Differential modulation of chemical and electrical components of mixed synapses in the lobster stomatogastric ganglion

1. Two pairs of neurons in the pyloric network of the spiny lobster, Panulirus interruptus, communicate through mixed graded chemical and rectifying electrical synapses. The anterior burster (AB) chemically inhibits and is electrically coupled to the ventricular dilator (VD); the lateral pyloric (LP) and pyloric (PY) neurons show reciprocal chemical inhibition and electrical coupling. We examined the effects of dopamine (DA), serotonin (5HT) and octopamine (Oct) on these mixed synapses to determine the plasticity possible with opposing modes of synaptic interaction.
2. Dopamine increased net inhibition at all three pyloric mixed synapses by both reducing electrical coupling and increasing chemical inhibition. This reversed the sign of the net synaptic interaction when electrotonic coupling dominated some mixed synapses, and activated silent chemical components of other mixed synapses.
3. Serofonin weakly enhanced LP → PY net inhibition, by reducing electrical coupling without altering chemical inhibition. Serotonin reduced AB→ VD electrical coupling, but variability in its effect on the chemical component made the net effect non-significant.
4. Octopamine enhanced LP→ PY and PY→ LP net inhibition by enhancing the chemical inhibitory component without altering electrical coupling.
5. Differential modulation of chemical and electrical components of mixed synapses markedly changes the net synaptic interactions. This contributes to the flexible outputs that modulators evoke from anatomically defined neural networks.

     

Synchronization in a network of fast-spiking interneurons

Experimental results revealed that in neocortex inhibitory fast-spiking (FS) interneurons interact also by electrical synapses (gap-junctions). They receive sensory information from thalamus and transfer it to principal cells by feedforward inhibition. Moreover, their synchronous discharge enhances their inhibitory control of pyramidal neurons. By using a biophysical model of FS interneurons the synchronization properties of a network of two synaptically coupled units are investigated. In the case they interact only by inhibitory synapses, well defined regions exist in the parameters space described by the strength and duration of the synaptic current, where synchronous regimes occur. Then an empirical protocol is proposed to determine approximately the borders of the synchronization manifold (SM). When electrical synapses are included, the region of synchronous discharge of the two interneurons becomes larger. In both cases, the coherent states are characterized by discharge frequencies in the gamma range. Lastly, the effects of heterogeneity, either obtained by using different stimulation currents or unidirectional inhibitory coupling, are studied.     

Vergleich zweier Modelle für laterale Inhibition

Summary Two semi-linear models for lateral inhibition are discussed. The interaction between receptor units is assumed to be linear, as demonstrated by Hartline and Ratliff in the eye of the horseshoe crab Limulus polyphemus. Yet a model of such an inhibitory system must be nonlinear, since the output values correspond to nerve activities, which cannot be negativ. Models with forward inhibition were used often to describe contrast phenomena in the human nervous system. However, in order to simulate the input-output relation in systems similar to the eye of Limulus, a model with backward inhibition must be constructed. Two important properties of backward inhibition not shared by forward inhibition are: (1) Inhibition in a receptor unit has an influence upon its excitation, as well as upon its ability to inhibit other units (Disinhibition). (2) The range of interaction between sensory units is not necessarily the same as the range of direct cross connections. It is shown in this paper, that also forward inhibition may possess these two properties, provided that it is repeated on subsequent levels. Some properties of systems with backward and forward inhibition are studied and compared in models consisting of three units. The input-output relation for large systems with backward inhibition was calculated under special assumptions concerning the inhibitory coefficients. If the inhibitory coefficients in a system with backward inhibition decrease like a power series, as a function of the distance between receptor units, only neighboring receptors have an effect upon each other. That is, in an equivalent system with forward inhibition the inhibitory interaction is confined to neighbouring receptors. Conversely, when backward inhibition exists only between neighbouring receptors, the inhibitory coefficients in an equivalent system with forward inhibition are described, as a function of the distance between the receptor units, by a power series with alternating sign.     

Dynamics of spiking neurons connected by both inhibitory and electrical coupling

We study the dynamics of a pair of intrinsically oscillating leaky integrate-and-fire neurons (identical and noise-free) connected by combinations of electrical and inhibitory coupling. We use the theory of weakly coupled oscillators to examine how synchronization patterns are influenced by cellular properties (intrinsic frequency and the strength of spikes) and coupling parameters (speed of synapses and coupling strengths). We find that, when inhibitory synapses are fast and the electrotonic effect of the suprathreshold portion of the spike is large, increasing the strength of weak electrical coupling promotes synchrony. Conversely, when inhibitory synapses are slow and the electrotonic effect of the suprathreshold portion of the spike is small, increasing the strength of weak electrical coupling promotes antisynchrony (see Fig. 10). Furthermore, our results indicate that, given a fixed total coupling strength, either electrical coupling alone or inhibition alone is better at enhancing neural synchrony than a combination of electrical and inhibitory coupling. We also show that these results extend to moderate coupling strengths.     

Mechanisms of long-term plasticity of hippocampal GABAergic synapses

Long-term potentiation and depression of synaptic transmission have been considered as cellular mechanisms of memory in studies conducted in recent decades. These studies were predominantly focused on mechanisms underlying plasticity at excitatory synapses. Nevertheless, normal central nervous system functioning requires maintenance of a balance between inhibition and excitation, suggesting existence of similar modulation of glutamatergic and GABAergic synapses. Here we review the involvement of G-protein-coupled receptors in the generation of long-term changes in synaptic transmission of inhibitory synapses. We considered the role of endocannabinoid and glutamate systems, GABA_B and opioid receptors in the induction of long-term potentiation and long-term depression in inhibitory synapses. The preand postsynaptic effects of activation of these receptors are also discussed.     

Hair Cell Interactions in the Statocyst of Hermissenda

Hair cells in the statocyst of Hermissenda crassicornis respond to mechanical stimulation with a short latency (<2 ms) depolarizing generator potential that is followed by hyperpolarization and inhibition of spike activity. Mechanically evoked hyperpolarization and spike inhibition were abolished by cutting the static nerve, repetitive mechanical stimulation, tetrodotoxin (TTX), and Co⁺⁺. Since none of these procedures markedly altered the generator potential it was concluded that the hyperpolarization is an inhibitory synaptic potential and not a component of the mechanotransduction process. Intracellular recordings from pairs of hair cells in the same statocyst and in statocysts on opposite sides of the brain revealed that hair cells are connected by chemical and/or electrical synapses. All chemical interactions were inhibitory. Hyperpolarization and spike inhibition result from inhibitory interactions between hair cells in the same and in opposite statocysts.     

Molecular dynamics of postsynaptic receptors and scaffold proteins

The activity of neurotransmitter receptors determines the strength of synaptic transmission. Therefore, the clustering of receptors at synapses is an important mechanism underlying synaptic plasticity. The dynamic exchange of receptors between synaptic and extrasynaptic membranes is dependent on their interaction with synaptic scaffold proteins. Here, we review the recent advances and emerging concepts related to the dynamics of synaptic proteins at inhibitory and excitatory synapses. These include the imaging techniques that enable the study of protein dynamics in cells, the differences and similarities of receptor dynamics at excitatory and inhibitory synapses, the relationship between the exchange of receptor and scaffold proteins, as well as the role of receptor fluxes in the modulation of synaptic strength.     

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

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

Gap junctions

Electrical coupling through gap junctions constitutes a mode of signal transmission between neurons (electrical synaptic transmission). Originally discovered in invertebrates and in lower vertebrates, electrical synapses have recently been reported in immature and adult mammalian nervous systems. This has renewed the interest in understanding the role of electrical synapses in neural circuit function and signal processing. The present review focuses on the role of gap junctions in shaping the dynamics of neural networks by forming electrical synapses between neurons. Electrical synapses have been shown to be important elements in coincidence detection mechanisms and they can produce complex input-output functions when arranged in combination with chemical synapses. We postulate that these synapses may also be important in redefining neuronal compartments, associating anatomically distinct cellular structures into functional units. The original view of electrical synapses as static connecting elements in neural circuits has been revised and a considerable amount of evidence suggests that electrical synapses substantially affect the dynamics of neural circuits.     

Synchronization of Firing in Cortical Fast-Spiking Interneurons at Gamma Frequencies: A Phase-Resetting Analysis

Fast-spiking (FS) cells in the neocortex are interconnected both by inhibitory chemical synapses and by electrical synapses, or gap-junctions. Synchronized firing of FS neurons is important in the generation of gamma oscillations, at frequencies between 30 and 80 Hz. To understand how these synaptic interactions control synchronization, artificial synaptic conductances were injected in FS cells, and the synaptic phase-resetting function (SPRF), describing how the compound synaptic input perturbs the phase of gamma-frequency spiking as a function of the phase at which it is applied, was measured. GABAergic and gap junctional conductances made distinct contributions to the SPRF, which had a surprisingly simple piecewise linear form, with a sharp midcycle break between phase delay and advance. Analysis of the SPRF showed how the intrinsic biophysical properties of FS neurons and their interconnections allow entrainment of firing over a wide gamma frequency band, whose upper and lower frequency limits are controlled by electrical synapses and GABAergic inhibition respectively.     

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 enigma of transmitter-selective receptor accumulation at developing inhibitory synapses

The control of synaptic inhibition is crucial for normal brain function. More than 20 years ago, glycine and gamma-aminobutyric acid (GABA) were shown to be the two major inhibitory neurotransmitters. They can be released independently from different terminals or co-released from the same terminal to activate postsynaptic glycine and GABA(A) receptors. The anchoring protein gephyrin is involved in the postsynaptic accumulation of both glycine and GABA(A) receptors. In lower brain regions, both receptors can be concentrated in synapses, whereas in higher brain regions, glycine receptors are mostly excluded from postsynaptic sites. The activation of glycine and/or GABA(A) receptors determines the strength and precise timing of inhibition. Therefore, tight regulation of postsynaptic glycine versus GABA(A) receptor localization is crucial for optimizing synaptic inhibition in neurons. This review focuses on recent findings and discusses questions concerning the specificity of postsynaptic inhibitory neurotransmitter receptor accumulation during inhibitory synapse formation and development.     

When inhibition not excitation synchronizes neural firing

Excitatory and inhibitory synaptic coupling can have counter-intuitive effects on the synchronization of neuronal firing. While it might appear that excitatory coupling would lead to synchronization, we show that frequently inhibition rather than excitation synchronizes firing. We study two identical neurons described by integrate-and-fire models, general phase-coupled models or the Hodgkin-Huxley model with mutual, non-instantaneous excitatory or inhibitory synapses between them. We find that if the rise time of the synapse is longer than the duration of an action potential, inhibition not excitation leads to synchronized firing.     

Repeated neonatal separation stress alters the composition of neurochemically characterized interneuron subpopulations in the rodent dentate gyrus and basolateral amygdala

Emotional experience during early life has been shown to interfere with the development of excitatory synaptic networks in the prefrontal cortex, hippocampus, and the amygdala of rodents and primates. The aim of the present study was to investigate a developmental "homoeostatic synaptic plasticity" hypothesis and to test whether stress-induced changes of excitatory synaptic composition are counterbalanced by parallel changes of inhibitory synaptic networks. The impact of repeated early separation stress on the development of two GABAergic neuronal subpopulations was quantitatively analyzed in the brain of the semiprecocial rodent Octodon degus. Assuming that PARV- and CaBP-D28k-expression are negatively correlated to the level of inhibitory activity, the previously described reduced density of excitatory spine synapses in the dentate gyrus of stressed animals appears to be "amplified" by elevated GABAergic inhibition, reflected by reduced PARV- (down to 85%) and CaBP-D28k-immunoreactivity (down to 74%). In opposite direction, the previously observed elevated excitatory spine density in the CA1 region of stressed animals appears to be amplified by reduced inhibition, reflected by elevated CaPB-D28k-immunoreactivity (up to 149%). In the (baso)lateral amygdala, the previously described reduction of excitatory spine synapses appears to be "compensated" by reduced inhibitory activity, reflected by dramatically elevated PARV- (up to 395%) and CaPB-D28k-immunoreactivity (up to 327%). No significant differences were found in the central nucleus of the amygdala, the piriform, and somatosensory cortices and in the hypothalamic paraventricular nucleus. Thus during stress-evoked neuronal and synaptic reorganization, a homeostatic balance between excitation and inhibition is not maintained in all regions of the juvenile brain.     

D-Serine and Glycine Differentially Control Neurotransmission during Visual Cortex Critical Period

N-methyl-D-aspartate receptors (NMDARs) play a central role in synaptic plasticity. Their activation requires the binding of both glutamate and d-serine or glycine as co-agonist. The prevalence of either co-agonist on NMDA-receptor function differs between brain regions and remains undetermined in the visual cortex (VC) at the critical period of postnatal development. Here, we therefore investigated the regulatory role that d-serine and/or glycine may exert on NMDARs function and on synaptic plasticity in the rat VC layer 5 pyramidal neurons of young rats. Using selective enzymatic depletion of d-serine or glycine, we demonstrate that d-serine and not glycine is the endogenous co-agonist of synaptic NMDARs required for the induction and expression of Long Term Potentiation (LTP) at both excitatory and inhibitory synapses. Glycine on the other hand is not involved in synaptic efficacy per se but regulates excitatory and inhibitory neurotransmission by activating strychnine-sensitive glycine receptors, then producing a shunting inhibition that controls neuronal gain and results in a depression of synaptic inputs at the somatic level after dendritic integration. In conclusion, we describe for the first time that in the VC both D-serine and glycine differentially regulate somatic depolarization through the activation of distinct synaptic and extrasynaptic receptors.     

Direct imaging of lateral movements of AMPA receptors inside synapses

Trafficking of AMPA receptors in and out of synapses is crucial for synaptic plasticity. Previous studies have focused on the role of endo/exocytosis processes or that of lateral diffusion of extra-synaptic receptors. We have now directly imaged AMPAR movements inside and outside synapses of live neurons using single-molecule fluorescence microscopy. Inside individual synapses, we found immobile and mobile receptors, which display restricted diffusion. Extra-synaptic receptors display free diffusion. Receptors could also exchange between these membrane compartments through lateral diffusion. Glutamate application increased both receptor mobility inside synapses and the fraction of mobile receptors present in a juxtasynaptic region. Block of inhibitory transmission to favor excitatory synaptic activity induced a transient increase in the fraction of mobile receptors and a decrease in the proportion of juxtasynaptic receptors. Altogether, our data show that rapid exchange of receptors between a synaptic and extra-synaptic localization occurs through regulation of receptor diffusion inside synapses.     

Disruption of KCC2 reveals an essential role of K-Cl cotransport already in early synaptic inhibition

Synaptic inhibition by GABA(A) and glycine receptors, which are ligand-gated anion channels, depends on the electrochemical potential for chloride. Several potassium-chloride cotransporters can lower the intracellular chloride concentration [Cl(-)](i), including the neuronal isoform KCC2. We show that KCC2 knockout mice died immediately after birth due to severe motor deficits that also abolished respiration. Sciatic nerve recordings revealed abnormal spontaneous electrical activity and altered spinal cord responses to peripheral electrical stimuli. In the spinal cord of wild-type animals, the KCC2 protein was found at inhibitory synapses. Patch-clamp measurements of embryonic day 18.5 spinal cord motoneurons demonstrated an excitatory GABA and glycine action in the absence, but not in the presence, of KCC2, revealing a crucial role of KCC2 for synaptic inhibition.     

Steps in the development of chemical and electrical synapses by pairs of identified leech neurons in culture

Experiments have been made to follow the development of chemical and electrical transmission between pairs of leech neurons in culture. 1. The cell bodies of identified neurons were isolated from the CNS by suction after mild enzyme treatment, together with a length of the initial segment (or 'stump'). The neurons tested were Retzius cells (R), annulus erector motoneurons (AE), Anterior pagoda cells (AP) and pressure sensory cells (P). Pairs of cells were placed together in various configurations, with different sites on their surfaces making contact. 2. When pairs of Retzius cells were apposed with their stumps touching, serotonergic, chemically mediated synaptic transmission became apparent before electrical transmission. By 2.5 h impulses in either of the two Retzius cells produced hyperpolarizing inhibitory potentials in the other. These potentials were reversed by raised intracellular Cl and showed clear facilitation. The strength of chemical transmission between Retzius cells increased over the next 72 h. 3. After chemical transmission had been established, weak non-rectifying electrical transmission became apparent between Retzius cells at about 24-72 h. By 4 days coupling became stronger and tended to obscure chemically evoked synaptic potentials. 4. When pairs of Retzius cells were aligned in culture with the tip of one cell stump touching the soma of the other, chemical transmission also developed rapidly. Transmission was, however, in one direction, from stump to soma. At later stages non-rectifying electrical coupling developed as with stump-stump configuration. With the cell bodies of two Retzius cells apposed, electrical coupling developed after several days, before chemical transmission could be observed. 5. When Retzius and P cells were cultured with their stumps in contact, inhibitory chemical synaptic transmission developed within 24 h. Transmission was always in one direction, from Retzius to P cell. Electrical coupling of Retzius and P cells never occurred whatever the spatial relations of the cells to one another. 6. Annulus erector motoneurons, which contain ACh and a peptide resembling FMRFamide, first developed electrical coupling when the two stumps were in contact and then, later, bi-directional chemical transmission. Anterior Pagoda pairs placed stump-to-stump showed electrical connections. 7. Electronmicrographs revealed the presence of synaptic structures within 24 h after Retzius-Retzius, Retzius-P or AE-AE stumps were apposed. 8. The specificity of connections between cultured cells was similar to that observed in earlier experiments.(ABSTRACT TRUNCATED AT 400 WORDS)     

Silent glutamatergic synapses in the mammalian brain

Excitatory synaptic transmission in the mammalian brain is mediated primarily by alpha-amino-3-hydroxy-5-methylisoxazolepropionic acid (AMPA) and N-methyl-D-aspartate (NMDA) receptors that are thought to be co-localized at individual synapses. However, recent electrophysiological and anatomical data suggest that the synaptic localization of AMPA and NMDA receptors may be independently regulated by neural activity. These data are reviewed here and the implications of these findings for the mechanisms underlying synaptic plasticity are discussed.