The role of coupling strength and internal delay between compartments in shaping the bursting behavior of cortical neuron

Bursting is a typical firing behavior intrinsically existing in neurons from many brain regions, which has been thought to have functional roles in neuronal reliable signaling and synaptic plasticity. Meanwhile, many factors have been put forward to participate in the modulation of bursting behavior during the past decades. Here, in this research, the modulation of bursting behaviors was numerically investigated in a two-compartment model of cortical pyramidal neuron using the coupling strength and time delay between compartments as control parameters. By means of computer simulations, we showed that, for larger coupling strengths and smaller delays between the two compartments, a wide range of regular bursting can be observed, while too large coupling strengths and time delays would cause the model neuron to be quiescent. In addition, the dynamical firing range of regular spiking can be also obtained, which has two parts: one part corresponds to small coupling strengths irrespective of the values of time delay, while another part corresponds to larger coupling strengths and delays. These results suggested that coupling strength and internal time delay between the inner compartments possess potential roles in modulating the dynamical bursting behavior of neurons.     

Comparative distribution of the mammalian mediator subunit thyroid hormone receptor-associated protein (TRAP220) mRNA in developing and adult rodent brain

Disinhibition reliably induces regular synchronous bursting in networks of spinal interneurons in culture as well as in the intact spinal cord. We have combined extracellular multisite recording using multielectrode arrays with whole cell recordings to investigate the mechanisms involved in bursting in organotypic and dissociated cultures from the spinal cords of embryonic rats. Network bursts induced depolarization and spikes in single neurons, which were mediated by recurrent excitation through glutamatergic synaptic transmission. When such transmission was blocked, bursting ceased. However, tonic spiking persisted in some of the neurons. In such neurons intrinsic spiking was suppressed following the bursts and reappeared in the intervals after several seconds. The suppression of intrinsic spiking could be reproduced when, in the absence of fast synaptic transmission, bursts were mimicked by the injection of current pulses. Intrinsic spiking was also suppressed by a slight hyperpolarization. An afterhyperpolarization following the bursts was found in roughly half of the neurons. These afterhyperpolarizations were combined with a decrease in excitability. No evidence for the involvement of synaptic depletion or receptor desensitization in bursting was found, because neither the rate nor the size of spontaneous excitatory postsynaptic currents were decreased following the bursts. Extracellular stimuli paced bursts at low frequencies, but failed to induce bursts when applied too soon after the last burst. Altogether these results suggest that bursting in spinal cultures is mainly based on intrinsic spiking in some neurons, recurrent excitation of the network and auto-regulation of neuronal excitability.     

Synaptic excitability of the burst firing neurons in cat sensorimotor cortex in vitro

We have recently reported that the burst firing neurons are found in layer III as well as in layer V of cat sensorimotor cortex in vitro. In the present study, we examined the synaptic excitability of layer III neurons by white matter stimulation and compared with their firing patterns against the current injections through the recording microelectrodes. The firing patterns of layer III neurons were classified into three main classes as in our previous study, i.e., (1) regular spiking (RS), i.e., the tonic firing that often exhibited spike-frequency adaptation, (2) burst-and-single spiking (BS), i.e., the initial bursting followed by tonic firing, (3) repetitive-bursting (RB), the burst firing that recurred at fast frequency. In RS cells, single action potential was superimposed on the largest EPSPs among all cell types analyzed. BS cells also fired single action potential and never exhibited burst firing synaptically. Only in a part of RB cells, synaptic bursting instead of single action potential was evoked on smaller EPSPs. IPSPs could be observed in about 60% of all the recorded RS and BS cells, however, they were observed in only 10% of the RB cells.     

Interacting biological and electronic neurons generate realistic oscillatory rhythms

Small assemblies of neurons such as central pattern generators (CPG) are known to express regular oscillatory firing patterns comprising bursts of action potentials. In contrast, individual CPG neurons isolated from the remainder of the network can generate irregular firing patterns. In our study of cooperative behavior in CPGs we developed an analog electronic neuron (EN) that reproduces firing patterns observed in lobster pyloric CPG neurons. Using a tuneable artificial synapse we connected the EN bidirectionally to neurons of this CPG. We found that the periodic bursting oscillation of this mixed assembly depends on the strength and sign of the electrical coupling. Working with identified, isolated pyloric CPG neurons whose network rhythms were impaired, the EN/biological network restored the characteristic CPG rhythm both when the EN oscillations are regular and when they are irregular.     

Bursting as a source of non‐linear determinism in the firing patterns of nigral dopamine neurons

Nigral dopamine (DA) neurons in vivo exhibit complex firing patterns consisting of tonic single‐spikes and phasic bursts that encode information for certain types of reward‐related learning and behavior. Non‐linear dynamical analysis has previously demonstrated the presence of a non‐linear deterministic structure in complex firing patterns of DA neurons, yet the origin of this non‐linear determinism remains unknown. In this study, we hypothesized that bursting activity is the primary source of non‐linear determinism in the firing patterns of DA neurons. To test this hypothesis, we investigated the dimension complexity of inter‐spike interval data recorded in vivo from bursting and non‐bursting DA neurons in the chloral hydrate‐anesthetized rat substantia nigra. We found that bursting DA neurons exhibited non‐linear determinism in their firing patterns, whereas non‐bursting DA neurons showed truly stochastic firing patterns. Determinism was also detected in the isolated burst and inter‐burst interval data extracted from firing patterns of bursting neurons. Moreover, less bursting DA neurons in halothane‐anesthetized rats exhibited higher dimensional spiking dynamics than do more bursting DA neurons in chloral hydrate‐anesthetized rats. These results strongly indicate that bursting activity is the main source of low‐dimensional, non‐linear determinism in the firing patterns of DA neurons. This finding furthermore suggests that bursts are the likely carriers of meaningful information in the firing activities of DA neurons.     

M‐type channels selectively control bursting in rat dopaminergic neurons

Midbrain dopaminergic neurons in the substantia nigra, pars compacta and ventral tegmental area are critically important in many physiological functions. These neurons exhibit firing patterns that include tonic slow pacemaking, irregular firing and bursting, and the amount of dopamine that is present in the synaptic cleft is much increased during bursting. The mechanisms responsible for the switch between these spiking patterns remain unclear. Using both in‐vivo recordings combined with microiontophoretic or intraperitoneal drug applications and in‐vitro experiments, we have found that M‐type channels, which are present in midbrain dopaminergic cells, modulate the firing during bursting without affecting the background low‐frequency pacemaker firing. Thus, a selective blocker of these channels, 10,10‐bis(4‐pyridinylmethyl)‐9(10H)‐anthracenone dihydrochloride, specifically potentiated burst firing. Computer modeling of the dopamine neuron confirmed the possibility of a differential influence of M‐type channels on excitability during various firing patterns. Therefore, these channels may provide a novel target for the treatment of dopamine‐related diseases, including Parkinson’s disease and drug addiction. Moreover, our results demonstrate that the influence of M‐type channels on the excitability of these slow pacemaker neurons is conditional upon their firing pattern.     

Passive dendritic integration heavily affects spiking dynamics of recurrent networks.

According to dendritic cable theory, proximal synapses give rise to inputs with short delay, high amplitude, and short duration. In contrast, inputs from distal synapses have long delays, low amplitude, and long duration. Nevertheless, large scale neural networks are seldom built with realistically layered synaptic architectures and corresponding electrotonic parameters. Here, we use a simple model to investigate the spike response dynamics of networks with different electrotonic structures. The networks consist of a layer of neurons receiving a sparse feedforward projection from a set of inputs, as well as sparse recurrent connections from within the layer. Firing patterns are set in the inputs, and recorded from the neuron (output) layer. The feedforward and recurrent synapses are independently set as proximal or distal, representing dendritic connections near or far from the soma, respectively. Analyses of firing dynamics indicate that recurrent distal synapses tend to concentrate network activity in fewer neurons, while proximal recurrent synapses result in a more homogeneous activity distribution. In addition, when the feedforward input is regular (spiking or bursting) and asynchronous, the output is regular if recurrent synapses are more distal than feedforward ones, and irregular in the opposite configuration. Finally, the amplitude of network fluctuations in response to asynchronous input is lower if feedforward and recurrent synapses are electrotonically distant from one another (in either configuration). In conclusion, electrotonic effects reflecting different dendritic positions of synaptic inputs significantly influence network dynamics.     

Intrinsic connectivity of the rat subiculum: II. Properties of synchronous spontaneous activity and a demonstration of multiple generator regions.

Brain structures that can generate epileptiform activity possess excitatory interconnections among principal cells and a subset of these neurons that can be spontaneously active ("pacemaker" cells). We describe electrophysiological evidence for excitatory interactions among rat subicular neurons. Subiculum was isolated from presubiculum, CA1, and entorhinal cortex in ventral horizontal slices. Nominally zero magnesium perfusate, picrotoxin (100 microM), or NMDA (20 microM) was used to induce spontaneous firing in subicular neurons. Synchronous population activity and the spread of population events from one end of subiculum to the other in isolated subicular subslices indicate that subicular pyramidal neurons are coupled together by excitatory synapses. Both electrophysiological classes of subicular pyramidal cells (bursting and regular spiking) exhibited synchronous activity, indicating that both cell classes are targets of local excitatory inputs. Burst firing neurons were active in the absence of synchronous activity in field recordings, indicating that these cells may serve as pacemaker neurons for the generation of epileptiform activity in subiculum. Epileptiform events could originate at either proximal or distal segments of the subiculum from ventral horizontal slices. In some slices, events originated in both proximal and distal locations and propagated to the other location. Finally, propagation was supported over axonal paths through the cell layer and in the apical dendritic zone. We conclude that subicular burst firing and regular spiking neurons are coupled by means of glutamatergic synapses. These connections may serve to distribute activity driven by topographically organized inputs and to synchronize subicular cell activity.     

Transition in subicular burst firing neurons from epileptiform activity to suppressed state by feedforward inhibition

The subiculum, a para‐hippocampal structure positioned between the cornu ammonis 1 subfield and the entorhinal cortex, has been implicated in temporal lobe epilepsy in human patients and in animal models of epilepsy. The structure is characterized by the presence of a significant population of burst firing neurons that has been shown previously to lead epileptiform activity locally. Phase transitions in epileptiform activity in neurons following a prolonged challenge with an epileptogenic stimulus has been shown in other brain structures, but not in the subiculum. Considering the importance of the subicular burst firing neurons in the propagation of epileptiform activity to the entorhinal cortex, we have explored the phenomenon of phase transitions in the burst firing neurons of the subiculum in an in vitro rat brain slice model of epileptogenesis. Whole‐cell patch‐clamp and extracellular field recordings revealed a distinct phenomenon in the subiculum wherein an early hyperexcitable state was followed by a late suppressed state upon continuous perfusion with epileptogenic 4‐aminopyridine and magnesium‐free medium. The suppressed state was characterized by inhibitory post‐synaptic potentials in pyramidal excitatory neurons and bursting activity in local fast‐spiking interneurons at a frequency of 0.1–0.8 Hz. The inhibitory post‐synaptic potentials were mediated by GABA_A receptors that coincided with excitatory synaptic inputs to attenuate action potential discharge. These inhibitory post‐synaptic potentials ceased following a cut between the cornu ammonis 1 and subiculum. The suppression of epileptiform activity in the subiculum thus represents a homeostatic response towards the induced hyperexcitability. Our results suggest the importance of feedforward inhibition in exerting this homeostatic control.     

Endogenous bursting due to altered sodium channel function in rat hippocampal CA1 neurons

Intracellular recordings were obtained from pyramidal neurons in the rat hippocampal CA1 area in order to investigate membrane mechanisms involved in veratridine-induced epileptiform activity. Veratridine (0.03−0.2 μM) caused no changes in the passive membrane parameters including the resting potential, input resistance, and time constant. In the presence of small doses (0.03−0.1 μM) of veratridine, a single stimulus caused a relatively slow, large, synaptic-independent potential called the slow depolarizing after-potential (SDAP). When the hippocampal slice was treated with higher doses of veratridine (over 0.1 μM), bursting, or seizure-like activity (SLA) occurred in response to a brief super threshold intracellular stimulation. The duration of SLA bursting could be as long as ten seconds depending on the amplitude of SDAP, and was independent of the stimulus strength or duration. The frequency and configuration of SLA were sensitive to changes in membrane potential caused by applied DC current. At 0.3 μM or higher, veratridine induced spontaneous rhythmic bursting that was also sensitive to membrane potential changes. The evoked or spontaneous bursting is characterized by being: (1) independent of synaptic transmission in that it persisted after complete blockade of evoked synaptic potential with kynurenic acid (0.5 mM), (2) sensitive to selective inhibition by low doses of the specific sodium channel blockers tetrodotoxin (TTX) or cocaine with no apparent influence on the evoked action potential. These results indicate that endogenous SLA bursting can be induced in hippocampal CA1 pyramidal neurons when certain properties of sodium channels are altered by veratridine.     

Understanding of physiological neural firing patterns through dynamical bifurcation machineries

The characteristics of baroreceptor firing patterns were recognized in experiment, and their dynamics revealed in theoretical analysis. During blood pressure elevation, baroreceptors gradually exhibited bursting, continuous firing, and paradoxical bursting patterns. The bursting was generated through the repeated bifurcations between rest and spiking, the continuous firing was maintained without bifurcation, and the paradoxical bursting was generated through the bifurcations between spiking and a depolarization block. Thus, the change of blood pressure spans two bifurcations and such results imply a new way for baroreceptors to encode blood pressure information. Various firing patterns were generated from the evolution of the baroreceptor system on different parts of the system's bifurcation scenario with respect to parameter I, the excitative current modulated by blood pressure.     

Excitability of dopamine neurons: modulation and physiological consequences

This aim of this chapter is to review literature on the excitability and function of dopamine neurons that originate in the midbrain and project to cortico-limbic and motor structures (A9 and A10 dopamine pathways). Electrophysiological studies on rodent or non-human primates have shown that these dopamine neurons are silent or spontaneously active. The spontaneously active neurons show slow regular firing, slow irregular firing or fast bursting activity. In the first section, we will review how neuronal firing is modulated by intrinsic factors, such as impulse-regulating somatodendritic dopamine autoreceptors, a balance between inward voltage-gated sodium and calcium currents and outward potassium currents. We will then review the major excitatory and inhibitory pathways that play important roles in modulating dopamine cell excitability. In the second section, we will discuss how, in addition to being modulated by intrinsic and synaptic factors, excitability of dopamine neurons can also be modulated by life experiences. Dopamine neurons change their firing rate throughout the developmental period, their activity can be modified by stressful life events, and the firing mode can change as a consequence of acute or repeated exposure to psychoactive drugs. Finally, these cells change their firing pattern in response to behaviorally relevant stimuli and learning experiences. We will conclude by discussing how changes in the physiology of the dopamine neurons could participate in the development or exacerbation of psychiatric conditions such as drug addiction.     

Firing properties and dye coupling of neurons in the pigeon nucleus semilunaris

Our previous study indicated that the nucleus semilunaris in birds is a visual center. The present study using pigeon brain slices shows that 84 semilunar cells examined could be grouped into five types according to responses to depolarizing current injections. Type I cells (early bursting, 44%) fire a single burst followed by regular spiking. Type II cells (regular spiking, 13%) regularly produce spikes, the rates of which are enhanced as currents are increased. Type III cells (bursting, 17%) discharge a series of bursts each consisting of 2-4 spikes. Type IV cells (dual spiking, 15%) evoke both spikes and spikelets. Type V cells (inhibition-following, 11%) are characterized by regular spiking followed by an inhibitory period after current cessation. Morphologically, semilunar neurons have piriform, round, or fusiform somata of 12-23 mum in diameter, which give rise to 2-4 primary dendrites with sparse branches. Dual spiking activity is invariably correlated with dye coupling, and bursting cells have a tendency to be fusiform in shape. Other types of semilunar cells do not show a correlation between their firing patterns and morphological features.     

Neuron as a reward-modulated combinatorial switch and a model of learning behavior

This paper proposes a neuronal circuitry layout and synaptic plasticity principles that allow the (pyramidal) neuron to act as a “combinatorial switch”. Namely, the neuron learns to be more prone to generate spikes given those combinations of firing input neurons for which a previous spiking of the neuron had been followed by a positive global reward signal. The reward signal may be mediated by certain modulatory hormones or neurotransmitters, e.g., the dopamine. More generally, a trial-and-error learning paradigm is suggested in which a global reward signal triggers long-term enhancement or weakening of a neuron’s spiking response to the preceding neuronal input firing pattern. Thus, rewards provide a feedback pathway that informs neurons whether their spiking was beneficial or detrimental for a particular input combination. The neuron’s ability to discern specific combinations of firing input neurons is achieved through a random or predetermined spatial distribution of input synapses on dendrites that creates synaptic clusters that represent various permutations of input neurons. The corresponding dendritic segments, or the enclosed individual spines, are capable of being particularly excited, due to local sigmoidal thresholding involving voltage-gated channel conductances, if the segment’s excitatory and absence of inhibitory inputs are temporally coincident. Such nonlinear excitation corresponds to a particular firing combination of input neurons, and it is posited that the excitation strength encodes the combinatorial memory and is regulated by long-term plasticity mechanisms. It is also suggested that the spine calcium influx that may result from the spatiotemporal synaptic input coincidence may cause the spine head actin filaments to undergo mechanical (muscle-like) contraction, with the ensuing cytoskeletal deformation transmitted to the axon initial segment where it may modulate the global neuron firing threshold. The tasks of pattern classification and generalization are discussed within the presented framework.     

Cyclic AMP endogenously enhances synaptic strength of developing glutamatergic synapses in serum-free microcultures of rat hippocampal neurons

The time course of development of autaptic and synaptic connections and the contribution of endogenously activated cAMP signaling to the regulation of AMPA/kainate receptor-mediated synaptic transmission were studied in microcultures of isolated single hippocampal neurons or of pairs of neurons grown on astrocytic islands in serum-free culture medium. Standard whole cell patch clamp techniques were employed to monitor evoked and spontaneous autaptic and synaptic currents. Glutamatergic synaptic transmission became detectable after 4 days in vitro (DIV). After 9–10 DIV more than 80% of the neurons had developed glutamatergic autaptic and synaptic connections. Elevation of intracellular cAMP levels by application of forskolin (20 μM) or IBMX (200 μM) to autaptic neurons resulted in enhanced autaptic current amplitudes (forskolin: 146 ± 9%, IBMX: 177 ± 21% of control) and impaired paired pulse facilitation (PPF). Likewise, intracellular application of cAMP via the patch pipette into autaptic neurons or into the presynaptic neuron of a synaptically connected pair also resulted in enhanced autaptic/synaptic current amplitudes (170 ± 16% of control). In contrast, injection of cAMP into the postsynaptic neuron of a synaptic pair failed to significantly enhance the synaptic responses. The magnitude of the cAMP-mediated enhancement depended on the initial autaptic/synaptic strength observed in an individual cell, with small autapses/synapses being enhanced more effectively. Application of an inhibitor of cAMP-mediated processes (Rp-cAMPS) reversibly reduced autaptic/synaptic current amplitudes (to 75 ± 5% of control). Taken together, these results suggest that cAMP-mediated processes endogenously enhance the efficacy of developing glutamatergic autaptic and synaptic connections in serum-free microcultures of isolated hippocampal neurons.     

Effects of ethanol on rat somatosensory cortical neurons

In this study, we characterized the local effects of ethanol (EtOH) on postsynaptic potentials (PSPs) and membrane properties of layer II–III (L2–3) and layer V (L5) somatosensory cortical neurons. Intracellular recordings were done using the in vitro slice preparation of rat somatosensory cortex. Our results show that EtOH exerts local effects on cortical cell membrane at physiologically relevant concentrations. A predominant effect of EtOH was to reduce excitability of L2–3 and L5 neurons by increasing the rheobase, decreasing input resistance and repetitive firing, reducing PSPs amplitude and the probability of evoking action potentials. Early (6 ms) and late (18 ms) PSP components were affected differentially by EtOH, the late components being more suppressed. Overall, EtOH-mediated suppression of PSPs was stronger in L5 neurons. Cortical neurons were divided into three subtypes: regular spiking adapting (RS-A), regular spiking non-adapting (RS-NA) and bursting (D-IB) neurons. PSPs evoked in RS-A neurons were more sensitive to EtOH suppressant effects. EtOH effects on input resistance were distributed differentially among the three groups of neurons. These results support the notion that EtOH disrupts higher processing of somatosensory information via a differential alteration of cortical neuron's membrane properties and synaptic transmission.     

Firing pattern of neurons in the nucleus tractus solitarius: modulation by membrane hyperpolarization

Neurons in the ventral region of the nucleus tractus solitarius (NTS) of guinea pigs were studied using an in vitro brainstem slice preparation. One group of neurons was characterized electrophysiologically by a delay between the onset of a depolarizing stimulus and the first spike. This delay could be as large as 760 ms and was modulated by the membrane potential level preceding the stimulus. The firing rate during the depolarizing stimulus was also modulated by the preceding membrane potential level. A fast transient outward current, similar to A-current in molluscan neurons, appeared to be responsible for the delay in firing while a slower calcium-activated potassium current affected the firing rate. These data suggest that intrinsic membrane properties may play an important role in determining the firing pattern of NTS neurons. In vivo, inhibitory synaptic inputs could modulate the expression of these intrinsic properties during subsequent excitation.     

Effects of dendritic morphology on CA3 pyramidal cell electrophysiology: a simulation study

We investigated the effect of morphological differences on neuronal firing behavior within the hippocampal CA3 pyramidal cell family by using three-dimensional reconstructions of dendritic morphology in computational simulations of electrophysiology. In this paper, we report for the first time that differences in dendritic structure within the same morphological class can have a dramatic influence on the firing rate and firing mode (spiking versus bursting and type of bursting). Our method consisted of converting morphological measurements from three-dimensional neuroanatomical data of CA3 pyramidal cells into a computational simulator format. In the simulation, active channels were distributed evenly across the cells so that the electrophysiological differences observed in the neurons would only be due to morphological differences. We found that differences in the size of the dendritic tree of CA3 pyramidal cells had a significant qualitative and quantitative effect on the electrophysiological response. Cells with larger dendritic trees: (1) had a lower burst rate, but a higher spike rate within a burst, (2) had higher thresholds for transitions from quiescent to bursting and from bursting to regular spiking and (3) tended to burst with a plateau. Dendritic tree size alone did not account for all the differences in electrophysiological responses. Differences in apical branching, such as the distribution of branch points and terminations per branch order, appear to effect the duration of a burst. These results highlight the importance of considering the contribution of morphology in electrophysiological and simulation studies.     

Implications of synaptic biophysics for recurrent network dynamics and active memory

In cortical networks, synaptic excitation is mediated by AMPA- and NMDA-type receptors. NMDA differ from AMPA synaptic potentials with regard to peak current, time course, and a strong voltage-dependent nonlinearity. Here we illustrate based on empirical and computational findings that these specific biophysical properties may have profound implications for the dynamics of cortical networks, and via dynamics on cognitive functions like active memory. The discussion will be led along a minimal set of neural equations introduced to capture the essential dynamics of the various phenomena described. NMDA currents could establish cortical bistability and may provide the relatively constant synaptic drive needed to robustly maintain enhanced levels of activity during working memory epochs, freeing fast AMPA currents for other computational purposes. Perhaps more importantly, variations in NMDA synaptic input–due to their biophysical particularities–control the dynamical regime within which single neurons and networks reside. By provoking bursting, chaotic irregularity, and coherent oscillations their major effect may be on the temporal pattern of spiking activity, rather than on average firing rate. During active memory, neurons may thus be pushed into a spiking regime that harbors complex temporal structure, potentially optimal for the encoding and processing of temporal sequence information. These observations provide a qualitatively different view on the role of synaptic excitation in neocortical dynamics than entailed by many more abstract models. In this sense, this article is a plead for taking the specific biophysics of real neurons and synapses seriously when trying to account for the neurobiology of cognition.     

Activity deprivation leads to seizures in hippocampal slice cultures: is epilepsy the consequence of homeostatic plasticity?

SUMMARY: Neural networks operate robustly despite destabilizing factors, ranging from gene product turnover to circuit refinement, throughout life. Maintaining functional robustness of neuronal networks critically depends upon forms of homeostatic plasticity including synaptic scaling. Synaptic strength and intrinsic excitability have been shown to "scale" (up or down) in response to altered ambient activity levels, and this has led to the general idea that homeostatic plasticity operates along a continuum. After 48 hours of activity deprivation, cultured hippocampal networks exhibited a homeostatic-type reconfiguration that was discrete: a switch from spontaneous spiking to oscillatory bursting. Blockade of fast glutamatergic and GABAergic transmission abolished spontaneous network bursting, but the majority of neurons exhibited intrinsic bursting in response to current injection, which was not the case in control tissue. This de novo intrinsic bursting could be blocked by cadmium chloride, suggesting that this bursting involves calcium mechanisms. Immunohistochemistry confirmed that activity-deprived slice cultures exhibited a widespread upregulation of voltage-dependent calcium channels compared with controls. Calcium imaging studies from activity-deprived slices demonstrated that spontaneous bursting was not a local behavior, but rather a global, synchronous phenomenon, reminiscent of seizure activity. These data suggest that the input/output transformation of individual neurons undergoing homeostatic remodeling is more complex than simple scaling. Network consequences of this transformation include network destabilization of epileptic proportions. Spontaneous activity plays a critical role in actively maintaining homeostatic balance in networks, which is lost after activity deprivation.