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PubMed1987

Evidence for N-methyl-D-aspartic acid receptor-mediated modulation of the commissural input to central vestibular neurons of the frog.

We have investigated the role of N-methyl-D-aspartate (NMDA) receptors in the excitatory synaptic transmission to central vestibular neurons in the isolated superfused brainstem of the frog. In superfusate containing 1 mM Mg2+ field potentials in the vestibular nuclei evoked by electrical stimulation of either the ipsi- or the contralateral VIIIth nerve were not affected by bath-applied D-2-amino-5-phosphonovaleric acid (D-APV, 25-50 microM), a selective NMDA antagonist. In a low Mg2+ solution postsynaptic field potential components were larger than control but still unaffected by D-APV. Ipsi- and contralaterally evoked excitatory postsynaptic potentials (EPSPs) differed in their shape parameters as well as in their pharmacological sensitivity. Ipsilaterally evoked EPSPs were not affected by D-APV and has a rise time that was faster than that of contralaterally evoked EPSPs. The peak amplitude of hte latter was reduced by D-APV (25-50 microM) to about 65% of the control value in the presence of 1 mM Mg2+. During bath application of NMDA (100 microM) an increased input resistance and repetitive de- and hyperpolarizing membrane potential shifts were observed. Similar events were observed during a reduction of the Mg2+ concentration. Bath application of NMDA (0.1-1 microM) resulted in an enhanced size of the recorded EPSPs. Dendritic and somatic EPSPs were simulated on a computer with the assumption of a constant NMDA receptor activation and a pulse-like non-NMDA receptor activation. The results of these simulations are consistent with the hypothesis that the efficacy of non-NMDA-mediated vestibular commissural synaptic transmission is modulated through tonically activated NMDA receptors.

2-Amino-5-phosphonovalerate↗
PubMed2006

Volume changes in neurons: hyperexcitability and neuronal death.

Hyponatremia propitiates and increases susceptibility to seizure episodes. In vitro, hyposmolarity induces hyperexcitability and epileptiform activity and increases the amplitude of excitatory postsynaptic potentials. Synaptic (increased glutamate vesicular release) and non-synaptic (swelling-induced extracellular space shrinkage and ephaptic interactions) might be responsible for the hyposmolarity effects on brain excitability. Neuronal volume constancy in hyponatremia is preserved by the isovolumetric regulation, relying importantly on organic osmolytes. Changes in cell volume are closely linked to neuronal death: swelling characterizes necrotic death as in acute ischemic episodes or brain trauma, whereas volume decrease is typical of apoptotic death. Swelling in necrotic death results from the intracellular Na(+) increase followed by Cl(-) and water influx. Na(+) accumulation is due initially to the Na(+)/K(+)ATPase dysfunction and subsequently from the Na(+) influx through the overactivated ionotropic glutamate receptors. A second wave of swelling generates by excitotoxic derived formation of reactive oxygen species, membrane lipoperoxidation and further ion overload. Excessive swelling contributes to membrane rupture and release of cell debris, propagating the damage to adjacent cells. Apoptotic death is characterized by cell volume decrease termed apoptotic volume decrease, which in neurons seems to occur by mechanisms remarkably similar to those operating in the hyposmotic swelling-activated volume regulatory decrease, i.e. channel-mediated efflux of K(+) and Cl(-). A variety of K(+) channels and the volume-regulated anion channel participate in apoptotic volume decrease. K(+) has a protagonic role as an early element in neuronal apoptosis since a delayed rectifier K(+) current IK(DR) is enhanced by apoptosis prior to the caspase activation, increased extracellular K(+) and IK(DR) blockers attenuate apoptosis and intracellular K(+) loss through ionophores induces apoptosis. Volume-regulated anion channel participates as well in the Cl(-) efflux although its role and hierarchy in the apoptotic program are not well defined. Efflux of organic osmolytes, such as taurine participate as well in apoptotic volume decrease.

Animals↗
PubMed2005

Phase-response curves give the responses of neurons to transient inputs.

Neuronal firing is determined largely by incoming barrages of excitatory postsynaptic potentials (EPSPs), each of which produce a transient increase in firing probability. To measure the effects of weak transient inputs on firing probability of cortical neurons, we compute phase-response curves (PRCs). PRCs, whose shape can be related to the dynamics of spike generation, document the changes in timing of spikes caused by an EPSP in a repetitively firing neuron as a function of when it arrives in the interspike interval (ISI). The PRC can be exactly related to the poststimulus time histogram (PSTH) so that knowledge of one uniquely determines the other. Typically, PRCs have zero values at the start and end of the ISI, where EPSPs have minimal effects and a peak in the middle. Where the peak occurs depends in part on the firing properties of neurons. The PRC can have regions of positivity and negativity corresponding respectively to speeding up and slowing down the time of the next spike. A simple canonical model for spike generation is introduced that shows how both the background firing rate and the degree of postspike afterhyperpolarization contribute to the shape of the PRC and thus to the PSTH. PRCs in strongly adapting neurons are highly skewed to the right (indicating a higher change in probability when the EPSPs appear late in the ISI) and can have negative regions (indicating a decrease in firing probability) early in the ISI. The PRC becomes more skewed to the right as the firing rate decreases. Thus at low firing rates, the spikes are triggered preferentially by inputs that occur only during a small time interval late in the ISI. This implies that the neuron is more of a coincidence detector at low firing frequencies and more of an integrator at high frequencies. The steady-state theory is shown to also hold for slowly varying inputs.

Animals↗
PubMed1997

Assessment of the reliability or amplitude histograms from excitatory synapses in rat hippocampal CA1 in vitro.

1. Excitatory postsynaptic potentials (EPSPs) were evoked using minimal extracellular stimulation and recorded from pyramidal cells from the CA1 region of slices taken from adult rats and maintained in vitro. 2. Segments of data were selected that gave EPSP amplitude frequency histograms that showed approximately equally spaced peaks. Selection was performed either on the basis of stationarity of the EPSP mean and standard deviation, or on the trajectory of a graph of the (coefficient of variation)-2 against mean for the EPSP, or, in some cases, by trial and error. 3. For each histogram, we determined the likelihood that peaks of similar sharpness and equality of spacing could have arisen by sampling artifact from a smooth distribution, using a method based on autocorrelation and Monte Carlo simulation. 4. Thirty-three histograms were analysed. For twenty-six of these, the likelihood of sampling artifact was estimated at 1 in 100 or less, and for eleven histograms the likelihood was less than 1 in 1000. For the histogram with the clearest peaks, the likelihood was less than 1 in 350,000. Histograms judged to be reliable by this method could occur when the EPSP mean amplitude was changing. 5. We conclude that random sampling artifact is very unlikely to be the explanation for the peaks in our data histograms. It seems more likely that they are due to a quantal synaptic transmission mechanism with low quantal variability. 6. The autocorrelation method also gives a measure of the mean peak spacing, and hence the mean quantal size, for each histogram. Quantal sizes ranged from 93 to 285 microV, with a mean +/- S.D. of 172 +/- 47 microV. 7. From these quantal sizes and the EPSP mean amplitudes we calculated the mean number of quanta released per trial for each histogram. This ranged from 0.36 to 6.9, with a mean of 3.3 +/- 1.67.

Animals↗
PubMed2002

Developmental changes in short-term synaptic depression in the neonatal mouse spinal cord.

We examined age-dependent changes in short-term synaptic depression of monosynaptic excitatory postsynaptic potentials (EPSPs) recorded in lumbar motoneurons in hemisected spinal cords of neonatal Swiss-Webster mice between postnatal day 2 (P2) and 12 (P12). We used four paradigms that sample the input-output dependence on stimulation history in different but complementary ways: 1) paired-pulse depression; 2) steady-state depression during constant frequency trains; 3) modulation during irregular stimulation sequences; and 4) recovery after high-frequency conditioning trains. Paired-pulse synaptic depression declined more than steady-state depression during 10-pulse trains at frequencies from 0.125 to 8 Hz in this age range. Depression during sequences of irregular stimulations that more closely mimic physiological activation also declined with postnatal age. On the other hand, the overall rate of synaptic recovery after a 4-Hz conditioning train exhibited surprisingly little change between P2 and P12. Control experiments indicated that these observations depend primarily, if not exclusively, on changes in presynaptic transmitter release. The data were examined using quantitative models that incorporate factors that have been suggested to exist at more specialized central synapses. The model that best predicted the observations included two presynaptic compartments that are depleted during activation, plus two superimposed processes that enhance transmitter release by different mechanisms. One of the latter produced rapidly-decaying enhancement of transmitter release fraction. The other mechanism indirectly enhanced the rate of renewal of one of the depleted presynaptic compartments. This model successfully predicted the constant frequency and irregular sequence data from all age groups, as well as the recovery curves following short, high-frequency tetani. The results suggest that a reduction in release fraction accounts for much of the decline in synaptic depression during early postnatal development, although changes in both enhancement processes also contribute. The time constants of resource renewal showed surprisingly little change through the first 12 days of postnatal life.

Aging↗
PubMed2004

Contribution of Ih and GABAB to synaptically induced afterhyperpolarizations in CA1: a brake on the NMDA response.

CA1 pyramidal cells receive two major excitatory inputs: the perforant path (PP) terminates in the most distal dendrites, whereas the Schaffer collaterals (SC) terminate more proximally. We have examined the mechanism of the afterhyperpolarization (AHP) that follows single subthreshold excitatory postsynaptic potentials (EPSPs) in these inputs. The AHPs were not reduced by a GABAA antagonist or by agents that block Ca2+ entry. Application of the Ih blocker, ZD7288, partially blocked the AHP in the PP; the substantial remaining component was blocked by 2-hydroxysaclofen, a GABAB antagonist. In contrast, the AHP in the SC depends nearly completely on Ih, with almost no GABAB component. Thus postsynaptic GABAB receptors appear to be preferentially involved at distal synapses, consistent with the spatial distribution of GABAB receptors and g protein-coupled inward rectifying potassium (GIRK) channels. GABAB does, however, play a role at proximal synapses through presynaptic suppression of glutamate release, a mechanism that is much weaker at distal synapses. Experiments were conducted to explore the functional role of the AHP in the PP, which has a higher N-methyl-D-aspartate (NMDA)/AMPA ratio than the SC. Blockade of the AHP converted a response that had a small NMDA component to one that had a large component. These results indicate that the Ih and postsynaptic GABAB conductances act as a brake on distally generated NMDA responses.

Animals↗
PubMed2005

Hidden function of neuronal nicotinic acetylcholine receptor beta2 subunits in ganglionic transmission: comparison to alpha5 and beta4 subunits.

Neuronal nicotinic acetylcholine receptors (nAChR), which modulate fast excitatory postsynaptic potentials (f-EPSP), are located on both pre- and postganglionic sites in the autonomic nervous system (ANS). The receptor subunits alpha3, alpha5, alpha7, beta2 and beta4 are present in autonomic ganglia in various combinations and modulate acetylcholine (ACh) transmission. In the present study, autonomic functions were systemically examined in mice lacking beta2 subunits (beta2-/-) to further understand the functional role of beta2 subunits in modulating ganglionic transmission. The results show normal autonomic functions, both under physiological conditions and in perturbed conditions, on thermoregulation, pupillary size, heart rate responses and ileal contractile reactions. This suggests that the function of beta2-containing receptors in ganglionic transmission is hidden by the predominant beta4 containing receptors and confirms previous studies which suggest that alpha3alpha5beta4 nAChRs are sufficient for autonomic transmission. On the other hand, beta2-containing receptors have only a minor function on postsynaptic responses to ACh, but may modulate ACh release presynaptically, although there is no evidence for this.

Acetylcholine↗
PubMed2006

Synaptic transmission changes in the pyramidal cells of the hippocampus in streptozotocin-induced diabetes mellitus in rats.

The central nervous system complications of diabetes mellitus (DM) include defects in hippocampal synaptic plasticity induction and difficulties in learning and memory. DM was induced by streptozotocin (STZ) injection in rats. After 12 weeks of DM duration, the rats were decapitated, and hippocampal slices were prepared for in vitro study. Field excitatory postsynaptic potentials (fEPSP) were recorded after repeated stimulations with 50 impulses given either in 10 or 20 Hz. The responses were significantly smaller in the diabetic animals than in the age-matched control rats. The summation of alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA) responses was tested in both groups by stimulating the synapses with five consecutive stimuli given in 50-Hz frequency. Intracellular recording from the pyramidal hippocampal cells of the AMPA summation responses from diabetic and aged-matched control animals revealed a significant lower summation in the diabetic animals compared to the control. It is concluded that responses evoked by high-frequency stimulation (HFS) were significantly higher in the control animals. The defects in diabetic slices could be related to pre- as well as postsynaptic changes, and these defects play an important role in the synaptic plasticity changes seen in STZ-induced diabetic animals.

2-Amino-5-phosphonovalerate↗
PubMed1998

Postsynaptic pyramidal target selection by descending layer III pyramidal axons: dual intracellular recordings and biocytin filling in slices of rat neocortex.

Paired intracellular recordings in slices of adult rat neocortex with biocytin filling of synaptically connected neurons were used to investigate the pyramidal targets, in layer V, of layer III pyramidal axons. The time-course and sensitivity of excitatory postsynaptic potentials to current injected at the soma, and locations of close appositions between presynaptic axons and postsynaptic dendrites, indicated that the majority of contributory synapses were located in layer V. Within a "column" of tissue, radius < or = 250 microm, the probability that a randomly selected layer III pyramid innervated a layer V pyramid was 1 in 4 if the target cell was a burst firing pyramid with an apical dendritic tuft in layers II/I. If, however, the potential target was a regular spiking pyramid, the probability of connectivity was only 1 in 40, and none of the 13 anatomically identified postsynaptic layer V targets had a slender apical dendrite terminating in layers IV/III. Morphological reconstructions indicated that layer III pyramids select target layer V cells whose apical dendrites pass within 50-100 microm of the soma of the presynaptic pyramid in layer III and which have overlapping apical dendritic tufts in the superficial layers. The probability that a layer V cell would innervate a layer III pyramid lying within 250 microm of its apical dendrite was much lower (one in 58). Both presynaptic layer III pyramids and their large postsynaptic layer V targets could therefore access similar inputs in layers I/II, while small layer V pyramids could not. One prediction from the present data would be that neither descending layer V inputs to the striatum or thalamus, nor transcallosal connections would be readily activated by longer distance cortico-cortical "feedback" connections that terminated in layers I/II. These could, however, activate corticofugal pathways to the superior colliculus or pons, both directly and via layer III.

Animals↗
PubMed2003

Synaptic strength between motoneurons and terminals of the dorsolateral funiculus is regulated by GABA receptors in the turtle spinal cord.

The role of GABAA and GABAB receptors in modulation of excitatory synaptic transmission between motoneurons and terminals from dorsolateral funiculus (DLF) was studied in in vitro spinal cord slices of adult turtles. Muscimol--a GABAA receptor agonist--depressed the monosynaptic excitatory postsynaptic potential (EPSP) induced by stimulation of the DLF and shortened its duration. The input resistance and the membrane time constant also were strongly reduced. The input membrane resistance, the amplitude, and the half-width of the EPSP were reduced at the same rate in the presence of muscimol. Bicuculline--a GABAA receptor antagonist--increased the EPSPs amplitude and the input membrane resistance. The EPSP amplitude ratio elicited by a paired-pulse protocol did not change significantly. Our results suggest that muscimol acts mainly by activation of postsynaptic GABAA receptors located on the motoneuron and the synaptic strength on motoneurons may be modulated by tonic activation of postsynaptic GABAA receptors. Baclofen--a GABAB receptor agonist--also depressed DLF-motoneuron synaptic transmission. However, it did not affect the falling phase of the EPSPs or the motoneuron membrane time constant but induced a small decrement in input resistance. In the presence of baclofen, the amplitude ratio produced by a paired-pulse protocol increased significantly. This suggests that baclofen decreased the synaptic strength by inhibition of neurotransmitter release from the DLF terminals via activation of presynaptic GABAB receptors.

Animals↗
PubMed2004

Caffeine-dependent stimulus-triggered oscillations in the CA3 region of hippocampal slices from rats chronically exposed to lead.

Yoshimura et al. [Yoshimura, H., Sugai, T., Onoda, N., Segami, N., Kato, N., 2002. Age-dependent occurrence of synchronized population oscillation suggestive of a developing functional coupling between NMDA and ryanodine receptors in the neocortex. Dev. Brain Res., 136, 63-68.] have shown that caffeine can elicit synchronized oscillations (10-12 Hz) dependent on calcium-induced calcium release in rat neocortex neurons. In the present work, synchronized oscillations in the CA3 region of rat hippocampus were studied by recording field excitatory postsynaptic potentials (fEPSPs) in vitro. In the presence of 0.1 mM caffeine, in CA3 of 44 of 45 (97.8%) slices from chronic lead-exposed rats, single electrical stimuli triggered a burst of high-frequency oscillations (approximately 230 Hz), whereas in CA3 of caffeine-treated slices from control rats, such oscillations could be elicited in only 2 of 24 (8.3%) slices. The complete (but fully reversible) block of caffeine-dependent oscillations by 6-cyano-7-nitro-quinoxaline-2,3-dione (CNQX; 20 microM) indicates that alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionate (AMPA) receptors are necessary for the high-frequency synchronized oscillations. 2-Amino-5-phosphonopentanoate (AP-5; 50 micoM) partially reduced the amplitude of caffeine-dependent oscillations without significantly altering their frequency. Caffeine-dependent oscillations could be abolished by application of AP-5 and 3 mM Mg2+ during the initial period of bursting, indicating that N-methyl-D-aspartate (NMDA) receptors play an important role in the generation of oscillations. The Ca2+ chelator ethylene glycol bis-(beta-aminoethyl ether)-N,N,N',N'-tetraacetic acid (EGTA; 5 mM) added in standard artificial cerebrospinal fluid (ACSF) containing 0.1 mM caffeine fully blocked the oscillations. Caffeine-dependent oscillations are insensitive to an antagonist of gamma-aminobutyric acid (GABAA) receptors (10 microM bicuculline), L-type Ca2+ channels (10 muM nicardipine), L-type and N-type voltage-dependent calcium channels (100 microM Cd2)), and T-type Ca2+ channels (100 microM Ni2+). Previous studies have demonstrated that expression and function of NMDA and AMPA receptors are altered in the hippocampus of chronic lead-exposed rats. We propose that caffeine-dependent stimulus-induced oscillations in CA3 area of hippocampus from chronic lead-exposed rats are mainly mediated by the entry of extracellular Ca2+ through NMDA and non-NMDA receptors, without participation of GABAA receptors. Additionally, the underlying mechanisms are also discussed.

Animals↗
PubMed1998

Endogenous serotonin inhibits epileptiform activity in rat hippocampal CA1 neurons via 5-hydroxytryptamine1A receptor activation.

The modulatory effects of endogenous serotonin on the synaptic transmission and epileptiform activity were studied in the rat hippocampus with the use of extracellular and intracellular recording techniques. Field excitatory postsynaptic potential was reversibly depressed by serotonin in a concentration-dependent manner. Intracellular recordings revealed that serotonin-mediated synaptic depression was unaffected by extracellular Ba2+ or intracellular application of Cs+ while the postsynaptic hyperpolarizing effect was completely blocked. Epileptiform activity induced by picrotoxin (50 microM), a GABA(A) receptor antagonist, was also dose-dependently suppressed by serotonin. The antiepileptic effect was mimicked by 5-hydroxytryptamine1A agonist and was blocked by 5-hydroxytryptamine1A antagonists. 5-Hydroxytryptamine2 antagonist had no effect on the modulation. Similarly, fluoxetine, a selective serotonin re-uptake blocker, potently inhibited the epileptiform activity and this effect was blocked by 5-hydroxytryptamine1A receptor antagonist. Depletion of endogenous serotonin by pretreating the slices with p-chloroamphetamine completely prevented the antiepileptic action of fluoxetine, without modifying the action of serotonin in the same cells. These results suggest that the antiepileptic action of fluoxetine is due to an enhancement of endogenous serotonin which in turn is mediated by 5-hydroxytryptamine1A receptor. Endogenous serotonin transmission in the hippocampus is therefore capable of limiting the development and propagation of seizure activity.

8-Hydroxy-2-(di-n-propylamino)tetralin↗
PubMed2001

A correlative physiological and morphological analysis of monosynaptically connected propriospinal axon-motoneuron pairs in the lumbar spinal cord of frogs.

Intracellular stimulation of single propriospinal axons evoked excitatory postsynaptic potentials (EPSPs) in lumbar motoneurons. Mean EPSP amplitudes differed by two orders of magnitude when measured in different connections. After analyzing the distribution of mean amplitudes of 47 single-fiber EPSPs, two populations of responses could be defined: (1) those with mean amplitudes between 0.1 and 1.2 mV (mean+/-S.D.: 0.48+/-0.30 mV, 34 pairs), which is in the range of values typical for single-fiber EPSPs evoked by stimulation of supraspinal fibers and primary muscle afferents, (2) those with mean amplitudes between 1.6 and 8 mV (4.2+/-2.0 mV, 13 pairs). Both populations of responses had similarly short latencies and rise times and responded similarly to paired-pulse stimulation, consistent with monosynaptic transmission. However, the high-efficacy connections had significantly smaller coefficients of variation of EPSPs, as well as increased quantal content and quantal size. Tetanic stimulation gradually depressed the amplitude of large EPSPs by 81-86%, but did not affect small EPSPs. Recovery of large EPSPs was exponential with a time constant of 3-5.6 min. During post-tetanic depression the amplitude ratio between the test and conditioned EPSPs evoked by paired-pulse stimulation was not changed but the coefficient of variation was increased, suggesting that the depression was due to depletion of synaptic vesicles available for release.Intracellular labeling of seven electrophysiologically studied propriospinal axon-motoneuron pairs revealed that the number of axon varicosities establishing close appositions with dendrites of the labeled motoneuron was higher for connections where large-amplitude EPSPs were recorded. These varicosities were more often located on proximal dendrites of motoneurons than those of low-efficacy connections. In addition, the number of boutons in highly effective connections was several times lower than the maximal number of available quanta estimated from physiological data, implying that the large EPSPs may be generated by multivesicular release from presynaptic boutons. We conclude that the efficacy and related mode of use-dependent modulation of propriospinal connections is determined by a number of factors, including the number and position of synaptic contacts and the number of active zones or vesicles available for release.

Animals↗
PubMed1997

Quantal analysis of excitatory synapses in rat hippocampal CA1 in vitro during low-frequency depression.

1. We have performed a detailed quantal analysis of excitatory postsynaptic potentials (EPSPs) evoked by minimal extracellular stimulation in the CA1 region of slices of adult rat hippocampus maintained in vitro. 2. EPSPs were evoked at 2-5 Hz, and the eight that were analysed all showed at least a 50% depression of mean peak amplitude during recording. 3. EPSP amplitude fluctuations were analysed by three methods: the use of amplitude frequency histograms with clear and reliable peaks where available, graphs of the EPSP (coefficient of variation)-2 against EPSP mean, and analysis of EPSP mean and standard deviation assuming simple binomial statistics with the number of release sites (N) kept constant but the quantal size (Q) and the release probability (Pr) allowed to vary over time. 4. The results of the three analysis procedures were in good agreement. Seven EPSPs showed a substantial reduction in the mean number of quanta released per trial, and in three cases this was the predominant mechanism of the depression. Five EPSPs showed a substantial decrease in Q. Values for N ranged between 3 and 18, with a median of 6; Pr ranged between 0.14 and 0.81 and Q between 66 and 275 microV. 5. We used the Q estimates from the binomial method to correct the recorded EPSP amplitudes for changes in quantal size over time. For seven out of the eight EPSPs, this rescaling procedure allowed histograms with clear peaks to be obtained from longer runs of data, or improved the sharpness of the peaks in histograms from all the recorded data. The improvement in peak sharpness was assessed using an autocorrelation-based method. The correction was much less successful if the Q estimates were obtained with a variant of the binomial method in which Pr was held constant and N was allowed to vary. 6. The only simple explanation for the success of the correction procedure is that changes in quantal size were a major factor in obscuring peaks in histograms based on large numbers of trials, and that the quantal size estimates from the binomial method with N held constant were reasonably accurate. 7. We conclude that transmission at these synapses was quantal with relatively low quantal variance, but repetitive stimulation often induced substantial changes in the quantal parameters that might prevent the success of conventional quantal analysis approaches.

Animals↗
PubMed2002

Patterns of canal and otolith afferent input convergence in frog second-order vestibular neurons.

Second-order vestibular neurons (2 degrees VN) were identified in the isolated frog brain by the presence of monosynaptic excitatory postsynaptic potentials (EPSPs) after separate electrical stimulation of individual vestibular nerve branches. Combinations of one macular and the three semicircular canal nerve branches or combinations of two macular nerve branches were stimulated separately in different sets of experiments. Monosynaptic EPSPs evoked from the utricle or from the lagena converged with monosynaptic EPSPs from one of the three semicircular canal organs in ~30% of 2 degrees VN. Utricular afferent signals converged predominantly with horizontal canal afferent signals (74%), and lagenar afferent signals converged with anterior vertical (63%) or posterior vertical (37%) but not with horizontal canal afferent signals. This convergence pattern correlates with the coactivation of particular combinations of canal and otolith organs during natural head movements. A convergence of afferent saccular and canal signals was restricted to very few 2 degrees VN (3%). In contrast to the considerable number of 2 degrees VN that received an afferent input from the utricle or the lagena as well as from one of the three canal nerves (~30%), smaller numbers of 2 degrees VN (14% of each type of 2 degrees otolith or 2 degrees canal neuron) received an afferent input from only one particular otolith organ or from only one particular semicircular canal organ. Even fewer 2 degrees VN received an afferent input from more than one semicircular canal or from more than one otolith nerve (~7% each). Among 2 degrees VN with afferent inputs from more than one otolith nerve, an afferent saccular nerve input was particularly rare (4-5%). The restricted convergence of afferent saccular inputs with other afferent otolith or canal inputs as well as the termination pattern of saccular afferent fibers are compatible with a substrate vibration sensitivity of this otolith organ in frog. The ascending and/or descending projections of identified 2 degrees VN were determined by the presence of antidromic spikes. 2 degrees VN mediating afferent utricular and/or semicircular canal nerve signals had ascending and/or descending axons. 2 degrees VN mediating afferent lagenar or saccular nerve signals had descending but no ascending axons. The latter result is consistent with the absence of short-latency macular signals on extraocular motoneurons during vertical linear acceleration. Comparison of data from frog and cat demonstrated the presence of a similar organization pattern of maculo- and canal-ocular reflexes in both species.

Animals↗
PubMed1999

alpha-latrocrustatoxin increases neurotransmitter release by activating a calcium influx pathway at crayfish neuromuscular junction.

alpha-latrocrustatoxin (alpha-LCTX), a component of black widow spider venom (BWSV), produced a 50-fold increase in the frequency of spontaneously occurring miniature excitatory postsynaptic potentials (mEPSPs) at crayfish neuromuscular junctions but did not alter their amplitude distribution. During toxin action, periods of high-frequency mEPSP discharge were punctuated by periods in which mEPSP frequency returned toward control levels. EPSPs were increased in amplitude during periods of enhanced mEPSP discharge. alpha-LCTX had no effect when applied in Ca(2+)-free saline, but subsequent addition of Ca(2+) caused an immediate enhancement of mEPSP frequency even when alpha-LCTX was previously washed out of the bath with Ca(2+)-free saline. Furthermore removal of Ca(2+) from the saline after alpha-LCTX had elicited an effect immediately blocked the action on mEPSP frequency. Thus alpha-LCTX binding is insensitive to Ca(2+), but toxin action requires extracellular Ca(2+) ions. Preincubation with wheat germ agglutinin prevented the effect of alpha-LCTX but not its binding. These binding characteristics suggest that the toxin may bind to a crustacean homologue of latrophilin/calcium-independent receptor for latrotoxin, a G-protein-coupled receptor for alpha-latrotoxin (alpha-LTX) found in vertebrates. alpha-LCTX caused "prefacilitation" of EPSP amplitudes, i.e., the first EPSP in a train was enhanced in amplitude to a greater degree than subsequent EPSPs. A similar alteration in the pattern of facilitation was observed after application of the Ca(2+) ionophore, A23187, indicating that influx of Ca(2+) may mediate the action of alpha-LCTX. In nerve terminals filled with the Ca(2+) indicator, calcium green 1, alpha-LCTX caused increases in the fluorescence of the indicator that lasted for several minutes before returning to rest. Neither fluorescence changes nor toxin action on mEPSP frequency were affected by the Ca(2+) channel blockers omega-agatoxin IVA or Cd(2+), demonstrating that Ca(2+) influx does not occur via Ca(2+) channels normally coupled to transmitter release in this preparation. The actions of alpha-LCTX could be reduced dramatically by intracellular application of the Ca(2+) chelator, bis-(o-aminophenoxy)-N,N,N', N'-tetraacetic acid. We conclude that induction of extracellular Ca(2+) influx into nerve terminals is sufficient to explain the action of alpha-LCTX on both spontaneous and evoked transmitter release at crayfish neuromuscular junctions.

Animals↗
PubMed2003

Involvement of intracellular calcium and protein phosphatases in long-term depression of A-fiber-mediated primary afferent neurotransmission.

Long-term depression (LTD) of monosynaptic and polysynaptic excitatory postsynaptic potentials (EPSPs) in substantia gelatinosa (SG) neurons can be induced by brief high-frequency electrical stimulation (HFS, 300 pulses at 100 Hz) of primary afferent fibers in dorsal roots. Here we examined the possible cellular mechanism underlying spinal LTD. Conventional intracellular recordings were made from SG neurons in a transverse slice-dorsal root preparation of the young rat lumbar spinal cord. LTD of both monosynaptic and polysynaptic EPSPs was induced in 16 of 24 SG neurons by HFS of dorsal root in either the presence or absence of the GABA(A) receptor antagonist bicuculline and the glycine receptor antagonist strychnine. Loading the postsynaptic cell with BAPTA, an intracellular Ca(2+) chelator, almost completely blocked the induction of LTD. Induction of LTD was abolished by bath application of calyculin A (100 nM), a potent inhibitor of protein phosphatases 1 and 2A. These results indicate that: (i) a rise in postsynaptic Ca(2+) is necessary for LTD induction, (ii) synaptic activation of protein phosphatases 1 and 2A plays an important role in the induction of LTD of primary afferent A-fiber neurotransmission in the young rat spinal cord, and (iii) the effect of LTD may be physiologically relevant for transmission and integration of sensory information, including nociception.

Animals↗
PubMed2001

Short-term synaptic depression in the neonatal mouse spinal cord: effects of calcium and temperature.

We have studied short-term synaptic depression of excitatory postsynaptic potentials (EPSPs) in lumbosacral motoneurons in the isolated, in vitro spinal cord of neonatal mice at 2-4 days postnatal age. We used 2-amino-5-phosphonovaleric acid (AP5; 100 microM) to suppress spontaneous and stimulus-evoked polysynaptic activity. Monosynaptic EPSPs were generated by trains of 10 pulses stimuli delivered to a dorsal root at eight frequencies between 0.125 and 16 Hz. The amplitudes of the second (R2), third (R3), and the average of R8, R9, and R10 (tail) EPSPs, normalized by the first EPSP (R1), defined the shapes of synaptic depression curves. Tail responses were increasingly depressed as stimulation frequency increased but R2 and R3 exhibited relative facilitation at frequencies >1 Hz. Control experiments indicated that the depression curves were not explained by presynaptic activation failure. Lowering external Ca(2+) concentration ([Ca(2+)](o)) from 2.0 to 0.8 mM without changing [Mg(2+)](o) reduced average R1 amplitudes and R2 depression with little change in tail depression. Conversely, increasing [Ca(2+)](o) to 4.0 mM increased average R1 amplitude and R2 depression but again did not change tail depression. Increasing the bath temperature from 24 to 32 degrees C produced little change in R1 amplitudes but markedly reduced the depression of all responses at most frequencies. We developed an empirical model, based on mechanisms described in more accessible synaptic systems, that assumes: transmitter is released from a constant fraction, f, of release-ready elements in two presynaptic compartments (N and S) that are subsequently renewed by independent processes with exponential time constants (tau(N) and tau(S)); an activation-dependent facilitation of transmitter release with constant increment and fast exponential decay; and a more slowly decaying, activation-dependent augmentation of the rate of renewal (tau(N)) of N. The model gave satisfactory fits to data from all [Ca(2+)](o) conditions and implied that f and the increments of the facilitation and augmentation processes were all changed in the same direction as [Ca(2+)](o), without changing the time constants. In contrast, model fits to the 32 degrees C data implied that the process time constants all decreased by 40-45% while the presumably Ca(2+)-related weighting factors were unchanged. The model also successfully matched the normalized amplitudes of EPSPs during trains with irregular intervals.

2-Amino-5-phosphonovalerate↗