Inhibitory Synaptic Noise Research Articles

Anesthesia modifies subthreshold critical slowing down in a stochastic Hodgkin-Huxley-like model with inhibitory synaptic input.

The dynamics of a stochastic type-I Hodgkin-Huxley-like point neuron model exposed to inhibitory synaptic noise are investigated as a function of distance from spiking threshold and the inhibitory influence of the general anesthetic agent propofol. The model is biologically motivated and includes the effects of intrinsic ion-channel noise via a stochastic differential equation description as well as inhibitory synaptic noise modeled as multiple Poisson-distributed impulse trains with saturating response functions. The effect of propofol on these synapses is incorporated through this drug's principal influence on fast inhibitory neurotransmission mediated by γ-aminobutyric acid (GABA) type-A receptors via reduction of the synaptic response decay rate. As the neuron model approaches spiking threshold from below, we track membrane voltage fluctuation statistics of numerically simulated stochastic trajectories. We find that for a given distance from spiking threshold, increasing the magnitude of anesthetic-induced inhibition is associated with augmented signatures of critical slowing: fluctuation amplitudes and correlation times grow as spectral power is increasingly focused at 0 Hz. Furthermore, as a function of distance from threshold, anesthesia significantly modifies the power-law exponents for variance and correlation time divergences observable in stochastic trajectories. Compared to the inverse square root power-law scaling of these quantities anticipated for the saddle-node bifurcation of type-I neurons in the absence of anesthesia, increasing anesthetic-induced inhibition results in an observable exponent <-0.5 for variance and >-0.5 for correlation time divergences. However, these behaviors eventually break down as distance from threshold goes to zero with both the variance and correlation time converging to common values independent of anesthesia. Compared to the case of no synaptic input, linearization of an approximating multivariate Ornstein-Uhlenbeck model reveals these effects to be the consequence of an additional slow eigenvalue associated with synaptic activity that competes with those of the underlying point neuron in a manner that depends on distance from spiking threshold.

In Vivo Analysis of Inhibitory Synaptic Inputs and Rebounds in Deep Cerebellar Nuclear Neurons

Neuronal function depends on the properties of the synaptic inputs the neuron receive and on its intrinsic responsive properties. However, the conditions for synaptic integration and activation of intrinsic responses may to a large extent depend on the level of background synaptic input. In this respect, the deep cerebellar nuclear (DCN) neurons are of particular interest: they feature a massive background synaptic input and an intrinsic, postinhibitory rebound depolarization with profound effects on the synaptic integration. Using in vivo whole cell patch clamp recordings from DCN cells in the cat, we find that the background of Purkinje cell input provides a tonic inhibitory synaptic noise in the DCN cell. Under these conditions, individual Purkinje cells appear to have a near negligible influence on the DCN cell and clear-cut rebounds are difficult to induce. Peripheral input that drives the simple spike output of the afferent PCs to the DCN cell generates a relatively strong DCN cell inhibition, but do not induce rebounds. In contrast, synchronized climbing fiber activation, which leads to a synchronized input from a large number of Purkinje cells, can induce profound rebound responses. In light of what is known about climbing fiber activation under behaviour, the present findings suggest that DCN cell rebound responses may be an unusual event. Our results also suggest that cortical modulation of DCN cell output require a substantial co-modulation of a large proportion of the PCs that innervate the cell, which is a possible rationale for the existence of the cerebellar microcomplex.

Slow inhibitory potentials in the teleost Mauthner cell

In vivo recordings from Mauthner cells in adult zebrafish ( Danio rerio) and goldfish ( Carassius auratus) preparations with potassium chloride filled electrodes revealed a new class of long-lasting synaptic events in these cells. Their decay time constant ranged from 20 to 80 ms, which is about 20 times longer than that of previously identified fast glycinergic inhibitory postsynaptic potentials in this neuron. The average time to peak of these slow events ranged from 1 to 6 ms. We demonstrated that they are also inhibitory since (i) they were resistant to antagonists of the excitatory glutamatergic receptors; (ii) their amplitude was increased following chloride loading of the Mauthner cell; (iii) their reversal potential was the same as that of fast, glycinergic inhibitory postsynaptic potentials; and (iv) they produced an inhibitory shunt of the cell's membrane resistance. Furthermore, as with the fast inhibitory postsynaptic potentials, the decay time of the slow events is voltage dependent, increasing when the Mauthner cell is depolarized. However, these inhibitory postsynaptic potentials had a different pharmacological profile to the fast glycinergic ones. That is, they persisted in the presence of strychnine at doses that abolished the fast ones and they were more sensitive to bicuculline. These data are compatible with the notion that these inhibitory postsynaptic potentials are mediated by activation of a different inhibitory receptor type, and may be GABAergic. In addition, the decay time constant of the fast inhibitory postsynaptic current was shorter than the first of the two components that contribute to the bi-exponential decay reported previously for miniature inhibitory postsynaptic currents in Mauthner cells of larval zebrafish. This suggests developmental modifications and/or a switch in the assembly of glycine receptor subtypes. While amplitude distributions of the fast miniature inhibitory postsynaptic potentials recorded in the presence of tetrodotoxin generally could fit with a single Gaussian function, the amplitude histograms of slow miniature events were skewed, often with multiple nearly equally spaced peaks, consistent with the synchronous release of several quantal units. These previously undescribed slow unitary inhibitory postsynaptic potentials contribute to inhibitory synaptic noise recorded in the Mauthner cells. Specifically, autocorrelation analysis revealed gamma-like rhythms (30–80 Hz) in each of two phases, characterized as “noisy” and “quiet”, and dominated by the fast and slow inhibitory postsynaptic potentials, respectively. The major frequencies of these two states were significantly different (i.e. around 90 and 40 Hz, respectively), suggesting that the fast and slow inhibitory postsynaptic potentials are derived from different inhibitory networks. Chloride-filled Mauthner cells gradually hyperpolarized in the presence of tetrodotoxin, reflecting the effect of ongoing activity in the interneurons that produce the slow events. We conclude that this new class of inhibitory postsynaptic potentials contributes to the tonic inhibition which controls the Mauthner cell's excitability. In physiological conditions, this regulatory influence is expressed as a continuous shunt of this neuron's input resistance and responsiveness to sensory inputs.

Tonic inhibition alternates in paired neurons that set direction of fish escape reaction.

Crossed antagonism between activities in neurons subserving alternating movements such as swimming or walking has been described in a number of systems. The role of reciprocal inhibition has been implicated in these activities, but involvement of rhythmic ongoing fluctuations of membrane potential, called synaptic "noise," has not been examined. In the Mauthner (M) cells, which control the direction of escape, this activity is inhibitory. We report that in the zebrafish (Danio rerio), inhibitory synaptic noise exhibits prolonged bursts of rhythmic, inhibitory postsynaptic potentials, which attenuate the M cell's sensibility to excitatory sensory drives. Furthermore, paired intracellular recordings have shown that inhibitory synaptic noise alternates between two distinct states, noisy and quiet, which are out of phase in the two cells. Firing of either M cell resets this pattern by reducing the inhibition in the contralateral one. This suggests that an avoidance reflex in one direction may favor initiation, by the opposite M cell, of a subsequent escape toward a more appropriate location.

A nonrandom dynamic component in the synaptic noise of a central neuron.

Continuous segments of synaptic noise were recorded in vivo from teleost Mauthner cells and were studied with the methods of nonlinear analysis. As in many central neurons, this ongoing activity is dominated by consecutive inhibitory postsynaptic potentials. Recurrence plots and first or third order Poincaré maps combined with surrogate shuffling revealed nonrandom patterns consistent with the notion that synaptic noise is a continuously varying mixture of periodic and chaotic phases. Chaos was further demonstrated by the occurrence of unstable periodic orbits. The nonrandom component of the noise is reproducibly and persistently reduced when the level of background sound, a natural stimulus for networks afferent to the Mauthner cell, is briefly elevated. These data are consistent with a model involving a reciprocally connected inhibitory network, presynaptic to the Mauthner cell and its intrinsic properties. The presence of chaos in the inhibitory synaptic noise that regulates the excitability of the Mauthner cell and its sensitivity to external stimuli suggests that it modulates this neuron's function, namely to trigger a fast escape motor reaction following unexpected sensory information.

Synaptic noise and multiquantal release at dendritic synapses.

1. The quantal nature of inhibitory synaptic noise recorded intracellularly from the lateral dendrite of the goldfish Mauthner cell was studied, using new detection and measurement procedures that eliminate operator intervention. In addition, we employed an analytical algorithm, not previously applied to this problem, which treats composite amplitude distributions as mixtures of gaussians of unknown separations and variances. 2. As in the soma of this neuron, the dendritic inhibitory noise is quantal, with the exception that in the dendrite multiple equally spaced classes may persist in the presence of tetrodotoxin (TTX), an observation that may be correlated with the finding that the inhibitory afferents at this level often contain more than one release site. The validity of the analysis was confirmed by superfusing with saline containing low calcium and high magnesium, which reduces composite histograms that are gaussian mixtures to a single class, equal in amplitude to that of the first component detected in the control. 3. These results suggest that spontaneous exocytotic events may be synchronized at adjacent active zones within single terminals and that lowering the probability of release by reducing calcium may then be a more effective method for isolating single miniature events than is TTX.

Excitation of rat prefrontal cortical neurons by dopamine: An in vitro electrophysiological study

The effects of dopamine (DA) on prefrontal pyramidal neurons were studied in vitro on rat cerebral cortex slices using intracellular recordings. Pyramidal neurons were first identified by Lucifer yellow and some of their basic bioelectrical properties were analysed. At resting potential, white matter stimulation mainly evoked depolarizing inhibitory postsynaptic potentials (IPSPs) which reversed between -60 and -50 mV and were almost totally abolished by bicuculline. Furthermore, pyramidal cells often exhibited spontaneous depolarizing IPSPs abolished by bicuculline. Under tetrodotoxin (TTX) this synaptic noise was partly blocked suggesting that it was due both to the spontaneous firing of presynaptic γ-aminobutyric acid (GABA)ergic neurons and to a spontaneous quantal release from these afferent fibers. In pyramidal cells, DA enhanced the number of spikes evoked by depolarizing current pulses, and the input resistanc was increased by 10–20%. DA also clearly increased the inhibitory synaptic noise. This effect was blocked by fluphenazine. In contrast, evoked IPSPs were not consistently affected by DA. Taken altogether, these results suggest, that in the prefrontal cortex, dopamine has a mild excitatory effect on both pyramidal cells and GABAergic interneurons impinging on them.

Effects of lateral inhibition on fluctuations of the impulse rate.

Inhibition from neighboring eccentric cells has an effect on the variability of firing of a given eccentric cell. The reduction in the average impulse rate which is caused by inhibition decreases the variance of the impulse rate. However, this reduction of the average rate increases the coefficient of variation of the impulse rate. Inhibitory synaptic noise should add to the low frequency portion of the variance spectrum of the impulse rate. This occurs because of the slow time course of inhibitory synaptic potentials. As a consequence, inhibition decreases the signal-to-noise ratio for low frequency modulated stimuli.

The mossy fibre-granule cell relay of the cerebellum and its inhibitory control by Golgi cells.

1. The glomerulus in the cerebellar granular layer is composed of the three elements; the mossy fibre terminal, the granule cell dendrites and the Golgi cell axons. The afferent input to the cerebellar cortex through the glomerulus, the mossy fibre-granule cell relay (M.G.R.), and its inhibitory control by the Golgi cells were studied by recording, a) extracellular field potentials in the granular and molecular layers, b) unitary spikes of granule cells, and c) intracellular postsynaptic potentials in Purkinje cells. 2. Mossy fibres were activated by juxta-fastigial, transfolial, lateral cuneate nucleus and radial nerve stimulation. Stimulation of an adjacent folium (transfolial stimulation) could excite branches of mossy fibres under the stimulating electrode which supply other branches also to the folium under the recording electrode. This technique was utilized to distinguish the response due to mossy fibre activation from those due to the climbing fibre and Purkinje cell axons. 3. These stimulations resulted in, through the M.G.R., a powerful activation of granule cells whose axons (parallel fibres) excited in turn the Purkinje cells and the inhibitory interneurones, including the Golgi cells, in the molecular layer. 4. Field potentials and unitary spikes due to granule cell activity elicited by the stimulation of mossy fibres were markedly depressed for hundreds of milliseconds after the direct stimulation of parallel fibres (LOC stimulation). The postsynaptic potential in Purkinje cells evoked by mossy fibre activation was also depressed by the conditioning LOC stimulation in the same manner. The “spontaneous” background activities recorded from granule cells as unitary spikes and from Purkinje cells as inhibitory synaptic noise were silenced for hundreds of milliseconds after the LOC stimulation. 5. These depressions indicate that the parallel fibre activation evokes an inhibitory action upon M.G.R. On anatomical grounds this inhibition can be mediated only by the Golgi cell, and it is postulated that the inhibitory action is postsynaptic upon the dendrites of granule cells. 6. It is concluded that the Golgi cell inhibition regulates the mossy fibre input to the cerebellar cortex at the M.G.R. by a form of negative feed-back.