Properties and function of somatostatin-containing inhibitory interneurons in the somatosensory cortex of the mouse

GABAergic inhibitory interneurons play a pivotal role in balancing neuronal activity in the neocortex. They can be classified into different classes according to their variable morphological, electrophysiological, and neurochemical properties, including two major groups: parvalbumin-containing (PV+), fast-spiking (FS) cells and somatostatin-containing (SOM+) cells. Using transgenic mice, we identified two subgroups, distinct by all criteria, of SOM+ cells in the somatosensory (barrel) cortex of the mouse, one (called X94) in layer 4 and 5B, and the other one (X98) in deep layers (Ma et al., 2006). We found that X98 cells were calbindin-expressing (CB+), infragranular, layer 1--targeting Martinotti cells, and had a propensity to fire low-threshold calcium spikes, whereas X94 cells did not express CB, targeted mostly layer 4, discharged in stuttering pattern and with quasi fast-spiking properties. In the barrel cortex, it was previously shown that SOM+ cells mediate disynaptic inhibition in supragranular and infragranular layers. However, the roles of layer 4 SOM+ cells remain largely unknown. We used dual whole-cell recording to elucidate the synaptic circuits in layer 4 and the function of layer 4 SOM+ cells during cortical network activities. We found that layer 4 X94 SOM+ cells received strongly facilitating excitatory input and generated relatively slow rising inhibitory postsynaptic currents (IPSCs) compared to those evoked by FS cells. Strikingly, our data showed that SOM+ cells mediated strong synaptic inhibition of FS cells with connection probability greater than 90% in layer 4, but received very little reciprocal inhibition from FS cells, and no reciprocal inhibition from other SOM+ cells. Moreover, 100% of recorded SOM+-SOM+ cell pairs were electrically coupled with higher coupling ratio compared to that of electrically coupled FS cell pairs. In order to examine the functions of SOM+ cells, we applied 0 Mg2+ artificial cerebrospinal fluid (ACSF) to induce episodes of cortical network activity and observed that, during episodes of network activity, SOM+ cells fired robustly and synchronously, and produced strong inhibition of regular-spiking (RS) excitatory cells and inhibitory FS cells, especially the latter. Taken together, our data reveal that SOM+ cells in the barrel cortex can be sub-divided into different subtypes, and that layer 4 SOM+ cells exert a powerful inhibitory effect during high frequency network activity

Striatal Fast-Spiking Interneurons: From Firing Patterns to Postsynaptic Impact

In the striatal microcircuit, fast-spiking (FS) interneurons have an important role in mediating inhibition onto neighboring medium spiny (MS) projection neurons. In this study, we combined computational modeling with in vitro and in vivo electrophysiological measurements to investigate FS cells in terms of their discharge properties and their synaptic efficacies onto MS neurons. In vivo firing of striatal FS interneurons is characterized by a high firing variability. It is not known, however, if this variability results from the input that FS cells receive, or if it is promoted by the stuttering spike behavior of these neurons. Both our model and measurements in vitro show that FS neurons that exhibit random stuttering discharge in response to steady depolarization do not show the typical stuttering behavior when they receive fluctuating input. Importantly, our model predicts that electrically coupled FS cells show substantial spike synchronization only when they are in the stuttering regime. Therefore, together with the lack of synchronized firing of striatal FS interneurons that has been reported in vivo, these results suggest that neighboring FS neurons are not in the stuttering regime simultaneously and that in vivo FS firing variability is more likely determined by the input fluctuations. Furthermore, the variability in FS firing is translated to variability in the postsynaptic amplitudes in MS neurons due to the strong synaptic depression of the FS-to-MS synapse. Our results support the idea that these synapses operate over a wide range from strongly depressed to almost fully recovered. The strong inhibitory effects that FS cells can impose on their postsynaptic targets, and the fact that the FS-to-MS synapse model showed substantial depression over extended periods of time might indicate the importance of cooperative effects of multiple presynaptic FS interneurons and the precise orchestration of their activity

Intrinsic and synaptic membrane properties of neurons in the thalamic reticular nucleus

Tableau d’honneur de la Faculté des études supérieures et postdoctorales, 2004-2005Le noyau réticulaire thalamique (RE) est une structure qui engendre des fuseaux, une oscillation bioélectrique de marque pendant les stades précoces du sommeil. De multiples propriétés neuronales, intrinsèques et synaptiques, sont impliquées dans la génération, la propagation, le maintien et la terminaison des ondes en fuseaux. D’un autre côté, ce rythme constitue un état spécial de l’activité du réseau qui est généré par le réseau lui-même et affecte les propriétés cellulaires du noyau RE. Cette étude se concentre sur ces sujets: comment les propriétés cellulaires et les propriétés du réseau sont inter-reliées et interagissent pour engendrer les ondes fuseaux dans les neurones du RE et leurs cibles, les neurones thalamocorticaux. La présente thèse fournit de nouvelles évidences montrant le rôle fondamental joué par les neurones du noyau RE dans la genèse des ondes en fuseaux, dû aux synapses chimiques établies par ces neurones. La propagation et la synchronisation de l’activité sont modulées par les synapses électriques entre les neurones réticulaires thalamiques, mais aussi par les composantes dépolarisantes secondaires des réponses synaptiques évoquées par le cortex. De plus, la forme générale et la terminaison des oscillations thalamiques sont probablement contrôlées en grande partie par les neurones du RE, lesquels expriment une conductance intrinsèque leurs procurant une membrane avec un comportement bistable. Finalement, les oscillations thalamiques en fuseaux sont aussi capables de moduler les propriétés membranaires et l’activité des neurones individuels du RE.The thalamic reticular nucleus (RE) is a key structure related to spindles, a hallmark bioelectrical oscillation during early stages of sleep. Multiple neuronal properties, both intrinsic and synaptic, are implicated in the generation, propagation, maintenance and termination of spindle waves. On the other hand, this rhythm constitutes a special state of network activity, which is generated within, and affects single-cell properties of the RE nucleus. This study is focused on these topics: how cellular and network properties are interrelated and interact to generate spindle waves in the pacemaking RE neurons and their targets, thalamocortical neurons. The present thesis provides new evidence showing the fundamental role played by the RE nucleus in the generation of spindle waves, due to chemical synapses established by its neurons. The propagation and synchronization of activity is modulated by electrical synapses between thalamic reticular neurons, but also by the secondary depolarizing component of cortically-evoked synaptic responses. Additionally, the general shaping and probably the termination of thalamic oscillations could be controlled to a great extent by RE neurons, which express an intrinsic conductance endowing them with membrane bistable behaviour. Finally, thalamic spindle oscillations are also able to modulate the membrane properties and activities of individual RE neurons

Structure and Function in the Inferior Olivary Nucleus

The inferior olivary nucleus is the source of the climbing fibres, one of the two major afferent pathways into the cerebellum. This thesis is concerned with aspects of the cellular anatomy and physiology of neurons in the inferior olive. In the first chapter, I report on the first direct patch-clamp recordings from olivary axons, and show that they fire in short bursts that can relay information about the state of olivary network and modulate plasticity in the cerebellar cortex. A remarkable feature of the olive is the widespread electrotonic coupling between neurons underlying their synchronous firing. In the second chapter I combine electrophysiological and immunohistological methods to characterize the coupling. I reveal the first morphological reconstructions of coupled pairs of olivary neurons, and show that the dendritic spines responsible for coupling neurons have very heterogeneous morphologies. Furthermore, I show that olivary dendrites may contact olivary somata and oligodendrocytes. In the third chapter, I use pharmacology and modelling to study the effect of inhibitory synapses on the coupling between olivary neurons. Confirming a popular theory, I show that GABA-A receptor activation reduces coupling between neurons, and use models to study the effect of location, timing and stochastic properties of the inhibitory input on electrical coupling. The common theme for all our findings is that the remarkable interplay between the anatomy and electrophysiological characteristics of the inferior olive underlies a unique computational unit in the central nervous system

Axonal gap junctions between principal neurons: a novel source of network oscillations, and perhaps epileptogenesis

We hypothesized in 1998 that gap junctions might be located between the axons of principal hippocampal neurons, based on the shape of spikelets (fast prepotentials), occurring during gap junction-mediated very fast (to approximately 200 Hz) network oscillations in vitro. More recent electrophysiological, pharmacological and dye-coupling data indicate that axonal gap junctions exist; so far, they appear to be located about 100 microm from the soma, in CA1 pyramidal neurons. Computer modeling and theory predict that axonal gap junctions can lead to very fast network oscillations under three conditions: a) there are spontaneous axonal action potentials; b) the number of gap junctions in the network is neither too low (not less than to approximately 1.5 per cell on average), nor too high (not more than to approximately 3 per cell on average); c) action potentials can cross from axon to axon via gap junctions. Simulated oscillations resemble biological ones, but condition (c) remains to be demonstrated directly. Axonal network oscillations can, in turn, induce oscillatory activity in larger neuronal networks, by a variety of mechanisms. Axonal networks appear to underlie in vivo ripples (to approximately 200 Hz field potential oscillations superimposed on physiological sharp waves), to drive gamma (30-70 Hz) oscillations that appear in the presence of carbachol, and to initiate certain types of ictal discharge. If axonal gap junctions are important for seizure initiation in humans, there could be practical consequences for antiepileptic therapy: at least one gap junction-blocking compound, carbenoxolone, is already in clinical use (for treatment of ulcer disease), and it crosses the blood-brain barrier

A biophysical model of striatal microcircuits suggests gamma and beta oscillations interleaved at delta/theta frequencies mediate periodicity in motor control

Striatal oscillatory activity is associated with movement, reward, and decision-making, and observed in several interacting frequency bands. Local field potential recordings in rodent striatum show dopamine- and reward-dependent transitions between two states: a "spontaneous" state involving β (∼15-30 Hz) and low γ (∼40-60 Hz), and a state involving θ (∼4-8 Hz) and high γ (∼60-100 Hz) in response to dopaminergic agonism and reward. The mechanisms underlying these rhythmic dynamics, their interactions, and their functional consequences are not well understood. In this paper, we propose a biophysical model of striatal microcircuits that comprehensively describes the generation and interaction of these rhythms, as well as their modulation by dopamine. Building on previous modeling and experimental work suggesting that striatal projection neurons (SPNs) are capable of generating β oscillations, we show that networks of striatal fast-spiking interneurons (FSIs) are capable of generating δ/θ (ie, 2 to 6 Hz) and γ rhythms. Under simulated low dopaminergic tone our model FSI network produces low γ band oscillations, while under high dopaminergic tone the FSI network produces high γ band activity nested within a δ/θ oscillation. SPN networks produce β rhythms in both conditions, but under high dopaminergic tone, this β oscillation is interrupted by δ/θ-periodic bursts of γ-frequency FSI inhibition. Thus, in the high dopamine state, packets of FSI γ and SPN β alternate at a δ/θ timescale. In addition to a mechanistic explanation for previously observed rhythmic interactions and transitions, our model suggests a hypothesis as to how the relationship between dopamine and rhythmicity impacts motor function. We hypothesize that high dopamine-induced periodic FSI γ-rhythmic inhibition enables switching between β-rhythmic SPN cell assemblies representing the currently active motor program, and thus that dopamine facilitates movement in part by allowing for rapid, periodic shifts in motor program execution.R01 MH114877 - NIMH NIH HHSPublished versio

Inferring connection proximity in networks of electrically coupled cells by subthreshold frequency response analysis

Electrical synapses continuously transfer signals bi-directionally from one cell to another, directly or indirectly via intermediate cells. Electrical synapses are common in many brain structures such as the inferior olive, the subcoeruleus nucleus and the neocortex, between neurons and between glial cells. In the cortex, interneurons have been shown to be electrically coupled and proposed to participate in large, continuous cortical syncytia, as opposed to smaller spatial domains of electrically coupled cells. However, to explore the significance of these findings it is imperative to map the electrical synaptic microcircuits, in analogy with in vitro studies on monosynaptic and disynaptic chemical coupling. Since "walking” from cell to cell over large distances with a glass pipette is challenging, microinjection of (fluorescent) dyes diffusing through gap-junctions remains so far the only method available to decipher such microcircuits even though technical limitations exist. Based on circuit theory, we derive analytical descriptions of the AC electrical coupling in networks of isopotential cells. We then suggest an operative electrophysiological protocol to distinguish between direct electrical connections and connections involving one or more intermediate cells. This method allows inferring the number of intermediate cells, generalizing the conventional coupling coefficient, which provides limited information. We validate our method through computer simulations, theoretical and numerical methods and electrophysiological paired recording

Investigating the role of fast-spiking interneurons in neocortical dynamics

PhD ThesisFast-spiking interneurons are the largest interneuronal population in neocortex. It is well documented that this population is crucial in many functions of the neocortex by subserving all aspects of neural computation, like gain control, and by enabling dynamic phenomena, like the generation of high frequency oscillations. Fast-spiking interneurons, which represent mainly the parvalbumin-expressing, soma-targeting basket cells, are also implicated in pathological dynamics, like the propagation of seizures or the impaired coordination of activity in schizophrenia. In the present thesis, I investigate the role of fast-spiking interneurons in such dynamic phenomena by using computational and experimental techniques. First, I introduce a neural mass model of the neocortical microcircuit featuring divisive inhibition, a gain control mechanism, which is thought to be delivered mainly by the soma-targeting interneurons. Its dynamics were analysed at the onset of chaos and during the phenomena of entrainment and long-range synchronization. It is demonstrated that the mechanism of divisive inhibition reduces the sensitivity of the network to parameter changes and enhances the stability and exibility of oscillations. Next, in vitro electrophysiology was used to investigate the propagation of activity in the network of electrically coupled fast-spiking interneurons. Experimental evidence suggests that these interneurons and their gap junctions are involved in the propagation of seizures. Using multi-electrode array recordings and optogenetics, I investigated the possibility of such propagating activity under the conditions of raised extracellular K+ concentration which applies during seizures. Propagated activity was recorded and the involvement of gap junctions was con rmed by pharmacological manipulations. Finally, the interaction between two oscillations was investigated. Two oscillations with di erent frequencies were induced in cortical slices by directly activating the pyramidal cells using optogenetics. Their interaction suggested the possibility of a coincidence detection mechanism at the circuit level. Pharmacological manipulations were used to explore the role of the inhibitory interneurons during this phenomenon. The results, however, showed that the observed phenomenon was not a result of synaptic activity. Nevertheless, the experiments provided some insights about the excitability of the tissue through scattered light while using optogenetics. This investigation provides new insights into the role of fast-spiking interneurons in the neocortex. In particular, it is suggested that the gain control mechanism is important for the physiological oscillatory dynamics of the network and that the gap junctions between these interneurons can potentially contribute to the inhibitory restraint during a seizure.Wellcome Trust

Synchronization and oscillatory dynamics in heterogeneous mutually inhibited neurons

We study some mechanisms responsible for synchronous oscillations and loss of synchrony at physiologically relevant frequencies (10-200 Hz) in a network of heterogeneous inhibitory neurons. We focus on the factors that determine the level of synchrony and frequency of the network response, as well as the effects of mild heterogeneity on network dynamics. With mild heterogeneity, synchrony is never perfect and is relatively fragile. In addition, the effects of inhibition are more complex in mildly heterogeneous networks than in homogeneous ones. In the former, synchrony is broken in two distinct ways, depending on the ratio of the synaptic decay time to the period of repetitive action potentials ($\tau_s/T$), where $T$ can be determined either from the network or from a single, self-inhibiting neuron. With $\tau_s/T > 2$, corresponding to large applied current, small synaptic strength or large synaptic decay time, the effects of inhibition are largely tonic and heterogeneous neurons spike relatively independently. With $\tau_s/T < 1$, synchrony breaks when faster cells begin to suppress their less excitable neighbors; cells that fire remain nearly synchronous. We show numerically that the behavior of mildly heterogeneous networks can be related to the behavior of single, self-inhibiting cells, which can be studied analytically.Comment: 17 pages, 6 figures, Kluwer.sty. Journal of Compuational Neuroscience (in press). Originally submitted to the neuro-sys archive which was never publicly announced (was 9802001