The influences of somatic and dendritic inhibition on bursting patterns in a neuronal circuit model

The balance between inhibition and excitation plays a crucial role in the generation of synchronous bursting activity in neuronal circuits. In human and animal models of epilepsy, changes in both excitatory and inhibitory synaptic inputs are known to occur. Locations and distribution of these excitatory and inhibitory synaptic inputs on pyramidal cells play a role in the integrative properties of neuronal activity, e.g., epileptiform activity. Thus the location and distribution of the inputs onto pyramidal cells are important parameters that influence neuronal activity in epilepsy. However, the location and distribution of inhibitory synapses converging onto pyramidal cells have not been fully studied. The objectives of this study are to investigate the roles of the relative location of inhibitory synapses on the dendritic tree and soma in the generation of bursting activity. We investigate influences of somatic and dendritic inhibition on bursting activity patterns in several paradigms of potential connections using a simplified multicompartmental model. We also investigate the effects of distribution of fast and slow components of GABAergic inhibition in pyramidal cells. Interspike interval (ISI) analysis is used for examination of bursting patterns. Simulations show that the inhibitory interneuron regulates neuronal bursting activity. Bursting behavior patterns depend on the synaptic weight and delay of the inhibitory connection as well as the location of the synapse. When the inhibitory interneuron synapses on the pyramidal neuron, inhibitory action is stronger if the inhibitory synapse is close to the soma. Alterations of synaptic weight of the interneuron can be compensatory for changes in the location of synaptic input. The relative changes in these parameters exert a considerable influence on whether synchronous bursting activity is facilitated or reduced. Additional simulations show that the slow GABAergic inhibitory component is more effective than the fast component in distal dendrites. Taken together, these findings illustrate the potential for GABAergic inhibition in the soma and dendritic tree to play an important modulatory role in bursting activity patterns.     

Long-Term Relationships between Synaptic Tenacity, Synaptic Remodeling, and Network Activity

Synaptic plasticity is widely believed to constitute a key mechanism for modifying functional properties of neuronal networks. This belief implicitly implies, however, that synapses, when not driven to change their characteristics by physiologically relevant stimuli, will maintain these characteristics over time. How tenacious are synapses over behaviorally relevant time scales? To begin to address this question, we developed a system for continuously imaging the structural dynamics of individual synapses over many days, while recording network activity in the same preparations. We found that in spontaneously active networks, distributions of synaptic sizes were generally stable over days. Following individual synapses revealed, however, that the apparently static distributions were actually steady states of synapses exhibiting continual and extensive remodeling. In active networks, large synapses tended to grow smaller, whereas small synapses tended to grow larger, mainly during periods of particularly synchronous activity. Suppression of network activity only mildly affected the magnitude of synaptic remodeling, but dependence on synaptic size was lost, leading to the broadening of synaptic size distributions and increases in mean synaptic size. From the perspective of individual neurons, activity drove changes in the relative sizes of their excitatory inputs, but such changes continued, albeit at lower rates, even when network activity was blocked. Our findings show that activity strongly drives synaptic remodeling, but they also show that significant remodeling occurs spontaneously. Whereas such spontaneous remodeling provides an explanation for “synaptic homeostasis” like processes, it also raises significant questions concerning the reliability of individual synapses as sites for persistently modifying network function.     

A novel network of multipolar bursting interneurons generates theta frequency oscillations in neocortex

GABAergic interneurons can phase the output of principal cells, giving rise to oscillatory activity in different frequency bands. Here we describe a new subtype of GABAergic interneuron, the multipolar bursting (MB) cell in the mouse neocortex. MB cells are parvalbumin positive but differ from fast-spiking multipolar (FS) cells in their morphological, neurochemical, and physiological properties. MB cells are reciprocally connected with layer 2/3 pyramidal cells and are coupled with each other by chemical and electrical synapses. MB cells innervate FS cells but not vice versa. MB to MB cell as well as MB to pyramidal cell synapses exhibit paired-pulse facilitation. Carbachol selectively induced synchronized theta frequency oscillations in MB cells. Synchrony required both gap junction coupling and GABAergic chemical transmission, but not excitatory glutamatergic input. Hence, MB cells form a distinct inhibitory network, which upon cholinergic drive can generate rhythmic and synchronous theta frequency activity, providing temporal coordination of pyramidal cell output.     

LTP promotes a selective long-term stabilization and clustering of dendritic spines

Dendritic spines are the main postsynaptic site of excitatory contacts between neurons in the central nervous system. On cortical neurons, spines undergo a continuous turnover regulated by development and sensory activity. However, the functional implications of this synaptic remodeling for network properties remain currently unknown. Using repetitive confocal imaging on hippocampal organotypic cultures, we find that learning-related patterns of activity that induce long-term potentiation act as a selection mechanism for the stabilization and localization of spines. Through a lasting N-methyl-D-aspartate receptor and protein synthesis–dependent increase in protrusion growth and turnover, induction of plasticity promotes a pruning and replacement of nonactivated spines by new ones together with a selective stabilization of activated synapses. Furthermore, most newly formed spines preferentially grow in close proximity to activated synapses and become functional within 24 h, leading to a clustering of functional synapses. Our results indicate that synaptic remodeling associated with induction of long-term potentiation favors the selection of inputs showing spatiotemporal interactions on a given neuron.     

Noise-tolerant stimulus discrimination by synchronization with depressing synapses

 Some synapses between cortical pyramidal neurons exhibit a rapid depression of excitatory postsynaptic potentials for successive presynaptic spikes. Since depressing synapses do not transmit information on sustained presynaptic firing rates, it has been speculated that they are favorable for temporal coding. In this paper, we study the dynamical effects of depressing synapses on stimulus-induced transient synchronization in a simple network of inhibitory interneurons and excitatory neurons, assuming that the recurrent excitation is mediated by depressing synapses. This synchronization occurs in a temporal pattern which depends on a given stimulus. Since the presence of noise is always a potential hazard in temporal coding, we investigate the extent to which noise in stimuli influences the synchronization phenomena. It is demonstrated that depressing synapses greatly contribute to suppressing the influences of noise on the stimulus-specific temporal patterns of synchronous firing. The timing-based Hebbian learning revealed by physiological experiments is shown to stabilize the temporal patterns in cooperation with synaptic depression. Thus, the times at which synchronous firing occurs provides a reliable information representation in the presence of synaptic depression. Received: 5 July 2000 / Accepted in revised form: 12 January 2001     

Bursting Reverberation as a Multiscale Neuronal Network Process Driven by Synaptic Depression-Facilitation

Neuronal networks can generate complex patterns of activity that depend on membrane properties of individual neurons as well as on functional synapses. To decipher the impact of synaptic properties and connectivity on neuronal network behavior, we investigate the responses of neuronal ensembles from small (5–30 cells in a restricted sphere) and large (acute hippocampal slice) networks to single electrical stimulation: in both cases, a single stimulus generated a synchronous long-lasting bursting activity. While an initial spike triggered a reverberating network activity that lasted 2–5 seconds for small networks, we found here that it lasted only up to 300 milliseconds in slices. To explain this phenomena present at different scales, we generalize the depression-facilitation model and extracted the network time constants. The model predicts that the reverberation time has a bell shaped relation with the synaptic density, revealing that the bursting time cannot exceed a maximum value. Furthermore, before reaching its maximum, the reverberation time increases sub-linearly with the synaptic density of the network. We conclude that synaptic dynamics and connectivity shape the mean burst duration, a property present at various scales of the networks. Thus bursting reverberation is a property of sufficiently connected neural networks, and can be generated by collective depression and facilitation of underlying functional synapses.     

TNFα controls glutamatergic gliotransmission in the hippocampal dentate gyrus

Glutamatergic gliotransmission provides a stimulatory input to excitatory synapses in the hippocampal dentate gyrus. Here, we show that tumor necrosis factor-alpha (TNFα) critically controls this process. With constitutive TNFα present, activation of astrocyte P2Y1 receptors induces localized [Ca(2+)](i) elevations followed by glutamate release and presynaptic NMDA receptor-dependent synaptic potentiation. In preparations lacking TNFα, astrocytes respond with identical [Ca(2+)](i) elevations but fail to induce neuromodulation. We find that TNFα specifically controls the glutamate release step of gliotransmission. In cultured astrocytes lacking TNFα glutamate exocytosis is dramatically slowed down due to altered vesicle docking. Addition of low picomolar TNFα promptly reconstitutes both normal exocytosis in culture and gliotransmission in situ. Alternatively, gliotransmission can be re-established without adding TNFα, by limiting glutamate uptake, which compensates slower release. These findings demonstrate that gliotransmission and its synaptic effects are controlled not only by astrocyte [Ca(2+)](i) elevations but also by permissive/homeostatic factors like TNFα. VIDEO ABSTRACT:     

Inferring network activity from synaptic noise

During intense network activity in vivo, cortical neurons are in a high-conductance state, in which the membrane potential (V(m)) is subject to a tremendous fluctuating activity. Clearly, this "synaptic noise" contains information about the activity of the network, but there are presently no methods available to extract this information. We focus here on this problem from a computational neuroscience perspective, with the aim of drawing methods to analyze experimental data. We start from models of cortical neurons, in which high-conductance states stem from the random release of thousands of excitatory and inhibitory synapses. This highly complex system can be simplified by using global synaptic conductances described by effective stochastic processes. The advantage of this approach is that one can derive analytically a number of properties from the statistics of resulting V(m) fluctuations. For example, the global excitatory and inhibitory conductances can be extracted from synaptic noise, and can be related to the mean activity of presynaptic neurons. We show here that extracting the variances of excitatory and inhibitory synaptic conductances can provide estimates of the mean temporal correlation-or level of synchrony-among thousands of neurons in the network. Thus, "probing the network" through intracellular V(m) activity is possible and constitutes a promising approach, but it will require a continuous effort combining theory, computational models and intracellular physiology.     

Coordinated peripheral neuronal activities among the different regions of the digestive tract in Aplysia

Peripheral neuronal somata are scattered throughout the enteric nervous system (ENS) in Aplysia. We found that somata on the outer surface of the digestive tract were more densely distributed on the stomatogastric ring and the posterior gizzard than on other regions. In preparations with or without the central nervous system, two types of synchronous bursting activity were recorded from the nerves of the ENS. Some of the synchronous bursts were recorded from nerves on the crop and stomatogastric ring, whereas others were recorded from nerves on the crop, stomatogastric ring, and gizzard. Experiments using preparations in which the different regions were separated suggested that the former bursts originated in neurons on the crop and the latter originated in neurons on the gizzard. Axonal projections of neurons on the different regions were examined by backfilling and analysis of the direction of impulse conduction. Blocking chemical synapses in separated gizzards depressed EPSP-like potentials and eliminated the bursting activities. When chemical synapses on the crop and stomatogastric ring but not on the gizzard were blocked in a whole digestive tract preparation, bursting activity recorded from nerves on all the regions was decreased, although the frequency of the bursting rhythm did not change. Stimulation of a neuron on the crop elicited bursts in nerves on the gizzard. These results suggest that chemical synaptic connections and a feedback loop along the digestive tract coordinate the synchrony of bursting activity originating in the gizzard.     

Effects and mechanisms of wakefulness on local cortical networks

Mammalian brains generate internal activity independent of environmental stimuli. Internally generated states may bring about distinct cortical processing modes. To investigate how brain state impacts cortical circuitry, we recorded intracellularly from the same neurons, under anesthesia and subsequent wakefulness, in rat barrel cortex. In every cell examined throughout layers 2-6, wakefulness produced a temporal pattern of synaptic inputs?differing markedly from those under anesthesia. Recurring periods of synaptic quiescence, prominent under anesthesia, were abolished by wakefulness, which produced instead a persistently depolarized state. This switch in dynamics was unaffected by elimination of afferent synaptic input from thalamus, suggesting that arousal alters cortical dynamics by neuromodulators acting directly on cortex. Indeed, blockade of noradrenergic, but not cholinergic, pathways induced synaptic quiescence during wakefulness. We conclude that global brain states can switch local recurrent networks into different regimes via direct neuromodulation.     

Activity-dependent regulation of vesicular glutamate and GABA transporters: a means to scale quantal size

The functional balance of glutamatergic and GABAergic signaling in neuronal cortical circuits is under homeostatic control. That is, prolonged alterations of global network activity leads to opposite changes in quantal amplitude at glutamatergic and GABAergic synapses. Such scaling of excitatory and inhibitory transmission within cortical circuits serves to restore and maintain a constant spontaneous firing rate of pyramidal neurons. Our recent work shows that this includes alterations in the levels of expression of vesicular glutamate (VGLUT1 and VGLUT2) and GABA (VIAAT) transporters. Other vesicle markers, such as synaptophysin or synapsin, are not regulated in this way. Endogenous regulation at the level of mRNA and synaptic protein controls the number of transporters per vesicle and hence, the level of vesicle filling with transmitter. Bidirectional and opposite activity-dependent regulation of VGLUT1 and VIAAT expression would serve to adjust the balance of glutamate and GABA release and therefore the level of postsynaptic receptor saturation. In some excitatory neurons and synapses, co-expression of VGLUT1 and VGLUT2 occurs. Bidirectional and opposite changes in the levels of two excitatory vesicular transporters would enable individual neocortical neurons to scale up or scale down the level of vesicular glutamate storage, and thus, the amount available for release at individual synapses. Regulated vesicular transmitter storage and release via selective changes in the level of expression of vesicular glutamate and GABA transporters indicates that homeostatic plasticity of synaptic strength at cortical synapses includes presynaptic elements.     

Inhibitory Contribution to Suprathreshold Corticostriatal Responses: An Experimental and Modeling Study

Neostriatal neurons may undergo events of spontaneous synchronization as those observed in recurrent networks of excitatory neurons, even when cortical afferents are transected. It is necessary to explain these events because the neostriatum is a recurrent network of inhibitory neurons. Synchronization of neuronal activity may be caused by plateau-like depolarizations. Plateau-like orthodromic depolarizations that resemble up-states in medium spiny neostriatal neurons (MSNs) may be induced by a single corticostriatal suprathreshold stimulus. Slow synaptic depolarizations may last hundreds of milliseconds, decay slower than the monosynaptic glutamatergic synaptic potentials that induce them, and sustain repetitive firing. Because inhibitory inputs impinging onto MSNs have a reversal potential above the resting membrane potential but below the threshold for firing, they conform a type of “shunting inhibition”. This work asks if shunting GABAergic inputs onto MSNs arrive asynchronously enough as to help in sustaining the plateau-like corticostriatal response after a single cortical stimulus. This may help to begin explaining autonomous processing in the striatal micro-circuitry in the presence of a tonic excitatory drive and independently of spatio-temporally organized inputs. It is shown here that besides synaptic currents from AMPA/KA- and NMDA-receptors, as well as L-type intrinsic Ca²⁺- currents, inhibitory synapses help in maintaining the slow depolarization, although they accomplish the role of depressing firing at the beginning of the response. We then used a NEURON model of spiny cells to show that inhibitory synapses arriving asynchronously on the dendrites can help to simulate a plateau potential similar to that observed experimentally. Electronic supplementary material  The online version of this article (doi:) contains supplementary material, which is available to authorized users.     

A shift in protein S‐palmitoylation,with persistence of growth‐associated substrates,marks a critical period for synaptic plasticity in developing brain

In the mammalian cortex, the initial formation of synaptic connections is followed by a prolonged period during which synaptic circuits are functional, but retain an elevated capacity for activity‐dependent remodeling and functional plasticity. During this period, synaptic terminals appear fully mature, morphologically and physiologically. We show here, however, that synaptic terminals during this period are distinguished by their simultaneous accumulation of multiple growth‐associated proteins at levels characteristic of axonal growth cones, and proteins involved in synaptic transmitter release at levels characteristic of adult synapses. We show further that newly formed synapses undergo a switch in the dynamic S‐palmitoylation of proteins early in the critical period, which includes a large and specific decrease in the palmitoylation of GAP‐43 and other major substrates characteristic of growth cones. Previous studies have shown that a similar reduction in ongoing palmitoylation of growth cone proteins is sufficient to stop advancing axons in vitro, suggesting that a developmental switch in protein S‐palmitoylation serves to disengage the molecular machinery for axon extension in the absence of local triggers for remodeling during the critical period. Only much later does a decline in the availability of major growth cone components mark the molecular maturation of cortical synapses at the close of the critical period. © 1999 John Wiley & Sons, Inc. J Neurobiol 39: 423–437, 1999     

Some cholinergic themes related to Alzheimer's disease: Synaptology of the nucleus basalis,location of m2 receptors,interactions with amyloid metabolism,and perturbations of cortical plasticity

Cholinergic neurons in the nucleus basalis of Meynert (nbM) receive cholinergic, GABAergic and monoaminergic synapses. Only few of these neurons display the sort of intense m2 immunoreactivity that would be expected if they were expressing m2 as their presynaptic autoreceptor. The depletion of cortical m2 in Alzheimer's disease (AD) appears to reflect the loss of presynaptic autoreceptors located on incoming axons from the nucleus basalis of Meynert (nbM) and also the loss of postsynaptic receptors located on a novel group of nitric oxide producing interstitial neurons in the cerebral cortex. The defect of cholinergic transmission in AD may enhance the neurotoxicity of amyloid β, leading to a vicious cycle which can potentially accelerate the pathological process. Because acetylcholine plays a critical role in regulating axonal growth and synaptic remodeling, the cholinergic loss in AD can perturb cortical plasticity so as to undermine the already fragile compensatory reserve of the aging cerebral cortex.     

Population rate coding in recurrent neuronal networks with unreliable synapses

Neuron transmits spikes to postsynaptic neurons through synapses. Experimental observations indicated that the communication between neurons is unreliable. However most modelling and computational studies considered deterministic synaptic interaction model. In this paper, we investigate the population rate coding in an all-to-all coupled recurrent neuronal network consisting of both excitatory and inhibitory neurons connected with unreliable synapses. We use a stochastic on-off process to model the unreliable synaptic transmission. We find that synapses with suitable successful transmission probability can enhance the encoding performance in the case of weak noise; while in the case of strong noise, the synaptic interactions reduce the encoding performance. We also show that several important synaptic parameters, such as the excitatory synaptic strength, the relative strength of inhibitory and excitatory synapses, as well as the synaptic time constant, have significant effects on the performance of the population rate coding. Further simulations indicate that the encoding dynamics of our considered network cannot be simply determined by the average amount of received neurotransmitter for each neuron in a time instant. Moreover, we compare our results with those obtained in the corresponding random neuronal networks. Our numerical results demonstrate that the network randomness has the similar qualitative effect as the synaptic unreliability but not completely equivalent in quantity.     

Conflicting effects of excitatory synaptic and electric coupling on the dynamics of square-wave bursters

Using two-cell and 50-cell networks of square-wave bursters, we studied how excitatory coupling of individual neurons affects the bursting output of the network. Our results show that the effects of synaptic excitation vs. electrical coupling are distinct. Increasing excitatory synaptic coupling generally increases burst duration. Electrical coupling also increases burst duration for low to moderate values, but at sufficiently strong values promotes a switch to highly synchronous bursts where further increases in electrical or synaptic coupling have a minimal effect on burst duration. These effects are largely mediated by spike synchrony, which is determined by the stability of the in-phase spiking solution during the burst. Even when both coupling mechanisms are strong, one form (in-phase or anti-phase) of spike synchrony will determine the burst dynamics, resulting in a sharp boundary in the space of the coupling parameters. This boundary exists in both two cell and network simulations. We use these results to interpret the effects of gap-junction blockers on the neuronal circuitry that underlies respiration.     

State transitions through inhibitory interneurons in a cortical network model

Inhibitory interneurons shape the spiking characteristics and computational properties of cortical networks. Interneuron subtypes can precisely regulate cortical function but the roles of interneuron subtypes for promoting different regimes of cortical activity remains unclear. Therefore, we investigated the impact of fast spiking and non-fast spiking interneuron subtypes on cortical activity using a network model with connectivity and synaptic properties constrained by experimental data. We found that network properties were more sensitive to modulation of the fast spiking population, with reductions of fast spiking excitability generating strong spike correlations and network oscillations. Paradoxically, reduced fast spiking excitability produced a reduction of global excitation-inhibition balance and features of an inhibition stabilised network, in which firing rates were driven by the activity of excitatory neurons within the network. Further analysis revealed that the synaptic interactions and biophysical features associated with fast spiking interneurons, in particular their rapid intrinsic response properties and short synaptic latency, enabled this state transition by enhancing gain within the excitatory population. Therefore, fast spiking interneurons may be uniquely positioned to control the strength of recurrent excitatory connectivity and the transition to an inhibition stabilised regime. Overall, our results suggest that interneuron subtypes can exert selective control over excitatory gain allowing for differential modulation of global network state.     

Modeling of Rhythmogenesis in an Ensemble of Cortical Neurons Connected with Electrical Synapses

Based on our own data on generation of spindle-like field electrical activity in neuronal barrels of the rat somatic cortex and also on the published data on the properties of voltage-dependent channels in the membranes of cortical cells, we developed a model of the ensemble (simple network) of neurons connected by electrical synapses. Such connections were found earlier in neurophysiological and ultramicroscopic studies. Model neurons with membranes having sodium, potassium, and calcium channels described in the literature were capable of generating bursting rhythmic impulse activity under conditions of switching off of synaptic connections between cells (isolation). With switching on of electrical synapses, spiking generated by separate neurons, which initially was nonsynchronous, became synchronized in time. Ipso facto, we demonstrated the ability of pacemaker oscillatory activity to be electrotonically synchronized in ensembles of neurons connected with electrical synapses.     

An integrate-and-fire model for synchronized bursting in a network of cultured cortical neurons

It has been suggested that spontaneous synchronous neuronal activity is an essential step in the formation of functional networks in the central nervous system. The key features of this type of activity consist of bursts of action potentials with associated spikes of elevated cytoplasmic calcium. These features are also observed in networks of rat cortical neurons that have been formed in culture. Experimental studies of these cultured networks have led to several hypotheses for the mechanisms underlying the observed synchronized oscillations. In this paper, bursting integrate-and-fire type mathematical models for regular spiking (RS) and intrinsic bursting (IB) neurons are introduced and incorporated through a small-world connection scheme into a two-dimensional excitatory network similar to those in the cultured network. This computer model exhibits spontaneous synchronous activity through mechanisms similar to those hypothesized for the cultured experimental networks. Traces of the membrane potential and cytoplasmic calcium from the model closely match those obtained from experiments. We also consider the impact on network behavior of the IB neurons, the geometry and the small world connection scheme. Action Editor: David Golomb     

A shift in protein S-palmitoylation, with persistence of growth-associated substrates, marks a critical period for synaptic plasticity in developing brain.

In the mammalian cortex, the initial formation of synaptic connections is followed by a prolonged period during which synaptic circuits are functional, but retain an elevated capacity for activity-dependent remodeling and functional plasticity. During this period, synaptic terminals appear fully mature, morphologically and physiologically. We show here, however, that synaptic terminals during this period are distinguished by their simultaneous accumulation of multiple growth-associated proteins at levels characteristic of axonal growth cones, and proteins involved in synaptic transmitter release at levels characteristic of adult synapses. We show further that newly formed synapses undergo a switch in the dynamic S-palmitoylation of proteins early in the critical period, which includes a large and specific decrease in the palmitoylation of GAP-43 and other major substrates characteristic of growth cones. Previous studies have shown that a similar reduction in ongoing palmitoylation of growth cone proteins is sufficient to stop advancing axons in vitro, suggesting that a developmental switch in protein S-palmitoylation serves to disengage the molecular machinery for axon extension in the absence of local triggers for remodeling during the critical period. Only much later does a decline in the availability of major growth cone components mark the molecular maturation of cortical synapses at the close of the critical period.