Monosynaptic pathway responsible for generation of bursting activity in theHelix pomatia RPal neuron

The connection between a visceral ganglia interneuron initiating bursting pacemaker activity in the RPal neuron and the RPal neuron itself was investigated inHelix pomatia. Stimulating the interneuron either initiated or intensified bursting activity in the RPal neuron, depending on initial electrical activity in this cell. Replacing calcium with magnesium ions in the extracellular fluid and adding CdCl₂ to this fluid reversibly inhibited the effect of interneuronal stimulation on the RPal neuron. The latter effect was unaffected by increasing the concentration of extracellular Ca²⁺ 10 to 70 mM. Intracellular injection of both Cs⁺ and TEA into the interneuron produced an increase in the duration of its action potentials and rendered the link connecting the neurons more effective. It is deduced that a monosynaptic chemical connection exists between the interneuron and the RPal neuron for which a peptide compound serves as transmitter.A. A. Bogomolets Institute of Physiology, Academy of Sciences of the Ukrainian SSR, Kiev. Translated from Neirofiziologiya, Vol. 19, No. 1, pp. 20–28, January–February, 1987.     

Mechanisms of membrane potential oscillation in bursting neurons on the snail,Helix pomatia

• 1.1. The mechanism of generation of membrane potential (MP) oscillations was studied in identified bursting neurons from the snail Helix pomatia.
• 2.2. Long-lasting stimulation of an identified peptidergic interneuron produced a persistent bursting activity in a non-active burster.
• 3.3. External application of calcium channel blockers (1 mM Cd²⁺ or 5 mM La²⁺) resulted in a transient increase in the slow-wave amplitude and subsequent prevention of pacemaker activity generation in bursting neurons. Application of these blockers together with endogenous neuropeptide initiating bursting activity generation, increased MP wave amplitude without prevention of bursting activity generation.
• 4.4. Replacement of all NaCl in normal Ringer's solution with isoosmotic CaCl₂, glucose or Tris-HCl produced a reversible block of bursting activity generation. Stationary current-voltage relation (CVR) of bursting neuron membrane has a region of negative resistance (NRR) and does not intersect the potential axis in threshold region for action potential (AP) generation in normal Ringer's solution. In Na-free solution stationary CVR is linear and intersects the potential axis near — 52 mV.
• 5.5. Novel potential- and time-dependent outward (E_rev = − 58 mV) current, I_B, activated by hyperpolarization was found in the bursting neuron membrane. Having achieved a maximal value, this current decayed with a time constant of about 1 sec. Hyperpolarization inactivated maximal conductance, g_B, responsible for I_B, and depolarization abolished inactivation of g_B.
• 6.6. Short-lasting (0.01 sec) hyperpolarization of the bursting neuron membrane by inward current pulse induced the development of prolonged hyperpolarization wave lasting up to 10 sec.
• 7.7. These results suggest that: (a) persistent bursting activity of RPal neuron in the snail Helix pomatia is not endogenous but is due to a constant activation of peptidergic synaptic inputs of these neurons; (b) Ca²⁺ ions do not play a pivotal role in the ionic mechanism of MP oscillations but play a determining role in the process of secretion of a peptide initiating bursting activity by the interneuron presynaptic terminal; (c) depolarizing phase of the MP wave is due to specific properties of stationary CVR and hyperpolarization phase is due to regenerative properties of hyperpolarization-activated outward current I_B. The minimal mathematical version of MP oscillations based on the experimental data is presented.

     

Intrinsic bursting activity in the pre-Bötzinger Complex: Role of persistent sodium and potassium currents

Computational models of single pacemaker neuron and neural population in the pre-Bötzinger Complex (pBC) were developed based on the previous models by Butera et al. (1999a,b). Our modeling study focused on the conditions that could define endogenous bursting vs. tonic activity in single pacemaker neurons and population bursting vs. asynchronous firing in populations of pacemaker neurons. We show that both bursting activity in single pacemaker neurons and population bursting activity may be released or suppressed depending on the expression of persistent sodium (I_NaP) and delayed-rectifier potassium (I_K) currents. Specifically, a transition from asynchronous firing to population bursting could be induced by a reduction of I_K via a direct suppression of the potassium conductance or through an elevation of extracellular potassium concentration. Similar population bursting activity could be triggered by an augmentation of I_NaP. These findings are discussed in the context of the possible role of population bursting activity in the pBC in the respiratory rhythm generation in vivo vs. in vitro and during normal breathing in vivo vs. gasping.     

Effects of Salicylic Acid and Its Salts on Electrical Activity of Neurons of <Emphasis Type="Italic">Helix albescens</Emphasis>

We studied changes in the parameters of electrical activity of identified neurons of the parietal ganglion, PPa1 and PPa2, and of non-identified cells of the visceral ganglion (VG) of the snail Helix albescens; these changes were caused by application of salicylic acid and its salts (cobalt and zinc salicylates, CS and ZS, respectively). The above substances began to modify significantly the functional state of the neurons under study when applied in concentrations of 10⁻⁴ to 10⁻³ M. Salicylic acid suppressed the activity of all studied neurons. Application of salicylic acid in the concentration of 10⁻³ M led to a decrease in the impulsation frequency of VG neurons by factors of 1.2 to 1.5 and to an increase in the duration of AP (on average, by 2.8 ± ± 0.6 msec). In PPa1 and PPa2 cells, we observed increases in both the AP duration (by 2.4 ± 0.8 and 3.6 ± ± 1.3 msec, respectively) and that of postactivation hyperpolarization (by 29.8 ± 11 0 and 39.6 ± 9.4 msec). In the concentration of 10⁻² M, salicylic acid completely but relatively reversibly suppressed the impulse activity of all the neurons under study, causing deep hyperpolarization of their membranes. Salts of this acid, CS and ZS, demonstrated significant modulatory effects on the activity of the studied neurons; these substances initiated or enhanced the grouping of APs in bursts and also increased the AP duration. Application of 10⁻³ M CS resulted in an increase in the AP duration by, on average, 2.75 ± 0.4 msec (only in the PPa2 neuron), whereas 10⁻³ M ZS exerted analogous effects on both above neurons (in PPa1, by 2.7 ± 0.4, while in PPa2, by 3.1 ± 0.6 msec). In the case where the tested salicylates were applied in the concentration of 10⁻² M, the AP duration increased in all the cells under study (on average, by 11.8 ± 2.46 msec in VG neurons, and by 7.0 ± ± 0.4 and 7.8 ± 1.2 msec in PPa1 and PPa2 cells, respectively). With application of CS, analogous values determined by application of ZS were 14.6 ± 4.6, 6.8 ± 0.54, and 9.0 ± 0.89 msec. We assume that the modulatory effects of salicylates are mediated by their influence on the intracellular system of cyclic nucleotides. Neirofiziologiya/Neurophysiology, Vol. 37, No. 2, pp. 142–150, March–April, 2005.     

Inter-and intraganglionar synaptic connections formed by neurons of the <Emphasis Type="Italic">Helix</Emphasis> visceral ganglion

In experiments on the subpharyngeal complex of the Helix ganglia, we found an excitatory monosynaptic input to the pacemaker PPa2 neuron from an unidentified cell of the visceral ganglion and a polysynaptic inhibitory influence of another unidentified neuron of this ganglion on the PPa1 cell. In addition, we revealed three pairs of neurons synaptically connected with each other (excitatory connections) in the visceral ganglion. In the case where we used high-frequency (11 sec⁻¹) stimulation of presynaptic elements, synaptic transmission to the PPa2 neuron demonstrated the greatest efficiency and stability. Neirofiziologiya/Neurophysiology, Vol. 39, No. 1, pp. 32–36, January–February, 2007.     

Nonlinear dynamics and information processing in pacemaker neurons

The paper treats some nonlinear dynamic phenomena in oscillatory activity of a single nerve cell. Based on experiments with CNS bursting pacemaker neurons ofHelix pomatia snail, a mathematical model was studied. The model demonstrates the majority of experimentally observable phenomena and allows one to investigate the role of its separate components. The phenomena demonstrated by model neuron (chaotic behavior, bistability, and sensitivity to parameter variations, initial conditions, and stimuli) may be relevant to information processing in nerve cells. The complexity of [Ca²⁺] _in −V phase diagrams of initial conditions depends on parameters. Transient synaptic impulse produces stable parameter-independent changes in activity of model neuron. These results indicate that a single bursting neuron can work in the neuronal ensemble as a dynamic switch. The sensitivity of this switch is regulated by a neurotransmitter.     

Effect of cadmium ions on bursting electrical activity of an identified snail neuron

The effect of cadmium ions, a specific blocker of the inward calcium current in molluscan neurons, on electrical activity of identified neuron RPal ofHelix pomatia was studied. Cadmium ions in a concentration of 1 mM were shown to block bursting activity of the neuron completely. The membrane potential increased under these circumstances to about ?65 mV. After rinsing out the cadmium ions electrical activity in the neuron was fully restored. If a modulating factor (a peptide fraction obtained from the water-soluble part of snail brain homogenate) was added to the solution containing cadmium ions, however, not only was bursting activity not blocked, but it was actually intensified. Addition of modulating factor to the solution after blocking induced by cadmium ions led to the reappearance of bursting activity if not more than a few tens of seconds had elapsed after blocking developed. As the time after the beginning of blocking increased, addition of the modulating factor became less effective and caused only rhythmic activity to develop. It was concluded from the results of these experiments that bursting activity of neuron RPal is not endogenous but is induced in it by a modulating factor secreted by an unidentified peptidergic interneuron. Calcium ions do not play an essential role in the generation of slow depolarization waves in the neuron under these circumstances but they are essential for secretion of the modulating factor.     

A sodium leak current regulates pacemaker activity of adult central pattern generator neurons in Lymnaea stagnalis

The resting membrane potential of the pacemaker neurons is one of the essential mechanisms underlying rhythm generation. In this study, we described the biophysical properties of an uncharacterized channel (U-type channel) and investigated the role of the channel in the rhythmic activity of a respiratory pacemaker neuron and the respiratory behaviour in adult freshwater snail Lymnaea stagnalis. Our results show that the channel conducts an inward leak current carried by Na(+) (I(Leak-Na)). The I(Leak-Na) contributed to the resting membrane potential and was required for maintaining rhythmic action potential bursting activity of the identified pacemaker RPeD1 neurons. Partial knockdown of the U-type channel suppressed the aerial respiratory behaviour of the adult snail in vivo. These findings identified the Na(+) leak conductance via the U-type channel, likely a NALCN-like channel, as one of the fundamental mechanisms regulating rhythm activity of pacemaker neurons and respiratory behaviour in adult animals.     

Rhythmic activities of isolated and clustered pacemaker neurons and photoreceptors of Aplysia retina in culture

Each eye of Aplysia contains a circadian clock that produces a robust rhythm of optic nerve impulse activity. To isolate the pacemaker neurons and photoreceptors of the eye and determine their participation in the circadian clock and its generation of rhythmic autoactivity, the retina was dissociated and its cells were placed in primary cell culture. The isolated neurons and photoreceptors survived and vigorously extended neurites tipped with growth cones. Many of the photoreceptors previously described from histological sections of the intact retina were identified in culture, including the large R-type photoreceptor, which gave robust photoresponses, and the smaller tufted, whorled, and flared photoreceptors. The pacemaker neurons responsible for the rhythmic impulse activity generated by the eye were identified by their distinctive monopolar morphology and recordings were made of their activity. Isolated pacemaker neurons produced spontaneous action potentials in darkness, and pacemaker neurons attached to fragments of retina or in an isolated cluster interacted to produce robust spontaneous activity. This study establishes that isolated retinal pacemaker neurons retain their innate autoactivity and ability to produce action potentials in culture and that clusters of coupled pacemaker neurons are capable of generating robust autoactivity comparable to pacemaker neuron rhythmic activity recorded in the intact retina, which was previously shown to correspond to 1:1 with the optic nerve compound action potential activity. © 1996 John Wiley & Sons, Inc.     

Two types of independent bursting mechanisms in inspiratory neurons: an integrative model

The network of coupled neurons in the pre-Bötzinger complex (pBC) of the medulla generates a bursting rhythm, which underlies the inspiratory phase of respiration. In some of these neurons, bursting persists even when synaptic coupling in the network is blocked and respiratory rhythmic discharge stops. Bursting in inspiratory neurons has been extensively studied, and two classes of bursting neurons have been identified, with bursting mechanism depends on either persistent sodium current or changes in intracellular Ca²⁺, respectively. Motivated by experimental evidence from these intrinsically bursting neurons, we present a two-compartment mathematical model of an isolated pBC neuron with two independent bursting mechanisms. Bursting in the somatic compartment is modeled via inactivation of a persistent sodium current, whereas bursting in the dendritic compartment relies on Ca²⁺ oscillations, which are determined by the neuromodulatory tone. The model explains a number of conflicting experimental results and is able to generate a robust bursting rhythm, over a large range of parameters, with a frequency adjusted by neuromodulators.     

Amphetamine-produced convulsive (bursting) firings in the neuron of the giant African snail Achatina fulica: Effects of inhibitors of phosphodiesterases

Effects of inhibitors of phosphodiesterases (PDE) on bursting activity, produced by d-amphetamine (d-AM) was studied in PPa4 neurons of the giant African snail Achatina fulica F. Action of the following PDE inhibitors was analyzed: vinpocetine (selective to PDE I), erythro-9-(2-hydroxi-3-nonyl) adenine (EHNA; selective to PDE 2), milrinone (selective to PDE 3), rolipram (selective to PDE 4), sildenafil citrate (Viagra^@; selective to PDE 5), and caffeine, a non-selective phosphodiesterase inhibitor. Amphetamine at a low concentration (67.5 × 10^?5 M) did not produce the bursting firing in the neurons; however, the convulsive activity appeared on addition to this solution of any if the PDE inhibitors except for sildenafil. Forskolin (an adenylyl cyclase activator, 10^?4 M) also decreased the neuronal threshold to the d-AM action. The bursting activity produced by d-AM did not develop after a previous administration of the protein kinase A inhibitor KT-5720. The phospholipase C blocker U73122 had no effect on the bursting activity produced by d-AM. It is concluded that the neuronal convulsive activity induced by d-AM is associated with the phosphodiesterase activity.     

Are pacemaker properties required for respiratory rhythm generation in adult turtle brain stems in vitro?

The role of pacemaker properties in vertebrate respiratory rhythm generation is not well understood. To address this question from a comparative perspective, brain stems from adult turtles were isolated in vitro, and respiratory motor bursts were recorded on hypoglossal (XII) nerve rootlets. The goal was to test whether burst frequency could be altered by conditions known to alter respiratory pacemaker neuron activity in mammals (e.g., increased bath KCl or blockade of specific inward currents). While bathed in artificial cerebrospinal fluid (aCSF), respiratory burst frequency was not correlated with changes in bath KCl (0.5-10.0 mM). Riluzole (50 microM; persistent Na(+) channel blocker) increased burst frequency by 31 +/- 5% (P < 0.05) and decreased burst amplitude by 42 +/- 4% (P < 0.05). In contrast, flufenamic acid (FFA, 20-500 microM; Ca(2+)-activated cation channel blocker) reduced and abolished burst frequency in a dose- and time-dependent manner (P < 0.05). During synaptic inhibition blockade with bicuculline (50 microM; GABA(A) channel blocker) and strychnine (50 muM; glycine receptor blocker), rhythmic motor activity persisted, and burst frequency was directly correlated with extracellular KCl (0.5-10.0 mM; P = 0.005). During synaptic inhibition blockade, riluzole (50 microM) did not alter burst frequency, whereas FFA (100 microM) abolished burst frequency (P < 0.05). These data are most consistent with the hypothesis that turtle respiratory rhythm generation requires Ca(2+)-activated cation channels but not pacemaker neurons, which thereby favors the group-pacemaker model. During synaptic inhibition blockade, however, the rhythm generator appears to be transformed into a pacemaker-driven network that requires Ca(2+)-activated cation channels.     

Caffeine-induced oscillations of the membrane potential inAplysia neurons

It has been found in culturedAplysia neurons, including L7 and L2–L6 neurons, that bath application of 40 mM caffeine evokes oscillations of the membrane potential (MP) with the amplitude of about 40 mV. The frequency of oscillations, on the crest of which action potentials (AP) arise, varied from 0.2 to 0.5 sec¹. The effect of caffeine was completely reversible. The MP waves demonstrated high sensitivity to membrane polarization: artificial depolarization increased the frequency of oscillations, while even subtle hyperpolarization resulted in a decrease in the frequency up to their complete disappearance. External application of CdCl₂ (1 mM), a nonspecific blocker of calcium channels, or ryanodine (50 μM, 20 min), release of Ca²⁻ from the intracellular stores, replacement of Ca²⁺ in the external medium by Mg²⁻, or Na⁺ by Li⁺, did not exert visible effect on the parameters of MP waves. It was concluded that Ca ions (changing of intracellular concentration of which is due to such processes as inward calcium current, ryanodine-sensitive caffeine-induced calcium release from the intracellular, stores, sodium-calcium exchange through the plasma membrane) do not play any significant part in generation of the MP waves. The most probable mechanism of caffeine-induced oscillations in the studied nerve cells is inhibition of voltage-activated outward potassium current and, as could be seen from our mathematical modeling, slowdown of inactivation of inward sodium current. It seems likely that these oscillations have a purely membrane origin. Neirofiziologiya/Neurophysiology, Vol. 32, No. 2, pp. 102–111, March–April, 2000.     

Cadmium modulates NADPH oxidase activity and expression in sunflower leaves

The production of reactive oxygen species (ROS) and the ways by which ROS are generated are very important facts related to heavy metal toxicity in plants. In this work, superoxide anion (O₂ ^·−) generation diminished in cadmium treated sunflower (Helianthus annuus L.) leaf discs, and this reduction was time and Cd-concentration dependent. In line with these findings, we observed that NADPH-dependent oxidase activity was significantly inhibited by 0.1 and 0.5 mM Cd²⁺ treatments and the expression of the NADPH oxidase putative gene related to O₂ ^·− synthesis in sunflower leaves was 83 % inhibited by 0.1 mM CdCl₂ and almost completely depleted by 0.5 mM CdCl₂.     

Serotonin-induced changes in the responses of the electroexcitable membrane of snail neurons

The effects of serotonin (5-HT) added to the washing solution on the plastic properties of the electroexcitable membrane of nonidentified neurons of the parietal ganglion and identified neurons RPa2 are studied on the isolated nervous system of the snail. The neurons of the first group, which became rapidly habituated to the intracellular stimulation, are shown to manifest the ability to restore action potential generation in the presence of 5-HT. In contrast, the neurons possessing endogenous rhythmic activity (RPa2) in the presence of 5-HT generate burst activity against the background of the development of slow waves of the membrane potential. A comparative analysis of the effect of 5-HT and compounds with a known effect on Ca²⁺ and the calcium-dependent potassium channels (quinine, CoCl₂ and CdCl₂) points to the existence of various mechanisms providing for the serotoninergic regulation of the plasticity of the electroexcitable neuron membrane. This difference stems from the processes of activation and blockade of the Ca-dependent mechanisms.A. I. Karaev Institute of Physiology Azerbaizhan Academy of Sciences, Baku. Translated from Neirofiziologiya, Vol. 24, No. 3, pp. 286–290, May–June, 1992.     

Effect of intracellular injection of cyclic amp on electrical characteristics of identified neurons in Helix pomatia

The effect of intracellular iontophoretic injection of cyclic AMP on electrical activity of neurons RPa1, RPa3, LPa2, LPa3, and LPl1 in the corresponding ganglia ofHelix pomatia was investigated. Injection of cyclic AMP into neuron LPl1 was found to cause the appearance of rhythmic activity (if the neuron was originally "silent"), an increase in the frequency of spike generation (if the neuron had rhythmic activity), and a decrease in amplitude of waves of membrane potential, in the duration of the interval between bursts, and in the number of action potentials in the burst (if the neuron demonstrated bursting activity). In the remaining "silent" neurons injection of cyclic AMP led to membrane depolarization. Injection of cyclic AMP into neurons whose membrane potential was clamped at the resting potential level evoked the development of an inward transmembrane current (cyclic AMP current), the rate of rise and duration of which increased proportionally to the size and duration of the injection. Theophylline in a concentration of 1 mM led to an increase in the amplitude and duration of the cyclic AMP current by about 50%. It is concluded that a change in the cyclic AMP concentration within the nerve cell may modify the ionic permeability of its membrane and, correspondingly, its electrical activity.A. A. Bogomolets Institute of Physiology, Academy of Sciences of the Ukrainian SSR, Kiev. Translated from Neirofiziologiya, Vol. 12, No. 5, pp. 517–525, September–October, 1980.     

The role of action potentials in determining neuron‐type‐specific responses to nitric oxide

The electrical activity in developing and mature neurons determines the intracellular calcium concentration ([Ca²⁺]_i), which in turn is translated into biochemical activities through various signaling cascades. Electrical activity is under control of neuromodulators, which can alter neuronal responses to incoming signals and increase the fidelity of neuronal communication. Conversely, the effects of neuromodulators can depend on the ongoing electrical activity within target neurons; however, these activity‐dependent effects of neuromodulators are less well understood. Here, we present evidence that the neuronal firing frequency and intrinsic properties of the action potential (AP) waveform set the [Ca²⁺]_i in growth cones and determine how neurons respond to the neuromodulator nitric oxide (NO). We used two well‐characterized neurons from the freshwater snail Helisoma trivolvis that show different growth cone morphological responses to NO: B5 neurons elongate filopodia, while those of B19 neurons do not. Combining whole‐cell patch clamp recordings with simultaneous calcium imaging, we show that the duration of an AP contributes to neuron‐specific differences in [Ca²⁺]_i, with shorter APs in B19 neurons yielding lower growth cone [Ca²⁺]_i. Through the partial inhibition of voltage‐gated K⁺ channels, we increased the B19 AP duration resulting in a significant increase in [Ca²⁺]_i that was then sufficient to cause filopodial elongation following NO treatment. Our results demonstrate a neuron‐type specific correlation between AP shape, [Ca²⁺]_i, and growth cone motility, providing an explanation to how growth cone responses to guidance cues depend on intrinsic electrical properties and helping explain the diverse effects of NO across neuronal populations. © 2014 Wiley Periodicals, Inc. Develop Neurobiol 75: 435–451, 2015     

Modeling of Rhythmogenesis in an Ensemble of Cortical Neurons Connected with Electrical Synapses

Based on our own data on generation of spindle-like field electrical activity in neuronal barrels of the rat somatic cortex and also on the published data on the properties of voltage-dependent channels in the membranes of cortical cells, we developed a model of the ensemble (simple network) of neurons connected by electrical synapses. Such connections were found earlier in neurophysiological and ultramicroscopic studies. Model neurons with membranes having sodium, potassium, and calcium channels described in the literature were capable of generating bursting rhythmic impulse activity under conditions of switching off of synaptic connections between cells (isolation). With switching on of electrical synapses, spiking generated by separate neurons, which initially was nonsynchronous, became synchronized in time. Ipso facto, we demonstrated the ability of pacemaker oscillatory activity to be electrotonically synchronized in ensembles of neurons connected with electrical synapses.     

Possible mechanism of bursting suppression in nociceptive neurons

The use of the mathematical model of rat nociceptive neuron membrane allowed us to predict a new mechanism of suppression of ectopic bursting discharges, which arise in neurons of dorsal root ganglia and are one of the causes of neuropathic pain. The treatment with comenic acid leads to switching off the ectopic bursting discharges due to a decrease in the effective charge transferring via the activation gating structure of the slow sodium channels (Na _V1.8a). Comenic acid is a drug substance of a new non-opioid analgesic [1] Thus, this analgesic not only reduces the frequency of rhythmic discharges of nociceptive neuron membrane [2] but also it suppresses its ectopic bursting discharges.     

Respiratory pattern generator model using Ca++-induced Ca++ release in neurons shows both pacemaker and reciprocal network properties

There are two contradictory explanations for central respiratory rhythmogenesis. One suggests that respiratory rhythm emerges from interaction between inspiratory and expiratory neural semicenters that inhibit each other and thereby provide reciprocal rhythmic activity (Brown 1914). The other uses bursting pacemaker activity of individual neurons to produce the rhythm (Feldman and Cleland 1982). Hybrid models have been developed to reconcile these two seemingly conflicting mechanisms (Smith et al. 2000; Rybak et al. 2001). Here we report computer simulations that demonstrate a unified mechanism of the two types of oscillator. In the model, we use the interaction of Ca⁺⁺-dependent K⁺ channels (Mifflin et al. 1985) with Ca⁺⁺-induced Ca⁺⁺ release from intracellular stores (McPherson and Campbell 1993), which was recently revealed in neurons (Hernandez-Cruz et al. 1997; Mitra and Slaughter 2002a,b; Scornik et al. 2001). Our computations demonstrate that uncoupled neurons with these intracellular mechanisms show conditional pacemaker properties (Butera et al. 1999) when exposed to steady excitatory inputs. Adding weak inhibitory synapses (based on increased K⁺ conductivity) between two model neural pools surprisingly synchronizes the activity of both neural pools. As inhibitory synaptic connections between the two pools increase from zero to higher values, the model produces first dissociated pacemaker activity of individual neurons, then periodic synchronous bursts of all neurons (inspiratory and expiratory), and finally reciprocal rhythmic activity of the neural pools.