GABA_ARs) present at the plasma membrane of the synapse-receiving, postsynaptic neurons. Activation of these GABA-gated ion channels leads to influx of chloride resulting in postsynaptic potential changes that decrease the probability that these neurons will generate action potentials. During development, diverse types of inhibitory neurons with distinct morphological, electrophysiological and neurochemical characteristics have the ability to recognize their target neurons and form synapses which incorporate specific GABA_ARs subtypes. This principle of selective innervation of neuronal targets raises the question as to how the appropriate synaptic partners identify each other. To elucidate the underlying molecular mechanisms, a novel in vitro co-culture model system was established, in which medium spiny GABAergic neurons, a highly homogenous population of neurons isolated from the embryonic striatum, were cultured with stably transfected HEK293 cell lines that express different GABA_AR subtypes. Synapses form rapidly, efficiently and selectively in this system, and are easily accessible for quantification. Our results indicate that various GABA_AR subtypes differ in their ability to promote synapse formation, suggesting that this reduced in vitro model system can be used to reproduce, at least in part, the in vivo conditions required for the recognition of the appropriate synaptic partners and formation of specific synapses. Here the protocols for culturing the medium spiny neurons and generating HEK293 cells lines expressing GABA_ARs are first described, followed by detailed instructions on how to combine these two cell types in co-culture and analyze the formation of synaptic contacts.     

Fast and slow excitation of inhibitory cells in the CA3 region of the hippocampus

Pyramidal cells form excitatory synaptic connections with local inhibitory neurons in the hippocampus. This recurrent synapse plays a crucial stabilizing role in the control of hippocampal activity, since it transforms pyramidal cell population. Using a combination of dual recording from presynaptic and postsynaptic cells and anatomical techniques, we show that these synaptic connections often comprise a single site for liberation of excitatory transmitter. The resulting excitatory postsynaptic potentials (EPSCs) have a fast time course and a similar amplitude to miniature EPSCs recorded in tetrodotoxin and cobalt. In contrast, activation of metabotropic glutamate receptors (mGluRs) by transmitter liberated during repetitive activation of these synapses produces an excitation with a much slower time course. In addition to somatodendritic mGluRs, which excite inhibitory cells, a different species of mGluR is present on inhibitory cell terminals. This mGluR is activated by higher concentrations of the agonist t-1-amino-cyclopentyl–1,3-decarboxylate and acts to reduce γ-aminobutyric acid release. mGluRs, thus, have a dual action to enhance and to depress synaptic inhibition in the hippocampus. © 1995 John Wiley & Sons, Inc.     

A non-linear model for the synaptic basis of neuronal memory.

We propose a mathematical model for the synaptic basis of neuronal memory. The model incorporates non-linear effects in analogy with population growth problems of human beings, animals, biological species, crystal growth, etc., and provides a mechanism whereby the excitatory and inhibitory inputs produce alterations in a neurone which result in a long-lasting increase in transmitter release at a synapse.     

Peptides in the Hydrozoa: are they transmitters?

A family of peptides with the carboxy-terminus Arg-Phe-amide has been localized to specific subpopulations of neurons in every cnidarian species examined. These neurons are typically sensory in character or are associated with smooth muscle. Although a transmitter role for these peptides has been suggested for anthozoans at neuromuscular synapses, no such evidence is available for hydrozoans. Instead there is evidence that RF-amides can be modulators of neuronal activity which takes the form of a biphasic (inhibitory then excitatory) response in vivo, while in vitro only the inhibitory response is seen. Voltage clamp studies of identified motor neurons showed large, transitory outward currents when Pol-RF-amide peptide was applied.     

Population rate coding in recurrent neuronal networks with unreliable synapses

Neuron transmits spikes to postsynaptic neurons through synapses. Experimental observations indicated that the communication between neurons is unreliable. However most modelling and computational studies considered deterministic synaptic interaction model. In this paper, we investigate the population rate coding in an all-to-all coupled recurrent neuronal network consisting of both excitatory and inhibitory neurons connected with unreliable synapses. We use a stochastic on-off process to model the unreliable synaptic transmission. We find that synapses with suitable successful transmission probability can enhance the encoding performance in the case of weak noise; while in the case of strong noise, the synaptic interactions reduce the encoding performance. We also show that several important synaptic parameters, such as the excitatory synaptic strength, the relative strength of inhibitory and excitatory synapses, as well as the synaptic time constant, have significant effects on the performance of the population rate coding. Further simulations indicate that the encoding dynamics of our considered network cannot be simply determined by the average amount of received neurotransmitter for each neuron in a time instant. Moreover, we compare our results with those obtained in the corresponding random neuronal networks. Our numerical results demonstrate that the network randomness has the similar qualitative effect as the synaptic unreliability but not completely equivalent in quantity.     

Computer simulation of shared input among projection neurons in the dorsal cochlear nucleus

Computer simulations of a network model of an isofrequency patch of the dorsal cochlear nucleus (DCN) were run to explore possible mechanisms for the level-dependent features observed in the cross-correlograms of pairs of type IV units in the cat and nominal type IV units in the gerbil DCN. The computer model is based on the conceptual model (of a cat) that suggests two sources of shared input to DCN's projection neurons (type IV units): excitatory input from auditory nerves and inhibitory input from interneurons (type II units). Use of tonal stimuli is thought to cause competition between these sources resulting in the decorrelation of type IV unit activities at low levels. In the model, P-cells (projection neurons), representing type IV units, receive inhibitory input from I-cells (interneurons), representing type II units. Both sets of model neurons receive a simulated excitatory auditory nerve (AN) input from same-CF AN fibers, where the AN input is modeled as a dead-time modified Poisson process whose intensity is given by a computationally tractable discharge rate versus sound pressure level function. Subthreshold behavior of each model neuron is governed by a set of normalized state equations. The computer model has previously been shown to reproduce the major response properties of both type IV and type II units (e.g., rate-level curves and peri-stimulus time histograms) and the level-dependence of the functional type II-type IV inhibitory interaction. This model is adapted for the gerbil by simulating a reduced population of I-cells. Simulations were carried out for several auditory nerve input levels, and cross-correlograms were computed from the activities of pairs of P-cells for a complete (cat model) and reduced (gerbil model) population of I-cells. The resultant correlograms show central mounds (CMs), indicative of either shared excitatory or inhibitory input, for both spontaneous and tone-evoked driven activities. Similar to experimental results, CM amplitudes are a non-monotonic function of level and CM widths decrease as a function of level. These results are consistent with the hypothesis that shared excitatory input correlates the spontaneous activities of type IV units and shared inhibitory input correlates their driven activities. The results also suggest that the decorrelation of the activities of type IV units can result from a reduced effectiveness of the AN input as a function of increasing level. Thus, competition between the excitatory and inhibitory inputs is not required.     

Chemical transmission and adaptation

Acetylcholine and factor I appear to be transmitter substances of excitatory and inhibitory regulatory nerve fibers supplying the sensory neurons of stretch receptor organs of the crayfish. Sudden application of a low concentration of acetylcholine causes the impulse frequency to jump to a peak value. But immediately the frequency falls again and gradually reaches a steady state which is not far above the previous frequency level. If the acetylcholine is now withdrawn there follows a silent period after which the frequency returns to its original level. The time course of these events is identical with that of adaptations to sudden increase or decrease of stretch. Factor I in sufficiently low concentrations causes an immediate fall in impulse frequency (silent period) which is followed by a return to a value near the previous frequency level. Withdrawal of factor I is followed by excitation and again return of the frequency to the rate measured before the application of factor I. The time course of these phenomena is identical with that of adaptations to sudden decrease and increase of stretch. It is suggested that adaptation may be a property not only of sensory neurons but of neurons in general and that even central neurons may be considered as receptor neurons inasmuch as they respond to chemically transmitted excitatory and inhibitory stimuli.     

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.     

Changes in synaptic transmission produced by hydrogen peroxide

The effect of hydrogen peroxide (H₂O₂) on excitatory and inhibitory synaptic transmission was studied at the lobster neuromuscular junction. H₂O₂ produced a dose dependent decrease in the amplitude of the junction potential (V_ejp). This decrease was due to changes in both presynaptic transmitter release and the postsynaptic response to the neurotransmitter. Observed presynaptic changes due to exposure to H₂O₂ were a decrease in the amount of transmitter released, that is, quantal content, as well as a decrease in the fast facilitation, that is, the amplitude increase of successive excitatory junction potentials at a rate of 3 Hz. To discern postsynaptic changes, glutamate, the putative excitatory neurotransmitter for this preparation was applied directly to the bathing medium in order to bypass the presynaptic release process. H₂O₂ produced a decreased response of the glutamate receptor/ ionophore. The action of H₂O₂ was not selective to excitatory (glutamate-mediated) transmission because inhibitory (GABA-mediated) transmission was also depressed by H₂O₂. This effect was primarily presynaptic since H₂O₂ produced no change in the postsynaptic response to applied GABA.     

Prolonged modification of action potential shape by synaptic inputs in molluscan neurones

1. Somatic action potentials of Lymnaea neurons are modified by excitatory or inhibitory synaptic inputs and have been studied using phase-plane techniques and an action potential duration monitor. 2. Excitatory synaptic inputs increase the rate of neuronal discharge, cause action potential broadening, a decrease in the maximum rate of depolarization (Vd) and a decrease in the maximum rate of repolarization (Vr). 3. Inhibitory synaptic inputs decrease the discharge rate and cause narrowing of action potentials, an increase in Vd and an increase in Vr. 4. The effects reported above outlast the original synaptic inputs by many seconds and, if the somatic action potentials are similar to those in the axon terminals, they may have far-reaching effects on transmitter release.     

猫初级视皮层内GIu/GABA表达比率的衰老性变化

最近的一些研究结果显示,视皮层内抑制性递质系统作用减弱可能是导致老年性视觉功能衰退的重要因素.是否皮层内兴奋性递质系统亦伴随衰老而发牛改变并影响皮层内神经兴奋与抑制的平衡尚不清楚.为此,利用Nissl染色和免疫组织化学染色方法以及Image-Pro Express图像分析软件对青、老年猫初级视皮层(17区)内各层神经元密度、兴奋性递质谷氨酸免疫反应阳性(Glu-immunoreactive,Glu-IR)神经元密度以及抑制性递质γ-氨基丁酸免疫反应阳性(γ-aminobutyric acid.immunoreactive,GABA-IR)神经元密度进行了统汁分析.结果显示,青、老年猫初级视皮层各层神经元密度均没有明显的年龄性差异(P>0.05);与青年猫相比,老年猫初级视皮层Glu-IR、GABA-IR神经元密度均显著减少(P<0.01),而Glu.IR/GABA.IR神经元密度比率去却显著增大(P<0.01).结果提示,老年猫初级视皮层内兴奋性递质系统作用相对增强,而抑制性递质系统的作用相对减弱,导致皮层内兴奋-抑制平衡关系失调,这可能是引起老年个体视觉功能衰退的重要原因之一.     

A neural network model of reliably optimized spike transmission

We studied the detailed structure of a neuronal network model in which the spontaneous spike activity is correctly optimized to match the experimental data and discuss the reliability of the optimized spike transmission. Two stochastic properties of the spontaneous activity were calculated: the spike-count rate and synchrony size. The synchrony size, expected to be an important factor for optimization of spike transmission in the network, represents a percentage of observed coactive neurons within a time bin, whose probability approximately follows a power-law. We systematically investigated how these stochastic properties could matched to those calculated from the experimental data in terms of the log-normally distributed synaptic weights between excitatory and inhibitory neurons and synaptic background activity induced by the input current noise in the network model. To ensure reliably optimized spike transmission, the synchrony size as well as spike-count rate were simultaneously optimized. This required changeably balanced log-normal distributions of synaptic weights between excitatory and inhibitory neurons and appropriately amplified synaptic background activity. Our results suggested that the inhibitory neurons with a hub-like structure driven by intensive feedback from excitatory neurons were a key factor in the simultaneous optimization of the spike-count rate and synchrony size, regardless of different spiking types between excitatory and inhibitory neurons.     

dynamics of responsiveness of cortical neurons towards the repeated combined action of L-glutamate and acetylcholine

The probability, direction, and intensity of changes in mean firing rate of spike activity elicited by application of L-glutamate (Gl) and acetylcholine (ACh) have been compared in a series of successive responses of neuronal units in the sensorimotor cortex of unanesthetized rats; delayed paired application of the above transmitters was used. It is shown that the neurons significantly more often decrease their excitatory responses to the associated action of transmitters, and that responses are not enhanced. In the population of neurons studied, decreases in responsiveness with respect to Gl and ACh occurred with the same probability and in similar fashion over the whole period of testing (60 applications). After long-term transmitter application, potentiation became more typical of the responses to Gl than to ACh.Translated from Neirofiziologiya, Vol. 25, No. 2, pp. 94–97, March–April, 1993.     

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     

GABA-like immunoreactivity of identified interneurons in the flight system of the locust,Locusta migratoria

Summary The transmitter content of identified inhibitory interneurons in the flight system of the locust, Locusta migratoria, has been characterized using antibodies raised against protein-conjugated gamma aminobutyric acid. Identified flight neurons were filled with the fluorescent dye, Lucifer Yellow. Serial sections of dye-filled neurons were incubated with an antibody to gamma aminobutyric acid which was subsequently tagged with a fluorescent marker. Excitatory motoneurons to wing muscles and 13 flight interneurons (3 excitatory, 7 inhibitory, and 3 with unknown synaptic effect) were examined. Neither the moto-neurons nor any of the 3 excitatory interneurons contained immunoreactive material. Six of the 7 inhibitory interneurons did contain immunoreactive material. All the neurons which contained immunoreactive material and whose synaptic effect is known were inhibitory. We conclude that most of the inhibitory flight interneurons which have been described use gamma aminobutyric acid as their transmitter. Interestingly, at least 1 set of interneurons known to be inhibitory does not use gamma aminobutyric acid. We predict that the 2 interneurons which do contain immunoreactive material and whose synaptic effect is not yet known will be found to have inhibitory roles in the operation of the flight circuitry.     

Synaptic and intrinsic activation of GABAergic neurons in the cardiorespiratory brainstem network

GABAergic pathways in the brainstem play an essential role in respiratory rhythmogenesis and interactions between the respiratory and cardiovascular neuronal control networks. However, little is known about the identity and function of these GABAergic inhibitory neurons and what determines their activity. In this study we have identified a population of GABAergic neurons in the ventrolateral medulla that receive increased excitatory post-synaptic potentials during inspiration, but also have spontaneous firing in the absence of synaptic input. Using transgenic mice that express GFP under the control of the Gad1 (GAD67) gene promoter, we determined that this population of GABAergic neurons is in close apposition to cardioinhibitory parasympathetic cardiac neurons in the nucleus ambiguus (NA). These neurons fire in synchronization with inspiratory activity. Although they receive excitatory glutamatergic synaptic inputs during inspiration, this excitatory neurotransmission was not altered by blocking nicotinic receptors, and many of these GABAergic neurons continue to fire after synaptic blockade. The spontaneous firing in these GABAergic neurons was not altered by the voltage-gated calcium channel blocker cadmium chloride that blocks both neurotransmission to these neurons and voltage-gated Ca(2+) currents, but spontaneous firing was diminished by riluzole, demonstrating a role of persistent sodium channels in the spontaneous firing in these cardiorespiratory GABAergic neurons that possess a pacemaker phenotype. The spontaneously firing GABAergic neurons identified in this study that increase their activity during inspiration would support respiratory rhythm generation if they acted primarily to inhibit post-inspiratory neurons and thereby release inspiration neurons to increase their activity. This population of inspiratory-modulated GABAergic neurons could also play a role in inhibiting neurons that are most active during expiration and provide a framework for respiratory sinus arrhythmia as there is an increase in heart rate during inspiration that occurs via inhibition of premotor parasympathetic cardioinhibitory neurons in the NA during inspiration.     

Axonal transport of [3H] GABA and [3H] glutamate in excitatory and inhibitory neurons innervating lobster exoskeletal musculature

This paper describes the results of intracellular injections of radiolabelled neurotransmitters and transmitter precursor substances, including glutamate, GABA, aspartate, octopamine, tyramine, tryptophan, and choline, into cell bodies of identified excitatory and inhibitory neurons innervating lobster extensor musculature. The distributions and identities of radioactive substances appearing in axons were examined at various times following injection and in vitro incubation. Injected GABA and glutamate were found in appreciable quantities in both excitatory and inhibitory axons and migrated down axons at an estimated rate of between 16 and 22 mm/day at 12 degrees C, whereas the other substances tested were present in substantially smaller quantities and migrated at an estimated rate of less than 7.5 mm/day at 12 degrees C. Injected GABA, D-glutamate and L-glutamate accumulated proximal to ligatures tied around nerves, whereas neither octopamine nor aspartate accumulated proximal to ligatures. Since GABA is the transmitter substance released by inhibitory neurons and L-glutamate is thought to be released from excitatory nerve terminals, these results are consistent with the suggestion that amino acids serving as neurotransmitters are axonally transported. The specificity of axonal transport does not appear to be restricted to the cognate neurotransmitter, as indicated by the movement of L-glutamate in inhibitory axons and GABA in excitatory axons and of D-glutamate in both excitatory and inhibitory axons, but rather may be relaxed to include substances closely related to the neurotransmitter. Some restrictions, however, are apparently placed on axonal transport of small charged molecules in these neurons in that other substances tested migrated down nerves at a considerably slower rate.     

The metabolism of gamma aminobutyric acid in the lobster nervous system. Enzymes in single excitatory and inhibitory axons

γ-aminobutyric acid (GABA) is the inhibitory transmitter compound at the lobster neuromuscular junction. This paper presents a comparison of the enzymes of GABA metabolism in single identified inhibitory and excitatory axons from lobster walking legs. Inhibitory axons contain more than 100 times as much glutamic decarboxylase activity as do excitatory axons. GABA-glutamic transaminase is found in both excitatory and inhibitory axons, but about 50% more enzyme is present in inhibitory axons. The kinetic and electrophoretic behavior of the transaminase activity in excitatory and inhibitory axons is similar. Succinic semialdehyde dehydrogenase is found in both axon types, as is an unknown enzyme which converts a contaminant in radioactive glutamic acid to GABA. In lobster inhibitory neurons, therefore, the ability to accumulate GABA ultimately rests on the ability of the neuron to accumulate the enzyme glutamic decarboxylase.     

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.