Cesar C. Ceballos

Dynamic range of vertebrate retina ganglion cells: importance of active dendrites and coupling by electrical synapses.

The vertebrate retina has a very high dynamic range. This is due to the concerted action of its diverse cell types. Ganglion cells, which are the output cells of the retina, have to preserve this high dynamic range to convey it to higher brain areas. Experimental evidence shows that the firing response of ganglion cells is strongly correlated with their total dendritic area and only weakly correlated with their dendritic branching complexity. On the other hand, theoretical studies with simple neuron models claim that active and large dendritic trees enhance the dynamic range of single neurons. Theoretical models also claim that electrical coupling between ganglion cells via gap junctions enhances their collective dynamic range. In this work we use morphologically reconstructed multi-compartmental ganglion cell models to perform two studies. In the first study we investigate the relationship between single ganglion cell dynamic range and number of dendritic branches/total dendritic area for both active and passive dendrites. Our results support the claim that large and active dendrites enhance the dynamic range of a single ganglion cell and show that total dendritic area has stronger correlation with dynamic range than with number of dendritic branches. In the second study we investigate the dynamic range of a square array of ganglion cells with passive or active dendritic trees coupled with each other via dendrodendritic gap junctions. Our results suggest that electrical coupling between active dendritic trees enhances the dynamic range of the ganglion cell array in comparison with both the uncoupled case and the coupled case with cells with passive dendrites. The results from our detailed computational modeling studies suggest that the key properties of the ganglion cells that endow them with a large dynamic range are large and active dendritic trees and electrical coupling via gap junctions.

A Negative Slope Conductance of the Persistent Sodium Current Prolongs Subthreshold Depolarizations

Neuronal subthreshold voltage-dependent currents determine membrane properties such as the input resistance (Rin) and the membrane time constant (τm) in the subthreshold range. In contrast with classical cable theory predictions, the persistent sodium current (INaP), a non-inactivating mode of the voltage-dependent sodium current, paradoxically increases Rin and τm when activated. Furthermore, this current amplifies and prolongs synaptic currents in the subthreshold range. Here, using a computational neuronal model, we showed that the creation of a region of negative slope conductance by INaP activation is responsible for these effects and the ability of the negative slope conductance to amplify and prolong Rin and τm relies on the fast activation of INaP. Using dynamic clamp in hippocampal CA1 pyramidal neurons in brain slices, we showed that the effects of INaP on Rin and τm can be recovered by applying an artificial INaP after blocking endogenous INaP with tetrodotoxin. Furthermore, we showed that injection of a pure negative conductance is enough to reproduce the effects of INaP on Rin and τm and is also able to prolong artificial excitatory post synaptic currents. Since both the negative slope conductance and the almost instantaneous activation are critical for producing these effects, the INaP is an ideal current for boosting the amplitude and duration of excitatory post synaptic currents near the action potential threshold.

Ih Equalizes Membrane Input Resistance in a Heterogeneous Population of Fusiform Neurons in the Dorsal Cochlear Nucleus

In a neuronal population, several combinations of its ionic conductances are used to attain a specific firing phenotype. Some neurons present heterogeneity in their firing, generally produced by expression of a specific conductance, but how additional conductances vary along in order to homeostatically regulate membrane excitability is less known. Dorsal cochlear nucleus principal neurons, fusiform neurons, display heterogeneous spontaneous action potential activity and thus represent an appropriate model to study the role of different conductances in establishing firing heterogeneity. Particularly, fusiform neurons are divided into quiet, with no spontaneous firing, or active neurons, presenting spontaneous, regular firing. These modes are determined by the expression levels of an intrinsic membrane conductance, an inwardly rectifying potassium current (IKir). In this work, we tested whether other subthreshold conductances vary homeostatically to maintain membrane excitability constant across the two subtypes. We found that Ih expression covaries specifically with IKir in order to maintain membrane resistance constant. The impact of Ih on membrane resistance is dependent on the level of IKir expression, being much smaller in quiet neurons with bigger IKir, but Ih variations are not relevant for creating the quiet and active phenotypes. Finally, we demonstrate that the individual proportion of each conductance, and not their absolute conductance, is relevant for determining the neuronal firing mode. We conclude that in fusiform neurons the variations of their different subthreshold conductances are limited to specific conductances in order to create firing heterogeneity and maintain membrane homeostasis.

The role of negative conductances in neuronal subthreshold properties and synaptic integration

Based on passive cable theory, an increase in membrane conductance produces a decrease in the membrane time constant and input resistance. Unlike the classical leak currents, voltage-dependent currents have a nonlinear behavior which can create regions of negative conductance, despite the increase in membrane conductance (permeability). This negative conductance opposes the effects of the passive membrane conductance on the membrane input resistance and time constant, increasing their values and thereby substantially affecting the amplitude and time course of postsynaptic potentials at the voltage range of the negative conductance. This paradoxical effect has been described for three types of voltage-dependent inward currents: persistent sodium currents, L- and T-type calcium currents and ligand-gated glutamatergic N-methyl-D-aspartate currents. In this review, we describe the impact of the creation of a negative conductance region by these currents on neuronal membrane properties and synaptic integration. We also discuss recent contributions of the quasi-active cable approximation, an extension of the passive cable theory that includes voltage-dependent currents, and its effects on neuronal subthreshold properties.

Reimplementation of the Potjans-Diesmann cortical microcircuit model: from NEST to Brian

This work targets the replicability of computational models to provide the community with tested and proven open-source models to be used in new studies and implementations. The Potjans-Diesmann model describes a cortical microcircuit containing two cell types (excitatory and inhibitory) distributed in four layers, and represents the cortical network below a surface of 1 mm2. The original implementation of the Potjans-Diesmann model was based on the NEST simulator and our goal here was to re-implement the model in the Brian 2 simulator and obtain the same results presented in the reference article. We did not replicate analyses that involve changes in the network structure. Our replicated network model presents activity dynamic patterns very similar to the ones observed in the original model, with comparisons made in terms of firing rates and synchrony and irregularity measures. In conclusion, the Potjans-Diesmann model was successfully replicated in a different platform than the one in which it was originally implemented.

Intrinsic and synaptic properties of hippocampal CA1 pyramidal neurons of the Wistar Audiogenic Rat (WAR) strain, a genetic model of epilepsy

Despite the many studies focusing on epilepsy, a lot of the basic mechanisms underlying seizure susceptibility are mainly unclear. Here, we studied cellular electrical excitability, as well as excitatory and inhibitory synaptic neurotransmission of CA1 pyramidal neurons from the dorsal hippocampus of a genetic model of epilepsy, the Wistar Audiogenic Rat (WARs) in which limbic seizures appear after repeated audiogenic stimulation. We examined intrinsic properties of neurons, as well as EPSCs evoked by Schaffer-collateral stimulation in slices from WARs and Wistar parental strain. We also analyzed spontaneous IPSCs and quantal miniature inhibitory events. Our data show that even in the absence of previous seizures, GABAergic neurotransmission is reduced in the dorsal hippocampus of WARs. We observed a decrease in the frequency of IPSCs and mIPSCs. Moreover, mIPSCs of WARs had faster rise times, indicating that they probably arise from more proximal synapses. Finally, intrinsic membrane properties, firing and excitatory neurotransmission mediated by both NMDA and non-NMDA receptors are similar to the parental strain. Since GABAergic inhibition towards CA1 pyramidal neurons is reduced in WARs, the inhibitory network could be ineffective to prevent the seizure-dependent spread of hyperexcitation. These functional changes could make these animals more susceptible to the limbic seizures observed during the audiogenic kindling.

Long-term high-intensity sound stimulation inhibits h current (I h) in CA1 pyramidal neurons

Afferent neurotransmission to hippocampal pyramidal cells can lead to long‐term changes to their intrinsic membrane properties and affect many ion currents. One of the most plastic neuronal currents is the hyperpolarization‐activated cationic current (Ih), which changes in CA1 pyramidal cells in response to many types of physiological and pathological processes, including auditory stimulation. Recently, we demonstrated that long‐term potentiation (LTP) in rat hippocampal Schaffer‐CA1 synapses is depressed by high‐intensity sound stimulation. Here, we investigated whether a long‐term high‐intensity sound stimulation could affect intrinsic membrane properties of rat CA1 pyramidal neurons. Our results showed that Ih is depressed by long‐term high‐intensity sound exposure (1 min of 110 dB sound, applied two times per day for 10 days). This resulted in a decreased resting membrane potential, increased membrane input resistance and time constant, and decreased action potential threshold. In addition, CA1 pyramidal neurons from sound‐exposed animals fired more action potentials than neurons from control animals; however, this effect was not caused by a decreased Ih. On the other hand, a single episode (1 min) of 110 dB sound stimulation which also inhibits hippocampal LTP did not affect Ih and firing in pyramidal neurons, suggesting that effects on Ih are long‐term responses to high‐intensity sound exposure. Our results show that prolonged exposure to high‐intensity sound affects intrinsic membrane properties of hippocampal pyramidal neurons, mainly by decreasing the amplitude of Ih.

Non-Decaying postsynaptics potentials and delayed spikes in hippocampal pyramidal neurons generated by a zero slope conductance created by the persistent Na+ current

ABSTRACT The negative slope conductance created by the persistent sodium current (INaP) prolongs the decay phase of excitatory postsynaptic potentials (EPSPs). In a recent study, we demonstrated that this effect was due to an increase of the membrane time constant. When the negative slope conductance opposes completely the positive slope conductances of the other currents it creates a zero slope conductance region. In this region the membrane time constant is infinite and the decay phase of the EPSPs is virtually absent. Here we show that non-decaying EPSPs are present in CA1 hippocampal pyramidal cells in the zero slope conductance region, in the suprathreshold range of membrane potential. Na+ channel block with tetrodotoxin abolishes the non-decaying EPSPs. Interestingly, the non-decaying EPSPs are observed only in response to artificial excitatory postsynaptic currents (aEPSCs) of small amplitude, and not in response to aEPSCs of big amplitude. We also observed concomitantly delayed spikes with long latencies and high variability only in response to small amplitude aEPSCs. Our results showed that in CA1 pyramidal neurons INaP creates non-decaying EPSPs and delayed spikes in the subthreshold range of membrane potentials, which could potentiate synaptic integration of synaptic potentials coming from distal regions of the dendritic tree.

THE CREATION OF A NEGATIVE SLOPE CONDUCTANCE REGION BY THE ACTIVATION OF THE PERSISTENT SODIUM CURRENT PROLONGS NEAR-THRESHOLD SYNAPTIC POTENTIALS

A change of the input resistance (Rin) of the neuron involves a change in the membrane conductances by opening and closing of ion channels. In passive membranes, i.e., membranes with only linear leak conductances, the increase or decrease of these conductances leads to a decrease or increase of the Rin and the membrane time constant (τm). However, the presence of subthreshold voltage dependent currents can produce non-linear effects generating deviations from this relationship, especially the contradictory effect of negative conductances, as produced by the sodium-persistent current (INaP), on the Rin. In this work we aimed to analyze experimentally and theoretically the impact of the negative conductance produced by INaP on Rin. Experiments of whole-cell patch-clamp conducted in CA1 hippocampus pyramidal cells from brain slices showed a paradoxical voltage-dependent decrease of the Rin and the τm in subthreshold membrane potentials close to the firing threshold after the perfusion with TTX, which inhibits INaP. This effect is postulated to be a result of the negative slope conductance in the subthreshold region produced by this conductance. The analysis of the experimental data, together with simulations found that the slope conductance of INaP is negative for subthreshold membrane potentials and its magnitude is voltage dependent in the same range observed for the voltage-dependence of Rin and τm. The injection of an artificial INaP using dynamic-clamp in the presence of TTX restored the Rin and τm to its original values. Additionally the injection of an artificial leak current with a negative conductance in the presence of TTX restored the Rin and τm as the artificial Inap did. On the other hand, the injection of an artificial leak current with a positive conductance in the presence of TTX had no effect on the Rin and τm. We conclude that INaP increases the Rin and τm by the negative slope conductance observed in its non-monotonic I-V relationship. These results demonstrate that the effect of Inap on Rin and τm is stronger in potentials near the firing threshold, which could potentiate the temporal summation of the EPSPs increasing their temporal integration and facilitating action potential firing. Because of its negative slope conductance, INaP is more effective in increasing excitability near threshold than a depolarizing leak current.