Activity-dependent plasticity in descending synaptic inputs to respiratory spinal motoneurons

This review focuses on recent evidence for short- and long-term activity-dependent plasticity in descending synaptic inputs to respiratory spinal motoneurons. In anesthetized rats, application of high frequency (100 Hz) conditioning stimulation to descending inputs to phrenic motoneurons elicits short-term potentiation of spontaneous inspiratory bursts. In turtle brainstem-spinal cords in vitro, 10-100 Hz conditioning stimulation elicits short-term potentiation in descending inputs to inspiratory-related serratus motoneurons; 100 Hz stimulation also elicits long-term potentiation in some preparations. In contrast, 1-10 Hz stimulation of descending synaptic inputs to expiratory-related pectoralis motoneurons elicits depression during conditioning stimulation (temporal depression), and long-term depression following stimulation. We hypothesize that inspiratory descending pathways to spinal motoneurons express short-term potentiation, with little evidence for long-term activity-dependent plasticity; other forms of long-lasting plasticity (e.g. serotonin-dependent long-term facilitation) may predominate in these pathways. In contrast, expiratory descending pathways appear biased towards activity-dependent depression possibly to conserve resources during passive expiration.     

Fast amplification of dynamic synaptic inputs in spinal motoneurons in vivo

The ability of voltage-dependent inward currents (likely Na(+)) of the adult cat lumbar motoneurons to amplify rapidly changing (i.e., dynamic) synaptic inputs was investigated using in vivo intracellular recording techniques. Fast amplification was assessed by measuring the magnitude of the high-frequency (180 Hz) component of the Ia synaptic input due to tendon vibration as a function of somatic voltage and was compared with the previously observed amplification of steady inputs (steady state response of PICs to slow inputs). Data from 17 experiments show that amplification of the dynamic input indeed occurred and was directly linked to neuromodulatory drive (standard state: decerebrate with intact descending neuromodulatory systems vs. minimal state: pentobarbital with said systems significantly inhibited). Fast amplification factors averaged 2.0 +/- 0.7 (mean +/- SD) in the standard neuromodulatory state. That is, the effective synaptic current was nearly twice as large at its peak as it was at hyperpolarized levels, ranging as high as 2.6. Although fast amplification was often smaller than the amplification of steady inputs, the difference was not statistically significant. However, the voltage at which fast amplification began was approximately 10 mV more depolarized (P < 0.01). It is concluded that both dynamic and steady inputs can be amplified, but there may be differences in mechanism.     

Ethanol dual modulatory actions on spontaneous postsynaptic currents in spinal motoneurons

Recently we have shown that acute ethanol (EtOH) exposure suppresses dorsal root-evoked synaptic potentials in spinal motoneurons. To examine the synaptic mechanisms underlying the reduced excitatory activity, EtOH actions on properties of action potential-independent miniature excitatory and inhibitory postsynaptic currents (mEPSCs and mIPSCs) were studied in spinal motoneurons of newborn rats. Properties of mEPSCs generated by activation of N-methyl-D-aspartate receptors (NMDARs) and non-NMDA receptors and of mIPSCs mediated by glycine and gamma-aminobutyric acid-A receptors (GlyR and GABA(A)R) were examined during acute exposure to 70 and 200 mM EtOH. In the presence of 70 mM EtOH, the frequency of NMDAR- and non-NMDAR-mediated mEPSCs decreased to 53 +/- 5 and 45 +/- 7% (means +/- SE) of control values, respectively. In contrast, the frequency of GlyR- and GABA(A)R-mediated mIPSCs increased to 138 +/- 15 and 167 +/- 23% of control, respectively. Based on the quantal theory of transmitter release, changes in the frequency of miniature currents are correlated with changes in transmitter release, suggesting that EtOH decreased presynaptic glutamate release and increased the release of both glycine and GABA. EtOH did not change the amplitude or rise and decay times of either mEPSCs or mIPSCs, indicating that the presynaptic changes were not associated with changes in the properties of postsynaptic receptors/channels. Acute exposure to 200 mM EtOH increased mIPSC frequency two- to threefold, significantly higher than the increase induced by 70 mM EtOH. However, the decrease in mEPSC frequency was similar to that observed in 70 mM EtOH. Those findings implied that the regulatory effect of EtOH on glycine and GABA release was dose-dependent. Exposure to the higher EtOH concentration had opposite actions on mEPSC and mIPSC amplitudes: it attenuated the amplitude of NMDAR- and non-NMDAR-mediated mEPSCs to ~80% of control and increased GlyR- and GABA(A)R-mediated mIPSC amplitude by ~20%. EtOH-induced changes in the amplitude of postsynaptic currents were not associated with changes in their basic kinetic properties. Our data suggested that in spinal networks of newborn rats, EtOH was more effective in modulating the release of excitatory and inhibitory neurotransmitters than changing the properties of their receptors/channels.     

Voltage-clamp analysis of taurine-induced suppression of excitatory postsynaptic potentials in frog spinal motoneurons

1. The depressant actions of taurine applications on lumbar motoneurons in the isolated frog spinal cord were studied using conventional intracellular recordings and the two-electrode voltage-clamp technique. 2. With microelectrodes containing K+-acetate, 0.75-2 mM taurine mostly induced a hyperpolarization that often faded or turned into depolarization during the continuous application. A higher concentration (5-7.5 mM) depolarized a majority of cells. The effects on the membrane potential were associated with an increase in input conductance (approximately 285%). 3. The reversal potential of the taurine-induced currents was approximately -70 mV, with microelectrodes containing K+-acetate. In recordings using KCl-filled electrodes, taurine (less than or equal to 2 mM) produced a large depolarization (greater than or equal to 20 mV) at resting potentials near -50 mV, thereby indicating that the reversal potential was positively shifted by loading the cell with Cl-. These results suggest that the taurine potentials were mediated predominantly by an increased Cl- permeability. 4. Voltage-dependent relaxations of taurine currents were observed in 10 of 14 neurons. 5. A linear relation was found between the input conductance and the amount of current required to generate a 1-mV increment in EPSP at resting potential. 6. Polysynaptic excitatory postsynaptic potentials (EPSPs) and currents (EPSCs) were more susceptible to taurine than the monosynaptic responses. Taurine (less than 1 mM) seemed to suppress the interneurons mediating polysynaptic pathways. 7. Monosynaptic EPSPs and EPSCs were decreased with higher concentrations of taurine (greater than 1 mM). The percent reduction of EPSPs and that of the corresponding EPSCs had a positive correlation (r = 0.95), whereas, there was no significant correlation between changes in EPSPs and in input conductance, and between changes in EPSCs and in input conductance. The amount of current required to produce a 1-mV increment of EPSP was increased in the presence of taurine, in association with the increased input conductance. 8. Taurine suppressed synaptic potentiation of EPSPs evoked by paired stimuli, at an interval of 60-180 ms. Gamma-D-glutamylglycine, an antagonist of receptors for excitatory amino acids, greatly reduced the amplitude of EPSPs, but had little effect on synaptic potentiation. 9. Taurine suppressed glutamate currents evoked at membrane potentials, clamped near rest in low Ca2+, high Mg2+ solution. 10. These findings suggest that the taurine-induced reduction of EPSPs is due mainly to suppression of EPSCs, through both presynaptic and postsynaptic mechanisms.(ABSTRACT TRUNCATED AT 400 WORDS)     

Excitatory amino acids and intracellular pH in motoneurons of the isolated frog spinal cord

Double-barrelled pH-sensitive micro-electrodes were used to measure changes of intracellular and extracellular pH in and around motoneurons of the isolated frog spinal cord during application of excitatory amino acids. It was found that N-methyl-D-aspartate, quisqualate and kainate produced a concentration-dependent intracellular acidification. Extracellularly, triphasic pH changes (acid-alkaline-acid going pH transients) were observed during the action of these amino acids. The possible significance of such pH changes for the physiological and pathophysiological effects of excitatory amino acids are discussed.     

Segmental distribution of common synaptic inputs to spinal motoneurons during fictive swimming in the lamprey.

These experiments were designed to measure the degree of shared synaptic inputs coming to pairs of myotomal motoneurons during swimming activity in the isolated spinal cord of the lamprey. In addition, the experiments measured the decrease in the degree of shared synaptic inputs with the distance between the motoneurons to assess the segmental distribution of these shared inputs. Intracellular microelectrode recordings of membrane potential were made simultaneously on pairs of myotomal motoneurons during swimming activity induced with an excitatory amino acid. The swim cycle oscillations of motoneuron membrane potentials were removed with a digital notch filter, thus leaving the fast synaptic activities that underlie these slower oscillations. Cross-correlations of the fast synaptic activities in two simultaneously recorded motoneurons were made to measure the degree of shared inputs. The cross-correlation was done on time windows restricted to one swim cycle or to part of a swim cycle, and 50 consecutive swim cycle cross-correlograms then were averaged. The peak coefficients of the cross-correlations exhibited a wide range, even for pairs of motoneurons located near one another (range = 0.06-0.74, for pairs located within 2 segments). This observation suggests that there may be different functional classes of myotomal motoneurons with inputs originating from different sets of premotor interneurons. In spite of this variability, the mean peak correlation coefficients of motoneuron pairs clearly decreased with the distance between them. With separations of more than five segments, there was little or no clear correlation between the motoneurons (range = 0.04-0.10). These results suggest that common synaptic inputs to motoneurons during fictive swimming originate from local premotor interneurons and that beyond five spinal segments, common premotor inputs are rare or weak to motoneurons. Thus the premotor signals originating from the locomotor network have relatively short distribution lengths, on the order of 5 segments of 120 total spinal segments.     

Beta-asarone inhibits synaptic inputs to airway preganglionic parasympathetic motoneurons

Therapeutic application of Asarum, a herbal medicine that has been used for centuries, reportedly causes acute respiratory disturbance. The responsible constituents, the sites of action, and the mechanisms involved in this side effect are unclear. We investigated the effects of β-asarone, a volatile constituent of Asarum, on neurotransmission in the medullary respiratory neuronal network using extracellular recording of the rhythmic hypoglossal activity and voltage clamp recordings of the postsynaptic activity of the airway preganglionic parasympathetic motoneurons (APPMs) in vitro. β-Asarone caused progressive decreases in the duration and area of the hypoglossal bursts in a concentration-dependent manner. The frequency and amplitude of the bursts were initially unaltered or temporarily increased, but were then inhibited progressively after prolonged exposure. As with the inhibition of the hypoglossal bursts, the tonic and the phasic excitatory and inhibitory postsynaptic currents in the APPMs were attenuated. These data suggest that the Asarum-caused acute respiratory disturbance involves β-asarone-induced inhibition of neurotransmission in the medullary respiratory neuronal network.     

Summation of effective synaptic currents and firing rate modulation in cat spinal motoneurons

The aim of this study was to examine how cat spinal motoneurons integrate the synaptic currents generated by the concurrent activation of large groups of presynaptic neurons. We obtained intracellular recordings from cat triceps surae motoneurons and measured the effects of repetitive activity in different sets of presynaptic neurons produced by electrical stimulation of descending fibers or peripheral nerves and by longitudinal vibration of the triceps surae muscles (to activate primary muscle spindle Ia afferent fibers). We combined synaptic activation with subthreshold injected currents to obtain estimates of effective synaptic currents at the resting potential (I(Nrest)) and at the threshold for repetitive discharge (I(Nthresh)). We then superimposed synaptic activation on suprathreshold injected current steps to measure the synaptically evoked change in firing rate. We studied eight different pairs of synaptic inputs. When any two synaptic inputs were activated concurrently, both the effective synaptic currents (I(Nrest)) and the synaptically evoked changes in firing rate generally were equal to or slightly less than the linear sum of the effects produced by activating each input alone. However, there were several instances in which the summation was substantially less than linear. In some motoneurons, we induced a partial blockade of potassium channels by adding tetraethylammonium (TEA) or cesium to the electrolyte solution in the intracellular pipette. In these cells, persistent inward currents were evoked by depolarization that led to instances of substantially greater-than linear summation of injected and synaptic currents. Overall our results indicate that the spatial distribution of synaptic boutons on motoneurons acts to minimize electrical interactions between synaptic sites permitting near linear summation of synaptic currents. However, modulation of voltage-gated conductances on the soma and dendrites of the motoneuron can lead to marked nonlinearities in synaptic integration.     

Excitatory inputs to CA1 interneurons show selective synaptic dynamics

The dynamic properties of synapses between neurons in the hippocampal CA1 area are important for the frequency-dependent signal transfer of the network. We have examined the synaptic dynamics of excitatory inputs to CA1 interneurons and pyramidal cells using whole cell voltage-clamp recordings. The CA1 network was activated using extracellular stimulation electrodes at the Schaffer collaterals (feedforward activation) or at the Alveus (activation of the feedback loop). The dynamic properties of input from the Schaffer collaterals to CA1 interneurons (basket and bistratified cells) were different from the synaptic dynamics of input from the Alveus. Synaptic input from the Schaffer collaterals to CA1 interneurons showed facilitation for most frequencies. After 10 stimuli the synaptic response reached a plateau level that was approximately 150% of the first response in the train. In contrast, the plateau levels of Alveus inputs to interneurons were not different from the first responses for frequencies 相似文献   

Excitatory and inhibitory postsynaptic potentials in cat hypoglossal motoneurons during swallowing

Summary The postsynaptic potentials produced in cat genioglossus and styloglossus motoneurons (GG- and SG-Mns) during swallowing were studied. During swallowing elicited by placing water on the dorsum of the tongue, the GG-muscle discharged for 80–210 ms (mean±S. D. 123±31 ms, N=59) and was abruptly suppressed, and the SG-muscle began discharging in synchrony with the GG-muscle and discharged for 200–360 ms (mean+ S. D. 247±36 ms, N=59). The GG and the SG-Mns were identified if unitary muscle activity followed the induced spike of the motoneuron one-for-one. During swallowing, excitatory postsynaptic potentials (EPSPs) were evoked in the SG-Mns regardless of the respiratory drive on the SG-Mns, and inhibitory postsynaptic potential (IPSP) or EPSP-IPSP was evoked on the GG-Mns regardless of the respiratory drive on the GG-Mns. By increasing the intracellular concentration of chloride ions, the IPSP elicited in the GG-Mn during swallowing was turned into a depolarizing potential. In immobilized cats, a depolarizing potential and a depolarizing-hyperpolarizing potential sequence was evoked successively on a tongue retractor motoneuron and a tongue protruder motoneuron by repetitive electrical stimulation of the superior laryngeal nerve.     

Effect of nonlinear summation of synaptic currents on the input-output properties of spinal motoneurons

A single spinal motoneuron receives tens of thousands of synapses. The neurotransmitters released by many of these synapses act on iontotropic receptors and alter the driving potential of neighboring synapses. This interaction introduces an intrinsic nonlinearity in motoneuron input-output properties where the response to two simultaneous inputs is less than the linear sum of the responses to each input alone. Our goal was to determine the impact of this nonlinearity on the current delivered to the soma during activation of predetermined numbers and distributions of excitatory and inhibitory synapses. To accomplish this goal we constructed compartmental models constrained by detailed measurements of the geometry of the dendritic trees of three feline motoneurons. The current "lost" as a result of local changes in driving potential was substantial and resulted in a highly nonlinear relationship between the number of active synapses and the current reaching the soma. Background synaptic activity consisting of a balanced activation of excitatory and inhibitory synapses further decreased the current delivered to the soma, but reduced the nonlinearity with respect to the total number of active excitatory synapses. Unexpectedly, simulations that mimicked experimental measures of nonlinear summation, activation of two sets of excitatory synapses, resulted in nearly linear summation. This result suggests that nonlinear summation can be difficult to detect, despite the substantial "loss" of current arising from nonlinear summation. The magnitude of this "loss" appears to limit motoneuron activity, based solely on activation of iontotropic receptors, to levels that are inadequate to generate functionally meaningful muscle forces.     

Differential synaptic effects on physiological flexor hindlimb motoneurons from cutaneous nerve inputs in spinal cat.

1. We previously demonstrated in the spinal cat that superficial peroneal cutaneous nerve stimulation produced strong reflex contraction in tibialis anterior (TA) and semitendinosus (St) muscles but unexpectedly produced mixed effects in another physiological flexor muscle, extensor digitorum longus (EDL). The goal of the present study was to further characterize the organization of ipsilateral cutaneous reflexes by examining the postsynaptic potentials (PSPs) produced in St, TA, and EDL motoneurons by superficial peroneal and saphenous nerve stimulation in decerebrate, spinal cats. 2. In TA and St motoneurons, low-intensity cutaneous nerve stimulation that activated only large (A alpha) fibers [i.e., approximately 2-3 times threshold (T)], typically produced biphasic PSPs consisting of an initial excitatory phase and subsequent inhibitory phase (EPSP, IPSP). Increasing the stimulus intensity to activate both large (A alpha) and small (A delta) myelinated cutaneous fibers supramaximally (15-45 T) tended to enhance later excitatory components in TA and St motoneurons. 3. In EDL motoneurons, 2-3 T stimulation of the superficial peroneal nerve evoked initial inhibition (of variable magnitude) in 7/10 EDL motoneurons tested, with either excitation (n = 2) or mixed effects (n = 1) observed in the remaining EDL motoneurons. Saphenous nerve stimuli produced excitation either alone, or preceded by an inhibitory phase in EDL. Increasing the stimulus intensity enhanced later inhibitory influences from superficial peroneal and excitatory influences both from superficial peroneal and saphenous nerve inputs in EDL motoneurons. 4. Short-latency (less than 1.8 ms) EPSPs were observed in a few motoneurons in all reflex pathways examined, except for EPSPs in EDL motoneurons evoked by saphenous stimulation. IPSPs with central latencies less than 1.8 ms were also produced by both saphenous (TA, n = 1; EDL, n = 2) and superficial peroneal (EDL, n = 4) nerve stimulation. 5. The results, in comparison with other reports employing spinal and nonspinal preparations, suggest that removal of influences from higher centers reveals inhibitory circuits from the superficial peroneal and saphenous nerves to EDL motoneurons in the spinal preparation. The inhibitory inputs observed are thought to reflect the activation of "specialized" reflex pathways. Additionally, the demonstration of short-latency EPSPs and IPSPs suggest that the minimal linkage in both the excitatory and inhibitory cutaneous reflex pathways examined is disynaptic. The results are discussed in relation to previous studies on classically conditioned flexion reflex facilitation in spinal cat.     

Excitatory and inhibitory postsynaptic currents in a rat model of epileptogenic microgyria

Developmental cortical malformations are common in patients with intractable epilepsy; however, mechanisms contributing to this epileptogenesis are currently poorly understood. We previously characterized hyperexcitability in a rat model that mimics the histopathology of human 4-layered microgyria. Here we examined inhibitory and excitatory postsynaptic currents in this model to identify functional alterations that might contribute to epileptogenesis associated with microgyria. We recorded isolated whole cell excitatory postsynaptic currents and GABA(A) receptor-mediated inhibitory currents (EPSCs and IPSCs) from layer V pyramidal neurons in the region previously shown to be epileptogenic (paramicrogyral area) and in homotopic control cortex. Epileptiform-like activity could be evoked in 60% of paramicrogyral (PMG) cells by local stimulation. The peak conductance of both spontaneous and evoked IPSCs was significantly larger in all PMG cells compared with controls. This difference in amplitude was not present after blockade of ionotropic glutamatergic currents or for miniature (m)IPSCs, suggesting that it was due to the excitatory afferent activity driving inhibitory neurons. This conclusion was supported by the finding that glutamate receptor antagonist application resulted in a significantly greater reduction in spontaneous IPSC frequency in one PMG cell group (PMG(E)) compared with control cells. The frequency of both spontaneous and miniature EPSCs was significantly greater in all PMG cells, suggesting that pyramidal neurons adjacent to a microgyrus receive more excitatory input than do those in control cortex. These findings suggest that there is an increase in numbers of functional excitatory synapses on both interneurons and pyramidal cells in the PMG cortex perhaps due to hyperinnervation by cortical afferents originally destined for the microgyrus proper.     

Excitatory postsynaptic potentials evoked by ventral root stimulation in neonate rat motoneurons in vitro

1. Intracellular recordings were made from antidromically identified motoneurons in transverse (500 microns) lumbar spinal cord slices of neonatal (12-20 day) rats. 2. Electrical stimulation of ventral rootlets evoked, with or without an antidromic spike or initial segment potential, a depolarizing response (latency, 1-4.2 ms), a hyperpolarizing response (latency, 1.5-3.5 ms), or a combination of two preceding responses in 38, 6, and 8% of motoneurons investigated. 3. The hyperpolarizing response was reversibly eliminated by low Ca2+ (0.25 mM), d-tubocurarine (d-Tc; 10 microM) or strychnine (1 microM), suggesting that this response represents an inhibitory post-synaptic potential (IPSP) mediated by glycine or a related substance release from inhibitory interneurons subsequent to their activation by axon collaterals in a manner analogous to the Renshaw cell circuitry described for the cat motoneurons. 4. The depolarizing responses were excitatory postsynaptic potentials (EPSPs), because they could be graded by varying the stimulus intensity and were reversibly abolished in low Ca2+ solution. 5. Membrane hyperpolarization increased the amplitude of EPSPs, and the mean extrapolated reversal potential was -4 mV. 6. EPSPs were augmented, rather than diminished, by dihydro-beta-erythroidine (1 microM) or d-Tc, arguing against a role of recurrent motor axon collaterals in initiating the responses. 7. The conduction velocity of the fibers initiating the EPSPs ranged from 0.35 to 0.96 m/s, indicating that these fibers were unmyelinated. Furthermore, the EPSP exhibited a constant delay when the stimulus frequency was varied from 1 to 5 Hz, and the synaptic delay estimated by extrapolation was less than 1 ms, suggesting that it was a monosynaptic event. 8. After complete separation of the ventral and dorsal horns by a knife cut, stimulation of ventral rootlets could still evoke an EPSP in motoneurons. 9. Superfusion of the slices with the nonselective glutamate receptor antagonist kynurenic acid (0.2-1 mM) or the selective quisqualate/kainate receptor antagonist 6,7-dinitroquinoxaline-2,3-dione (DNQX) (0.5-1 microM) reversibly diminished the EPSPs. 10. EPSPs evoked by stimulation of dorsal and ventral rootlets exhibited different latency and waveform in the same motoneurons. 11. The results provide evidence that activation of ventral root afferents evoked an EPSP mediated by glutamate or a related substance in a population of motoneurons. Furthermore, the afferent pathway mediating the EPSP appears to be monosynaptic and confined to the ventral horn.     

Changes of intracellular sodium and potassium ion concentrations in frog spinal motoneurons induced by repetitive synaptic stimulation

A post-tetanic membrane hyperpolarization following repetitive neuronal activity is a commonly observed phenomenon in the isolated frog spinal cord as well as in neurons of other nervous tissues. We have now used double-barrelled Na⁺- and K⁺-ion-sensitive microelectrodes to measure the intracellular Na⁺- and K⁺-concentrations and also the extracellular K⁺-concentration of lumbar spinal motoneurons during and after repetitive stimulation of a dorsal root. The results show that the posttetanic membrane hyperpolarization occurred at a time when the intracellular [Na⁺] reached its maximal value, intracellular [K⁺] had its lowest level and extracellular [K⁺] was still elevated. The hyperpolarization was blocked by ouabain and reduced by Li⁺.These data support the previous suggestion that an electrogenic Na^+/K⁺ pump mode may be the mechanism underlying the post-tetanic membrane hyperpolarization.