Location-dependent excitatory synaptic interactions in pyramidal neuron dendrites

Neocortical pyramidal neurons (PNs) receive thousands of excitatory synaptic contacts on their basal dendrites. Some act as classical driver inputs while others are thought to modulate PN responses based on sensory or behavioral context, but the biophysical mechanisms that mediate classical-contextual interactions in these dendrites remain poorly understood. We hypothesized that if two excitatory pathways bias their synaptic projections towards proximal vs. distal ends of the basal branches, the very different local spike thresholds and attenuation factors for inputs near and far from the soma might provide the basis for a classical-contextual functional asymmetry. Supporting this possibility, we found both in compartmental models and electrophysiological recordings in brain slices that the responses of basal dendrites to spatially separated inputs are indeed strongly asymmetric. Distal excitation lowers the local spike threshold for more proximal inputs, while having little effect on peak responses at the soma. In contrast, proximal excitation lowers the threshold, but also substantially increases the gain of distally-driven responses. Our findings support the view that PN basal dendrites possess significant analog computing capabilities, and suggest that the diverse forms of nonlinear response modulation seen in the neocortex, including uni-modal, cross-modal, and attentional effects, could depend in part on pathway-specific biases in the spatial distribution of excitatory synaptic contacts onto PN basal dendritic arbors.     

Inactivation of calcium currents in the molluscan neuron somatic membrane

The time course of weakening of inward calcium currents (inactivation) during prolonged (of the order of 1 sec) depolarizing shifts of membrane potential was studied in isolated dialyzed neurons of snailHelix pomatia. This decay of the current recorded in this way can be approximated by two exponential functions with time constants of 20–70 and 250–350 msec, respectively. With an increase in pH of the intracellular solution to 8.5 the fast component of the decay disappeared completely; the kinetics of the slow component in this case was very slightly retarded. It is concluded that the fast component of decay of the recorded current does not reflect a change in the calcium current but is due to parallel activation of the nonspecific outward current; the slow component, however, is true in activation of the calcium current. The rate of inactivation of this current was shown to be determined by its maximal value and not by the level of the depolarizing potential shift and it depends on the conditions of accumulation of calcium ions near the inner surface of the membrane.A. A. Bogomolets Institute of Physiology, Academy of Sciences of the Ukrainian SSR, Kiev. Translated from Neirofiziologiya, Vol. 14, No. 5, pp. 525–531, September–October, 1982.     

Study of neuronal gain in a conductance-based leaky integrate-and-fire neuron model with balanced excitatory and inhibitory synaptic input

Neurons receive a continual stream of excitatory and inhibitory synaptic inputs. A conductance-based neuron model is used to investigate how the balanced component of this input modulates the amplitude of neuronal responses. The output spiking rate is well described by a formula involving three parameters: the mean and variance of the membrane potential and the effective membrane time constant _Q. This expression shows that, for sufficiently small _Q, the level of balanced excitatory-inhibitory input has a nonlinear modulatory effect on the neuronal gain.     

Long-lasting potentiation of excitatory synaptic signaling to the crayfish lateral giant neuron

The neural circuit that underlies the lateral giant fiber (LG)-mediated reflex escape in crayfish has provided findings relating synaptic change to nonassociative learning such as sensitization and habituation. The LGs receive sensory inputs from the primary sensory afferents and a group of mechanosensory interneurons (MSIs). An increase of excitability by suprathreshold repetitive excitation of this circuit, which is similar to Hebbian long-term potentiation (LTP), has been reported [Miller et al. (1987) J Neurosci 7:1081]. This potentiation was previously thought to result from the enhancement of transmission at cholinergic synapses between primary afferents and MSIs but not the electrical synapses onto LG. In this study, we found that potentiation of synaptic signaling at the electrical synapse onto LG can also be induced when the synapse was activated with subthreshold repetitive pulses or with a few strong suprathreshold shocks. LG LTP was induced in the preparation which had received pulses at limited frequency range. Although whether this LTP is involved in the learning process of escape behavior in crayfish is not clear, the intensity and amount of sensory stimulation used here mimicked those that could easily be produced by a predator trying to catch a crayfish and could be of adaptive significance in life.     

Signal integration on the dendrites of a pyramidal neuron model

This paper studied the synaptic and dendritic integration with different spatial distributions of synapses on the dendrites of a biophysically-detailed layer 5 pyramidal neuron model. It has been observed that temporally synchronous and spatially clustered synaptic inputs make dendrites perform a highly nonlinear integration. The effect of clustering degree of synaptic distribution on neuronal responsiveness is investigated by changing the number of top apical dendrites where active synapses are allocated. The neuron shows maximum responsiveness to synaptic inputs which have an intermediate clustering degree of spatial distribution, indicating complex interactions among dendrites with the existence of nonlinear synaptic and dendritic integrations.     

Miniature excitatory synaptic ion currents in the earthworm Lumbricus terrestris body wall muscles

The miniature excitatory postsynaptic currents (MEPCs) of the muscle cells of the earthworm Lumbricus terrestris were recorded by glass microelectrodes. In a single synaptic zone, three types of MEPC were recorded: a fast single-exponential type that decayed with tau =0.9 ms, a slow single-exponential with tau = 9.2 ms and a two-exponential MEPC with tau = 1.3 and 8.5 ms, respectively. The muscle cells of earthworms contain populations of yet-unidentified ionic channels that might be different from the common nicotinic and muscarinic groups of acetylcholine receptors, since these MEPCs are not sensitive to d-tubocurarine, atropine, benzohexonium or proserine. Alternatively, besides ACh receptors, the membrane may contain receptors for another yet-unidentified excitatory transmitter.     

Presynaptic inhibition of miniature excitatory synaptic currents by baclofen and adenosine in the hippocampus.

Presynaptic inhibition of neurotransmitter release is thought to be mediated by a reduction of axon terminal Ca2+ current. We have compared the actions of several known inhibitors of evoked glutamate release with the actions of the Ca2+ channel antagonist Cd2+ on action potential-independent synaptic currents recorded from CA3 neurons in hippocampal slice cultures. Baclofen and adenosine decreased the frequency of miniature excitatory postsynaptic currents (mEPSCs) without affecting the distribution of their amplitudes. Cd2+ blocked evoked synaptic transmission, but had no effect on the frequency or amplitude of either mEPSCs or inhibitory postsynaptic currents (IPSCs). Inhibition of presynaptic Ca2+ current therefore appears not to be required for the inhibition of glutamate release by adenosine and baclofen. Baclofen had no effect on the frequency of miniature IPSCs, indicating that gamma-aminobutyric acid B-type receptors exert distinct presynaptic actions at excitatory and inhibitory synapses.     

Voltage clamp study of fast excitatory synaptic currents in bullfrog sympathetic ganglion cells

Excitatory postsynaptic currents (EPSCs) have been studied in voltage- clamped bullfrog sympathetic ganglion B cells. The EPSC was small, rose to a peak within 1-3 ms, and then decayed exponentially over most of its time-course. For 36 cells at --50 mV (21-23 degrees C), peak EPSC size was --6.5 +/- 3.5 nA (mean +/- SD), and the mean decay time constant tau was 5.3 +/- 0.9 ms. tau showed a small negative voltage dependence, which appeared independent of temperature, over the range -- 90 to --30 mV; the coefficient of voltage dependence was --0.0039 +/- 0.0014 mV-1 (n = 29). The peak current-voltage relationship was linear between --120 and --30 mV but often deviated from linearity at more positive potentials. The reversal potential determined by interpolation was approximately --5 mV. EPSC decay tau had a Q10 = 3. The commonly used cholinesterase inhibitors, neostigmine and physostigmine, exhibited complex actions at the ganglia. Neostigmine (1 X 10(-5)M) produced a time-dependent slowing of EPSC decay without consistent change in EPSC size. In addition, the decay phase often deviated from a single exponential function, although it retained its negative voltage dependence. With 1 x 10(-6) M physostigmine, EPSC decay was slowed by the decay phase remained exponential. At higher concentrations of physostigmine, EPSC decay was markedly prolonged and was composed of at least two decay components. High concentrations of atropine (10(-5) to 10(-4) M) produced complex alterations in EPSC decay, creating two or more exponential components; one decay component was faster and the other was slower than that observed in untreated cells. These results suggest that the time-course of ganglionic EPSC decay is primarily determined by the kinetics of the receptor-channel complex rather than hydrolysis or diffusion of transmitter away from the postsynaptic receptors.     

Activation and desensitization of glutamate-activated channels mediating fast excitatory synaptic currents in the visual cortex.

Brief glutamate applications to membrane patches, excised from neurons in the rat visual cortex, were used to assess the role of desensitization in determining the AMPA/kainate receptor-mediated excitatory postsynaptic current (EPSC) time course. A brief (1 ms) application of glutamate (1-10 mM) produced a response that mimicked the time course of miniature EPSCs (mEPSCs). Direct evidence is presented that the rate of onset of desensitization is much slower than the decay rate of the response to a brief application of glutamate, implying that the decay of mEPSCs reflects channel closure into a state readily available for reactivation. Rapid application of glutamate combined with nonstationary variance analysis provided an estimate of the single-channel conductance and open probability, allowing an approximation of the number of available channels at a single synaptic site.     

Mechanisms generating the time course of dual component excitatory synaptic currents recorded in hippocampal slices

We studied with the whole-cell recording techniques, the mechanisms underlying the time course of the slow N-methyl-D-aspartate (NMDA), and fast non-NMDA receptor-mediated excitatory postsynaptic currents (EPSCs) in hippocampal slices. The rising phase of the NMDA receptor-mediated component of the EPSC as well as the decaying phase of the NMDA and non-NMDA component were highly temperature-sensitive, suggesting that neither of these processes is determined by free diffusion of transmitter. Moreover, glutamate uptake blockers enhanced the responses to exogenously applied glutamate, but had no effect on the decay of either the NMDA or non-NMDA components of the EPSCs. On the other hand, open channel blockers known to modify NMDA channel kinetics reduced the EPSC decay time. Thus, the present results support a model in which the rise time and decay of the NMDA component are determined primarily by slow channel kinetics and the decay of the non-NMDA component is due either to channel kinetics or to desensitization.     

A nonlinear cascade model for action potential encoding in an insect sensory neuron.

Action potential encoding in the cockroach tactile spine neuron can be represented as a single-input single-output nonlinear dynamic process. We have used a new functional expansion method to characterize the nonlinear behavior of the neural encoder. This method, which yields similar kernels to the Wiener method, is more accurate than the latter and is efficient enough to obtain reasonable kernels in less than 15 min using a personal computer. The input stimulus was band-limited white Gaussian noise and the output consisted of the resulting train of action potentials, which were unitized to give binary values. The kernels and the system input-output signals were used to identify a model for encoding comprising a cascade of dynamic linear, static nonlinear, and dynamic linear components. The two dynamic linear components had repeatable and distinctive forms with the first being low-pass and the second being high-pass. The static nonlinearity was fitted with a fifth-order polynomial function over several input amplitude ranges and had the form of a half-wave rectifier. The complete model gave a good approximation to the output of the neuron when both were subjected to the same novel white noise input signal.     

Relation between currents and the growth of Palaeocene reef-mounds

The Lower Palaeocene (Danian) reef-mounds of southern Scandinavia are asymmetrical with steep SE flanks and more gently sloping NW flanks. Fragments of mainly arborescent bryozoans make up between 23 and 45% by weight of the sediment. The asymmetrical development of the mounds is a result of differences in the accumulation rate of bryozoans which was controlled by the growth and density of the fauna. Density was relatively high on the SE flank and low on the NW flank. The morphology of individual bryozoan species also changes across the mound. Colonics living on the summit and the SE flank were more robust than colonics living on the NW flank and in the basins. The patterns of morphological and distributional changes are compared with the current regime of the mound reconstructed on the basis of model experiments in a flume. The experiments indicate that the current velocity was highest on the summit and lowest in the basins. Velocities on the flanks were intermediate but considerably higher on the upcurrent SE flank than on the downcurrent NW flank. The robustness of the colonics is positively correlated with the estimated current velocities, whereas the density of the fauna was highest in areas of relatively moderate velocities. The changes in density of the bryozoans, and consequently the asymmetrical growth of the mounds, were controlled by differences in food availability. □ Bryozoans, density variation, flume experiments, morphological variation, reef-mounds, water currents.     

Principles governing the operation of synaptic inhibition in dendrites

Synaptic inhibition plays a key role in shaping the dynamics of neuronal networks and selecting cell assemblies. Typically, an inhibitory axon contacts a particular dendritic subdomain of its target neuron, where it often makes 10-20 synapses, sometimes on very distal branches. The functional implications of such a connectivity pattern are not well understood. Our experimentally based theoretical study highlights several new and counterintuitive principles for dendritic inhibition. We show that distal "off-path" rather than proximal "on-path" inhibition effectively dampens proximal excitable dendritic "hotspots," thus powerfully controlling the neuron's output. Additionally, with multiple synaptic contacts, inhibition operates globally, spreading centripetally hundreds of micrometers from the inhibitory synapses. Consequently, inhibition in regions lacking inhibitory synapses may exceed that at the synaptic sites themselves. These results offer new insights into the synergetic effect of dendritic inhibition in controlling dendritic excitability and plasticity and in dynamically molding functional dendritic subdomains and their output.     

The effect of metacaine on the slow variation of peak sodium currents in potential clamped Ranvier nodes following changes in holding potential

The effect of changes in the holding potential on peak sodium currents in isolated myelinated nerve fibres (peak INa) was investigated with the conventional sodium inactivation being kept at h infinity = 1. In Ringer solution no stationary values of peak INa could be obtained over the potential range tested. Near the normal resting potential, ER, peak INa changed with time clearly even after 10 min. Therefore, the individual values of peak INa as normalized by peak INa at ER and corrected for the unevitable run-down of peak INa could not serve as measure for stationary values of any membrane parameter. Under metacaine (1 mmol/l) peak INa changed comparably faster and proved to be less potential dependent as compared to peak INa of the untreated fibre. The effects observed are not necessarily governed by a specific process located inside the nodal membrane.     

A model of excitatory synaptic interactions between pacemakers. Its reality,its generality,and the principles involved

This is a model of the steady-state influence of one pacemaker neuron upon another across a synapse with EPSP's. Its postulates require firstly the spontaneous regularity of both cells, whose intervals are E and N, respectively. In addition, they require a special shortening or negative delay of the interspike interval by one or more EPSP's, with a V-shaped dependence of the delay on the position or phase of the EPSP's in the interval; the minimum of the delay function corresponds to the earliest EPSP arrival phase () that triggers a spike immediately. Finally, they impose on the variables certain bounds. The model's behavior has two main features. The first is a zig-zag relationship with an overall increasing trend between the steady-state pre- and post-synaptic discharge intensities (Fig. 7). The zig-zag is formed predominantly, if not exclusively, by segments with positive slopes that are rational fractions. Passage from one such segment to others is negatively-sloped (paradoxical), involving staggered positively-sloped segments whose details are unclear for weak presynaptic discharges and discontinuities for intense discharges. The same postsynaptic intensity may result from several presynaptic ones; the maximum postsynaptic intensity may reflect refractoriness, or the earliest instants of immediate triggering. The second main feature is the locking of the discharges in an invariant forward and backward temporal relation. With at most one EPSP per postsynaptic spike, locking is always present. If the presynaptic interval E is in the closed {rN+,(r+1)N} range, locking is 1:r+1, either stable at a greater-than- phase or unstable at a smaller one; arrivals at integral multiples of N do not affect the postsynaptic intensity. If E is in {rN, rN+} (r>0), locking is at other ratios (e.g., 2:3) and less apparent. With more than one EPSP per spike, when E is below bounds that depend on the interspike interval and the point of earliest triggering, locking happens in the simple s:1 ratio (s=2,3, ...) and is stable; when E is above those bounds, there are E ranges where locking is in other ratios (e.g., 3:2) and ranges where behavior is unclear. The validity of any model is based jointly upon an a priori judgment as to whether postulates depart reasonably little from nature, and upon an a posteriori experimental comparison of modelled and real behaviors. The model's domain of applicability depends on the specific embodiment, each of the latter tolerating characteristically each departure. The present model will be evaluated in the crayfish stretch-receptor neuron (Diez-Martínez et al., in preparation). The model is applicable to any physical system that complies with its postulates, and evidence compatible with this notion is available in many disparate fields. It illustrates the modelling path to a scientific proposition, other paths being inference from experimentation, or deduction from premises acceptable at other approach levels (in this case, for example, from that of synaptic mechanisms). The periodicity postulates set this model within the category of those for oscillators. The notion of an oscillator has a far broader applicability than appears at first sight, since all physically realizable systems have some predominant output frequency, i.e., to a certain extent are oscillators.Supported by funds from the Brain Research Institute, UCLASupported by FAPESP (Sao Paulo, Brazil). Present address: Esc. Politecnica, Dee, University of Sao Paulo, Cid. Univ., CP 8174 Sao Paulo, S.P., Brazil     

Differences in synaptic output between excitatory and inhibitory motoneurons in a crayfish muscle

A pair of antagonistic motoneurons, one excitatory and one inhibitory, innervates the distal accessory flexor muscle in the walking limb of the crayfish Procambarus clarkii. The number and size of synapses formed by these two axons on the muscle fibers (neuromuscular synapses) and on each other (axo-axonal synapses) were estimated using thin-section electron microscopy. Although profiles of nerve terminals of the two axons occur in roughly equal proportions, the frequency of occurrence of neuromuscular synapses differed markedly: 73% were excitatory and 27% were inhibitory. However, inhibitory synapses were 4–5 times larger than excitatory ones, and consequently, the total contact areas devoted to neuromuscular synapses were similar for both axons. Axo-axonal synapses were predominantly from the inhibitory axon to the excitatory axon (86%), and a few were from the excitatory axon to the inhibitory axon (14%). The role of the inhibitory axo-axonal synapse is presynaptic inhibition, but that of the excitatory axo-axonal synapse is not known. The differences in size of neuromuscular synapses between the two axons may reflect intrinsic determinants of the neuron, while the similarity in total synaptic area may reflect retrograde influences from the muscle for regulating synapse number.     

A nonlinear model of step responses in the cockroach tactile spine neuron

Rapid sensory adaptation in the cockroach tactile spine neuron has previously been associated with a labile threshold for action potentials, which changes with the membrane potential by a process involving two time constants. A feed-forward, variable-threshold model has previously been used to account for the frequency response function of the neuron when stimulated with small-signal, white-noise currents. Here, we used a range of accurately controlled steps of extracellular current to stimulate the neuron. The same model was able to predict the individual step responses and could also fit the entire set of step responses from a single neuron if an initial, saturating, static nonlinearity was included. These results indicate that the two-time-constant, variable-threshold model can account for most of the rapidly adapting behavior of the tactile spine neuron.     

Inhibitory effect of asiatic acid on acetylcholinesterase, excitatory post synaptic potential and locomotor activity

The asiatic acid, a triterpenoids isolated from Centella asiatica was used to delineate its inhibitory effect on acetylcholinesterase (AChE) properties, excitatory post synaptic potential (EPSP) and locomotor activity. This study is consistent with asiatic acid having an effect on AChE, a selective GABA(B) receptor agonist and no sedative effect on locomotor.