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There is evidence that olfactory cortex responds to its afferent input with the generation of cell assemblies: collections of principal neurons that fire together over a time scale of tens of ms. If such assemblies form an odor representation, then a fundamental question is how each assembly then induces neuronal activity in downstream structures. We have addressed this question in a detailed model of superficial layers of lateral entorhinal cortex, a recipient of input from olfactory cortex and olfactory bulb. Our results predict that the response of the fan cell subpopulation can be approximated by a relatively simple Boolean process, somewhat along the lines of the McCulloch/Pitts scheme; this is the case because of the sparsity of recurrent excitation amongst fan cells. However, because of recurrent excitatory connections between layer 2 and layer 3 pyramidal cells, synaptic and probably also gap junctional, the response of pyramidal cell subnetworks cannot be so approximated. Because of the highly structured anatomy of entorhinal output projections, our model suggests that downstream targets of entorhinal cortex (dentate gyrus, hippocampal CA3, CA1, piriform cortex, olfactory bulb) receive differentially processed information.

Grid cells, in entorhinal cortex (EC) and related structures, signal animal location relative to hexagonal tilings of 2D space. A number of modeling papers have addressed the question of how grid firing behaviors emerge using (for example) ideas borrowed from dynamical systems (attractors) or from coupled oscillator theory. Here we use a different approach: instead of asking how grid behavior emerges, we take as a given the experimentally observed intracellular potentials of superficial medial EC neurons during grid firing. Employing a detailed neural circuit model modified from a lateral EC model, we then ask how the circuit responds when group of medial EC principal neurons exhibit such potentials, simultaneously with a simulated theta frequency input from the septal nuclei. The model predicts the emergence of robust theta-modulated gamma/beta oscillations, suggestive of oscillations observed in an in vitro medial EC experimental model (Cunningham, M.O., Pervouchine, D.D., Racca, C., Kopell, N.J., Davies, C.H., Jones, R.S.G., Traub, R.D., and Whittington, M.A. (2006). Neuronal metabolism governs cortical network response state. Proc. Natl. Acad. Sci. U S A 103: 5597–5601). Such oscillations result because feedback interneurons tightly synchronize with each other – despite the varying phases of the grid cells – and generate a robust inhibition-based rhythm. The lack of spatial specificity of the model interneurons is consistent with the lack of spatial periodicity in parvalbumin interneurons observed by Buetfering, C., Allen, K., and Monyer, H. (2014). Parvalbumin interneurons provide grid cell-driven recurrent inhibition in the medial entorhinal cortex. Nat. Neurosci. 17: 710–718. If in vivo EC gamma rhythms arise during exploration as our model predicts, there could be implications for interpreting disrupted spatial behavior and gamma oscillations in animal models of Alzheimer’s disease and schizophrenia. Noting that experimental intracellular grid cell potentials closely resemble cortical Up states and Down states, during which fast oscillations also occur during Up states, we propose that the co-occurrence of slow principal cell depolarizations and fast network oscillations is a general property of the telencephalon, in both waking and sleep states.

Cell assemblies and central pattern generators (CPGs) are related types of neuronal networks: both consist of interacting groups of neurons whose collective activities lead to defined functional outputs. In the case of a cell assembly, the functional output may be interpreted as a representation of something in the world, external or internal; for a CPG, the output ‘drives’ an observable (i.e. motor) behavior. Electrical coupling, via gap junctions, is critical for the development of CPGs, as well as for their actual operation in the adult animal. Electrical coupling is also known to be important in the development of hippocampal and neocortical principal cell networks. We here argue that electrical coupling – in addition to chemical synapses – may therefore contribute to the formation of at least some cell assemblies in adult animals.

The piriform cortex is rich in recurrent excitatory synaptic connections between pyramidal neurons. We asked how such connections could shape cortical responses to olfactory lateral olfactory tract (LOT) inputs. For this, we constructed a computational network model of anterior piriform cortex with 2000 multicompartment, multiconductance neurons (500 semilunar, 1000 layer 2 and 500 layer 3 pyramids; 200 superficial interneurons of two types; 500 deep interneurons of three types; 500 LOT afferents), incorporating published and unpublished data. With a given distribution of LOT firing patterns, and increasing the strength of recurrent excitation, a small number of firing patterns were observed in pyramidal cell networks: first, sparse firings; then temporally and spatially concentrated epochs of action potentials, wherein each neuron fires one or two spikes; then more synchronized events, associated with bursts of action potentials in some pyramidal neurons. We suggest that one function of anterior piriform cortex is to transform ongoing streams of input spikes into temporally focused spike patterns, called here “cell assemblies”, that are salient for downstream projection areas.

Electrical synapses formed by gap junctions occur at a variety of neuronal subcellular sites in the mammalian central nervous system (CNS), including at somatic, dendritic and axon terminal compartments. Numerous electrophysiological studies using mice and rats, as well as computer modelling approaches, have predicted the additional occurrence of electrical synapses between axons near their emergence from neuronal somata. Here, we used immunofluorescence methods to search for localization of the neuronal gap junction-forming protein connexin36 (Cx36) along axon initial segments (AISs) labelled for the AIS marker ankyrinG. Immunofluorescent Cx36-puncta were found to be associated with AISs in several CNS regions of mice, including the spinal cord, inferior olive and cerebral cortex. Localization of Cx36-puncta at AISs was confirmed by confocal single scan and 3D imaging, immunofluorescence intensity profiling and high resolution structured illumination microscopy (SIM). AISs measuring up to 30 µm in length displayed typically a single Cx36-punctum and the incidence of these long AISs displaying Cx36-puncta ranged from 3% to 7% in the inferior olive and in various layers of the cerebral cortex. In the inferior olive, the gap junction associated protein zonula occludens-1 (ZO-1) was found to be co-localized with Cx36-puncta on AISs, indicating that these puncta have some of the molecular constituents of gap junctions. Our results add to the neuronal subcellular locations at which Cx36 is deployed, and raise possibilities for its involvement in novel functions in the AIS compartment.

Brain pH is thought to be important in epilepsy. The regulation of brain pH is, however, still poorly understood in animal models of chronic seizures (SZ) as well as in patients with intractable epilepsy. We used chemical exchange saturation transfer (CEST) MRI to noninvasively determine if the pH is alkaline shifted in a rodent model of the mesial temporal lobe (MTL) epilepsy with chronic SZ. Taking advantage of its high spatial resolution, we determined the pH values in specific brain regions believed to be important in this model produced by lithium-pilocarpine injection. All animals developed status epilepticus within 90 min after the lithium-pilocarpine administration, but one animal died within 24 hrs. All the surviving animals developed chronic SZ during the first 2 months. After SZ developed, brain pH was determined in the pilocarpine and control groups (n = 8 each). Epileptiform activity was documented in six pilocarpine rats with scalp EEG. The brain pH was estimated using two methods based on magnetization transfer asymmetry and amide proton transfer ratio. The pH was alkaline shifted in the pilocarpine rats (one outlier excluded) compared to the controls in the hippocampus (7.29 vs 7.17, t-test, p 0.03) and the piriform cortex (7.34 vs. 7.06, p 0.005), marginally more alkaline in the thalamus (7.13 vs. 7.01, p 0.05), but not in the cerebral cortex (7.18 vs. 7.08, p 0.05). Normalizing the brain pH may lead to an effective non-surgical method for treating intractable epilepsy as it is known that SZ can be eliminated by lowering the pH.

Alpha rhythms (9–11 Hz) are a dominant feature of EEG recordings, particularly over occipital cortex on cessation of a visual stimulation. Little is known about underlying neocortical mechanisms so here we constructed alpha rhythm models that follow cessation of cortical stimulation. The rhythm manifests following a period of gamma frequency activity in local V1 networks in layer 4. It associates with network level bias of excitatory synaptic activity in favour of NMDA- rather than AMPA-mediated signalling and reorganisation of synaptic inhibition in favour of fast GABAA receptor-mediated events. At the cellular level the alpha rhythm depended upon the generation of layer 4 pyramidal neuron dendritic bursting mediated primarily by PPDA-sensitive NR2C/D-containing NMDA receptors, which lack the magnesium-dependent open channel block. Subthreshold potassium conductances are also critical. The rhythm dynamically filters outputs from sensory relay neurons (stellate neurons in layer 4) such that they become temporally uncoupled from downstream population activity., The authors combine computational and electrophysiological approaches to study the neocortical mechanisms underlying alpha rhythms generated after visual stimuli cessation. They show that layer 4 pyramidal neuron bursting, as well as a shift towards NMDA- and GABAA- receptor transmission is critical for the generation of these alpha oscillations.

Neoplastic or dysplastic neuronal tissue in the brain stem and cerebellum can become epileptogenic in pediatric patients. However, it is unknown whether such tissue may transform intrinsic properties of the human cerebellum, making it capable of generating epileptic population activity. We noninvasively detected epileptiform signals unaveraged in a pediatric patient with epilepsy due to a tumor in the middle cerebellar peduncle. Analysis of generators of the signals revealed that the cerebellum ipsilateral and contralateral to the tumor was the dominant interictal spike generator and could initiate ictal activity, suggesting that human cerebellum may become capable of intrinsically generating epileptic activity. ANN NEUROL 2020;88:418-422.

Infantile spasms (IS) and seizures with focal onset have different clinical expressions, even when electroencephalography (EEG) associated with IS has some degree of focality. Oddly, identical pathology (with, however, age-dependent expression) can lead to IS in one patient vs. focal seizures in another or even in the same, albeit older, patient. We therefore investigated whether the cellular mechanisms underlying seizure initiation are similar in the two instances: spasms vs. focal. We noted that in-common EEG features can include (i) a background of waves at alpha to delta frequencies; (ii) a period of flattening, lasting about a second or more – the electrodecrement (ED); and (iii) often an interval of very fast oscillations (VFO; ~70 Hz or faster) preceding, or at the beginning of, the ED. With IS, VFO temporally coincides with the motor spasm. What is different between the two conditions is this: with IS, the ED reverts to recurring slow waves, as occurring before the ED, whereas with focal seizures the ED instead evolves into an electrographic seizure, containing high-amplitude synchronized bursts, having superimposed VFO. We used in vitro data to help understand these patterns, as such data suggest cellular mechanisms for delta waves, for VFO, for seizure-related burst complexes containing VFO, and, more recently, for the ED. We propose a unifying mechanistic hypothesis – emphasizing the importance of brain pH – to explain the commonalities and differences of EEG signals in IS versus focal seizures.

Neuronal oscillations represent the most obvious feature of electrical activity in the brain. They are linked in general with global brain state (awake, asleep, etc.) and specifically with organisation of neuronal outputs during sensory perception and cognitive processing. Oscillations can be generated by individual neurons on the basis of interaction between inputs and intrinsic conductances but are far more commonly seen at the local network level in populations of interconnected neurons with diverse arrays of functional properties. It is at this level that the brain’s rich and diverse library of oscillatory time constants serve to temporally organise large-scale neural activity patterns. The discipline is relatively mature at the microscopic (cell, local network) level – although novel discoveries are still commonplace – but requires a far greater understanding of mesoscopic and macroscopic brain dynamics than we currently hold. Without this, extrapolation from the temporal properties of neurons and their communication strategies up to whole brain function will remain largely theoretical. However, recent advances in large-scale neuronal population recordings and more direct, higher fidelity, non-invasive measurement of whole brain function suggest much progress is just around the corner.

Rhythmic activity in populations of neurons is associated with cognitive and motor function. Our understanding of the neuronal mechanisms underlying these core brain functions has benefitted from demonstrations of cellular, synaptic, and network phenomena, leading to the generation of discrete rhythms at the local network level. However, discrete frequencies of rhythmic activity rarely occur alone. Despite this, little is known about why multiple rhythms are generated together or what mechanisms underlie their interaction to promote brain function. One overarching theory is that different temporal scales of rhythmic activity correspond to communication between brain regions separated by different spatial scales. To test this, we quantified the cross-frequency interactions between two dominant rhythms—theta and delta activity—manifested during magnetoencephalography recordings of subjects performing a word-pair semantic decision task. Semantic processing has been suggested to involve the formation of functional links between anatomically disparate neuronal populations over a range of spatial scales, and a distributed network was manifest in the profile of theta-delta coupling seen. Furthermore, differences in the pattern of theta-delta coupling significantly correlated with semantic outcome. Using an established experimental model of concurrent delta and theta rhythms in neocortex, we show that these outcome-dependent dynamics could be reproduced in a manner determined by the strength of cholinergic neuromodulation. Theta-delta coupling correlated with discrete neuronal activity motifs segregated by the cortical layer, neuronal intrinsic properties, and long-range axonal targets. Thus, the model suggested that local, interlaminar neocortical theta-delta coupling may serve to coordinate both cortico-cortical and cortico-subcortical computations during distributed network activity. NEW & NOTEWORTHY Here, we show, for the first time, that a network of spatially distributed brain regions can be revealed by cross-frequency coupling between delta and theta frequencies in subjects using magnetoencephalography recording during a semantic decision task. A biological model of this cross-frequency coupling suggested an interlaminar, cell-specific division of labor within the neocortex may serve to route the flow of cortico-cortical and cortico-subcortical information to promote such spatially distributed, functional networks.

Spike-and-wave discharges (SpW) are seen in absence-type epilepsies. They are heterogeneous in terms of their clinical burden and their electrographic signature, which is used to classify different types of absence seizures; typical absence, in which SpW frequency is 3-4Hz and atypical absence, which shows a slower 1-2Hz frequency. Treatment of SpW varies dependent upon the syndrome, but both Valproic Acid (VPA) and Ethosuximide (ESM) are shown to be effective in controlling typical absence seizures. Other anti-epileptic′s (AED′s), Levetiracetam (LEV) and Rufinamide (RUF), have shown promise in treating absence epilepsies and their associated syndromes. Here we examine the efficacy of these AED′s on an in vitro model of SpW. Both LEV and RUF show an effective reduction in both the number of SpW events and the spike component amplitude; VPA shows no effect, whilst ESM enhances the spike amplitude. Phenytoin exacerbates the SpW activity, increasing both the number of SpW, amplitude of the SpW and the number of spikes within each event. These data suggest that both LEV and RUF could be effective in the treatment of absence-type epilepsies. They also suggest this model could be an effective tool to test other AED′s aimed at treating atypical absence syndromes. Key Words: Absence epilepsy, Anti-epileptic Drugs, Spike-and-Wave, Levetiracetam, Rufinamide

There is considerable experimental evidence, anatomical and physiological, that gap junctions exist in the hippocampus. Electrical coupling through these gap junctions may be divided into three types: between principal neurons, between interneurons and at mixed chemical (glutamatergic)/electrical synapses. An approach, combining in vitro experimental with modeling techniques, sheds some light on the functional consequences of electrical coupling, for network oscillations and for seizures. Additionally, in vivo experiments, using mouse connexin knockouts, suggest that the presence of electrical coupling is important for optimal performance on selected behavioral tasks; however, the interpretation of such data, in cellular terms, has so far proven difficult. Given that invertebrate central pattern generators so often depend on both chemical and electrical synapses, our hypothesis is that hippocampus-mediated and -influenced behaviors will act likewise. Experiments, likely hard ones, will be required to test this intuition.

Acute in vitro models have revealed a great deal of information about mechanisms underlying many types of epileptiform activity. However, few examples exist that shed light on spike-and-wave (SpW) patterns of pathological activity. SpW are seen in many epilepsy syndromes, both generalized and focal, and manifest across the entire age spectrum. They are heterogeneous in terms of their severity, symptom burden, and apparent anatomical origin (thalamic, neocortical, or both), but any relationship between this heterogeneity and underlying pathology remains elusive. In this study we demonstrate that physiological delta-frequency rhythms act as an effective substrate to permit modeling of SpW of cortical origin and may help to address this issue. For a starting point of delta activity, multiple subtypes of SpW could be modeled computationally and experimentally by either enhancing the magnitude of excitatory synaptic events ascending from neocortical layer 5 to layers 2/3 or selectively modifying superficial layer GABAergic inhibition. The former generated SpW containing multiple field spikes with long interspike intervals, whereas the latter generated SpW with short-interval multiple field spikes. Both types had different laminar origins and each disrupted interlaminar cortical dynamics in a different manner. A small number of examples of human recordings from patients with different diagnoses revealed SpW subtypes with the same temporal signatures, suggesting that detailed quantification of the pattern of spikes in SpW discharges may be a useful indicator of disparate underlying epileptogenic pathologies. NEW & NOTEWORTHY Spike-and-wave-type discharges (SpW) are a common feature in many epilepsies. Their electrographic manifestation is highly varied, as are available genetic clues to associated underlying pathology. Using computational and in vitro models, we demonstrate that distinct subtypes of SpW are generated by lamina-selective disinhibition or enhanced interlaminar excitation. These subtypes could be detected in at least some noninvasive patient recordings, suggesting more detailed analysis of SpW may be useful in determining clinical pathology.

Brain dynamic changes associated with schizophrenia are largely equivocal, with interpretation complicated by many factors, such as the presence of therapeutic agents and the complex nature of the syndrome itself. Evidence for a brain-wide change in individual network oscillations, shared by all patients, is largely equivocal, but stronger for lower (delta) than for higher (gamma) bands. However, region-specific changes in rhythms across multiple, interdependent, nested frequencies may correlate better with pathology. Changes in synaptic excitation and inhibition in schizophrenia disrupt delta rhythm-mediated cortico-cortical communication, while enhancing thalamo-cortical communication in this frequency band. The contrasting relationships between delta and higher frequencies in thalamus and cortex generate frequency mismatches in inter-regional connectivity, leading to a disruption in temporal communication between higher-order brain regions associated with mental time travel.

Network oscillations, at fast frequencies (>80 Hz), can occur experimentally in hippocampal and cortical preparations, when chemical synapses are blocked. Such oscillations, even at “ripple” frequencies, are generated by electrical coupling between principal neurons. In this chapter, we review the evidence that this type of coupling exists, and that it is mediated by gap junctions between axons. This is important for understanding the cellular mechanisms of very fast oscillations, which are important in disease (such oscillations can precede seizures and perhaps initiate them) and also in normal function: very fast oscillations contribute to the generation of a variety of slower oscillations that appear important for perceptual binding, motor control, and memory consolidation.

Purkinje cell (PC) firing represents the sole output from the cerebellar cortex onto the deep cerebellar and vestibular nuclei. Here, we explored the different modes of PC firing in alert mice by extracellular recording. We confirm the existence of a tonic and/or bursting and quiescent modes corresponding to UP and DOWN state, respectively. We demonstrate the existence of a novel 600-Hz buzz UP state of firing characterized by simple spikes (SS) of very small amplitude. Climbing fiber (CF) input is able to switch the 600-Hz buzz to the DOWN state, as for the classical UP-to-DOWN state transition. Conversely, the CF input can initiate a typical SS pattern terminating into 600-Hz buzz. The 600-Hz buzz was transiently suppressed by whisker pad stimulation demonstrating that it remained responsive to peripheral input. It must not be mistaken for a DOWN state or the sign of PC inhibition. Complex spike (CS) frequency was increased during the 600-Hz buzz, indicating that this PC output actively contributes to the cerebello-olivary loop by triggering a disinhibition of the inferior olive. During the 600-Hz buzz, the first depolarizing component of the CS was reduced and the second depolarizing component was suppressed. Consistent with our experimental observations, using a 559-compartment single-PC model – in which PC UP state (of about −43 mV) was obtained by the combined action of large tonic AMPA conductances and counterbalanclng GABAarglc Inhibition – removal of this inhibition produced the 600-Hz buzz; the simulated buzz frequency decreased following an artificial CS.

Fast ripples (FRs) are network oscillations, defined variously as having frequencies of > 150 to > 250 Hz, with a controversial mechanism. FRs appear to indicate a propensity of cortical tissue to originate seizures. Here, we demonstrate field oscillations, at up to 400 Hz, in spontaneously epileptic human cortical tissue in vitro, and present a network model that could explain FRs themselves, and their relation to ‘ordinary’ (slower) ripples. We performed network simulations with model pyramidal neurons, having axons electrically coupled. Ripples (< 250 Hz) were favored when conduction of action potentials, axon to axon, was reliable. Whereas ripple population activity was periodic, firing of individual axons varied in relative phase. A switch from ripples to FRs took place when an ectopic spike occurred in a cell coupled to another cell, itself multiply coupled to others. Propagation could then start in one direction only, a condition suitable for re-entry. The resulting oscillations were > 250 Hz, were sustained or interrupted, and had little jitter in the firing of individual axons. The form of model FR was similar to spontaneously occurring FRs in excised human epileptic tissue. In vitro, FRs were suppressed by a gap junction blocker. Our data suggest that a given network can produce ripples, FRs, or both, via gap junctions, and that FRs are favored by clusters of axonal gap junctions. If axonal gap junctions indeed occur in epileptic tissue, and are mediated by connexin 26 (recently shown to mediate coupling between immature neocortical pyramidal cells), then this prediction is testable.

Mechanisms of place cell replay occurring during sharp-wave ripples (SPW-Rs) remain obscure due to the fact that ripples in vitro depend on non-synaptic mechanisms, presumably via axo-axonal gap junctions between pyramidal cells. We suggest a model of in vivo SPW-Rs in which synaptic excitatory post-synaptic potentials (EPSPs) control the axonal spiking of cells in SPW-Rs: ripple activity remains hidden in the network of axonal collaterals (connected by gap junctions) due to conduction failures, unless there is a sufficient dendritic EPSP. The EPSP brings the axonal branching point to threshold, and action potentials from the collateral start to propagate to the soma and to the distal axon. The model coherently explains multiple experimental data on SPW-Rs, both in vitro and in vivo. The mechanism of synaptic gating leads to the following implication: a sequence of pyramidal cells can be replayed at ripple frequency by the superposition of subthreshold dendritic EPSPs and ripple activity in the axonal plexus. Replay is demonstrated in both forward and reverse directions. We discuss several testable predictions. In general, the mechanism of synaptic gating suggests that pyramidal cells under certain conditions can act like a transistor.

Delta oscillations (1–4 Hz) associate with deep sleep and are implicated in memory consolidation and replay of cortical responses elicited during wake states. A potent local generator has been characterized in thalamus, and local generators in neocortex have been suggested. Here we demonstrate that isolated rat neocortex generates delta rhythms in conditions mimicking the neuromodulatory state during deep sleep (low cholinergic and dopaminergic tone). The rhythm originated in an NMDA receptor-driven network of intrinsic bursting (IB) neurons in layer 5, activating a source of GABAB receptor-mediated inhibition. In contrast, regular spiking (RS) neurons in layer 5 generated theta-frequency outputs. In layer 2/3 principal cells, outputs from IB cells associated with IPSPs, whereas those from layer 5 RS neurons related to nested bursts of theta-frequency EPSPs. Both interlaminar spike and field correlations revealed a sequence of events whereby sparse spiking in layer 2/3 was partially reflected back from layer 5 on each delta period. We suggest that these reciprocal, interlaminar interactions may represent a “Helmholtz machine”-like process to control synaptic rescaling during deep sleep.

Evidence has been presented that CA1 pyramidal cells, during spontaneous in vitro sharp wave/ripple (SPW-R) complexes, generate somatic action potentials that originate in axons. 'Participating' (somatically firing) pyramidal cells fire (almost always) at most once during a particular SPW-R whereas non-participating cells virtually never fire during an SPW-R. Somatic spikelets were small or absent, while ripple-frequency EPSCs and IPSCs occurred during the SPW-R in pyramidal neurons. These experimental findings could be replicated with a network model in which electrical coupling was present between small pyramidal cell axonal branches. Here, we explore this model in more depth. Factors that influence somatic participation include: (i) the diameter of axonal branches that contain coupling sites to other axons, because firing in larger branches injects more current into the main axon, increasing antidromic firing probability; (ii) axonal K(+) currents and (iii) somatic hyperpolarization and shunting. We predict that portions of axons fire at high frequency during SPW-R, while somata fire much less. In the model, somatic firing can occur by occasional generation of full action potentials in proximal axonal branches, which are excited by high-frequency spikelets. When the network contains phasic synaptic inhibition, at the axonal gap junction site, gamma oscillations result, again with more frequent axonal firing than somatic firing. Combining the models, so as to generate gamma followed by sharp waves, leads to strong overlap between the population of cells firing during gamma and the population of cells firing during a subsequent sharp wave, as observed in vivo.

Morphological and electrophysiological studies have shown that granule cell axons, the mossy fibers (MFs), establish gap junctions and therefore electrical communication among them. That granule cells express gap junctional proteins in their axons suggests the possibility that their terminals also express them. If this were to be the case, mixed electrical–chemical communication could be supported, as MF terminals normally use glutamate for fast communication with their target cells. Here we present electrophysiological studies in the rat and modeling studies consistent with this hypothesis. We show that MF activation produced fast spikelets followed by excitatory postsynaptic potentials in pyramidal cells (PCs), which, unlike the spikelets, underwent frequency potentiation and were strongly depressed by activation of metabotropic glutamate receptors, as expected from transmission of MF origin. The spikelets, which persisted during blockade of chemical transmission, were potentiated by dopamine and suppressed by the gap junction blocker carbenoxolone. The various waveforms evoked by MF stimulation were replicated in a multi-compartment model of a PC by brief current-pulse injections into the proximal apical dendritic compartment, where MFs are known to contact PCs. Mixed electrical and glutamatergic communication between granule cells and some PCs in CA3 may ensure the activation of sets of PCs, bypassing the strong action of concurrent feed-forward inhibition that granule cells activate. Importantly, MF-to-PC electrical coupling may allow bidirectional, possibly graded, communication that can be faster than chemical synapses and subject to different forms of modulation.

Gamma rhythms (30–80 Hz) are a near-ubiquitous feature of neuronal population activity in mammalian cortices. Their dynamic properties permit the synchronization of neuronal responses to sensory input within spatially distributed networks, transient formation of local neuronal “cell assemblies,” and coherent response patterns essential for intercortical regional communication. Each of these phenomena form part of a working hypothesis for cognitive function in cortex. All forms of physiological gamma rhythm are inhibition based, being characterized by rhythmic trains of inhibitory postsynaptic potentials in populations of principal neurons. It is these repeating periods of relative enhancement and attenuation of the responsivity of major cell groups in cortex that provides a temporal structure shared across many millions of neurons. However, when considering the origins of these repeating trains of inhibitory events considerable divergence is seen depending on cortical region studied and mode of activation of gamma rhythm generating networks. Here, we review the evidence for involvement of multiple subtypes of interneuron and focus on different modes of activation of these cells. We conclude that most massively parallel brain regions have different mechanisms of gamma rhythm generation, that different mechanisms have distinct functional correlates, and that switching between different local modes of gamma generation may be an effective way to direct cortical communication streams. Finally, we suggest that developmental disruption of the endophenotype for certain subsets of gamma-generating interneuron may underlie cognitive deficit in psychiatric illness. © 2010 Wiley Periodicals, Inc. Develop Neurobiol 71: 92–106, 2011

Very fast oscillations (VFOs, >80 Hz) are important for physiological brain processes and, in excess, with certain epilepsies. Putative mechanisms for VFO include interneuron spiking and network activity in coupled pyramidal cell axons. It is not known whether either, or both, of these apply in pathophysiological conditions. Spontaneously occurring interictal discharges occur in human tissue in vitro, resected from neocortical epileptic foci. VFO associated with these discharges was manifest in both field potential and, with phase delay, in excitatory synaptic inputs to fast spiking interneurons. Recruitment of somatic pyramidal cell and interneuron spiking was low, with no correlation between VFO power and synaptic inputs to principal cells. Reducing synaptic inhibition failed to affect VFO occurrence, but they were abolished by reduced gap junction conductance. These data suggest a lack of a causal role for interneurons, and favor a nonsynaptic pyramidal cell network origin for VFO in epileptic human neocortex.

Numerous authors have reported the occurrence of very fast field potential/electroencephalography (EEG)/electrocorticography (ECoG) oscillations, at frequencies ≥80 Hz, prior to, during, and after paroxysmal epileptic events (either interictal or ictal), and both in patients and in experimental preparations, in vivo and in vitro (references include, but are not limited to: Fisher et al., 1992; Bragin et al., 1999a,b, 2002; Grenier et al., 2001, 2003; Jacobs et al., 2008; Khosravani et al., 2009; Worrell et al., 2004; Traub 2et al., 2001, 2005; Roopun et al., in prep.) In some cases, VFOs appear to arise in exquisitely localized regions of cortical tissue (Bragin et al., 1999b, 2002; Roopun et al., in 3prep.); sometimes other epileptiform events can also arise in highly localized regions (Schevon et al., 2008). On different occasions, however, VFOs occur simultaneously in a number of subdural grid ECoG electrodes (e.g., Fig. 1 of Traub et al., 2001), and such activity presumably encompasses several squared centimeters of cortical surface. Although VFOs may be useful in identifying seizure-onset zones (Roopun et al., 2009), it is interesting to note that VFO occurrence is not specific to particular pathologies, and it is not directly related to local pathologic changes (Jacobs et al., 2008). These latter observations suggest that the ability to generate VFOs might be a normal facet of cortical function, which is pathologically enhanced in epilepsy. Figure. 1 Very fast oscillations (VFOs) occur at the surface of human epileptic brain; in layer 5 of rat neocortex, in vitro, with chemical synapses blocked; and in a detailed network model of neurons coupled by gap junctions, without chemical synapses. (A) Electrocorticography ... To our knowledge, the detailed spatiotemporal patterns of VFOs have not yet been investigated. There also continues to be uncertainty concerning the cellular mechanisms of different sorts of VFOs and their significance for epileptogenesis (Engel et al., 2009). Clearer understanding of the two related issues—VFO spatiotemporal pattern and cellular mechanism—may have clinical importance: Factors in the brain that predispose to VFO may also predispose to seizures, or VFO itself may promote seizure onset. In our view, the evidence that in vitro VFO is generated by gap junctional coupling between principal neurons is compelling. The evidence is both positive and negative. On the positive side: Such VFO occurs when chemical synaptic transmission is globally suppressed with low-Ca2+ media, or selectively suppressed with blockers of particular synaptic receptors, including γ-aminobutyric acid (GABA)A receptors; in vitro VFO is associated with action potentials and spikelets in pyramidal cells that are phase-locked to field VFO and it is suppressed by carbenoxolone, halothane, and octanol, all blockers of gap junction conductance, and is augmented by alkalinization of the medium, which would open most types of gap junctions (Draguhn et al., 1998; Nimmrich et al., 2005; Roopun et al., in prep.—but see Gonzales-Nieto et al., 2008). Furthermore, a detailed network model, based on postulated gap junctional coupling between pyramidal cell axons, produces field and intracellular potentials closely resembling experiment (Traub et al., 1999; see also Fig. 1). (The evidence that such gap junctions actually exist is reviewed in the Discussion.) On the negative side, we are not aware of any cortical experimental preparation, dependent on chemical synapses, that has been shown to generate network oscillations at the requisite frequencies. With respect to in vivo epilepsy-related VFOs, Grenier et al. (2003) reported that the gap junction blocker halothane suppressed both the VFOs and seizures that spontaneously occurred in ketamine–xylazine anesthetized cats. However, the cellular mechanisms of in vivo VFO are difficult to study experimentally, at least in a direct fashion. For example, although intracellular and juxtacellular recordings are possible in vivo (in experimental animals), blockade of synaptic transmission is hard to achieve. There is a useful role for network models in a situation such as this, as such models can suggest novel experiments that may be practical to perform. Detailed neuronal network models, of the sort mentioned in the preceding and used to simulate VFOs, are computationally intensive. The original one (Traub et al., 1999) involved

Many types of electrographic seizures are readily identifiable by direct visual examination of electroencephalographic or electrocorticographic recordings. This process can, however, be painstakingly slow, and much effort has been expended to automate the process using various dynamic properties of epileptiform waveforms. As methods have become more subtle and powerful they have been used for seizure subclassification, seizure prediction, and seizure onset identification and localization. Here we concentrate on the last, with reference to seizures of neocortical origin. We briefly review some of the methods used and introduce preliminary results from a very simple dynamic model based on key electrophysiological properties found in some seizure types: occurrence of very fast oscillations (sometimes called ripples), excess gamma frequency oscillations, electroencephalographic/electrocorticographic flattening, and changes in global synchrony. We show how this multiscale analysis may reveal features unique to seizure onset and speculate on the underlying cellular and network phenomena responsible.

Summary: Purpose: We propose an experimentally and clinically testable hypothesis, concerning the origin of very fast (>∼70 Hz) EEG oscillations that sometimes precede the onset of focal seizures. These oscillations are important, as they may play a causal role in the initiation of seizures. Methods: Subdural EEG recordings were obtained from children with focal cortical dysplasias and intractable seizures. Intra- and extracellular recordings were performed in rat hippocampal slices, with induction of population activity, as follows: (a) bath-applied tetramethylamine (an intracellular alkalinizing agent, that opens gap junctions); (b) bath-applied carbachol, a cholinergic agonist; and (c) focal pressure ejection of hypertonic K+ solution. Detailed network simulations were performed, the better to understand the cellular mechanisms underlying oscillations. A major feature of the simulations was inclusion of axon–axon gap junctions between principal neurons, as supported by recent experimental data. Results: Very fast oscillations were found in children before seizure onset, but also superimposed on bursts during the seizure, and on interictal bursts. In slice experiments, very fast oscillations had previously been seen on interictal-like bursts; we now show such oscillations before, between, and after epileptiform bursts. Very fast oscillations were also seen superimposed on gamma (30–70 Hz) oscillations induced by carbachol or hypertonic K+, and in the latter case, very fast oscillations became continuous when chemical synapses were blocked. Simulations replicate these data, when axonal gap junctions are included. Conclusions: Electrical coupling between principal neurons, perhaps via axonal gap junctions, could underlie very fast population oscillations, in seizure-prone brain, but possibly also in normal brain. The anticonvulsant potential of gap-junction blockers such as carbenoxolone, now in clinical use for treatment of ulcer disease, should be considered.

SummaryBoth cerebellum and neocortex receive input from the somatosensory system. Interaction between these regions has been proposed to underpin the correct selection and execution of motor commands, but it is not clear how such interactions occur. In neocortex, inputs give rise to population rhythms, providing a spatiotemporal coding strategy for inputs and consequent outputs. Here, we show that similar patterns of rhythm generation occur in cerebellum during nicotinic receptor subtype activation. Both gamma oscillations (30–80 Hz) and very fast oscillations (VFOs, 80–160 Hz) were generated by intrinsic cerebellar cortical circuitry in the absence of functional glutamatergic connections. As in neocortex, gamma rhythms were dependent on GABAA receptor-mediated inhibition, whereas VFOs required only nonsynaptically connected intercellular networks. The ability of cerebellar cortex to generate population rhythms within the same frequency bands as neocortex suggests that they act as a common spatiotemporal code within which corticocerebellar dialog may occur.

Gap junctions have been postulated to exist between the axons of excitatory cortical neurons based on electrophysiological, modeling, and dye-coupling data. Here, we provide ultrastructural evidence for axoaxonic gap junctions in dentate granule cells. Using combined confocal laser scanning microscopy, thin-section transmission electron microscopy, and grid-mapped freeze–fracture replica immunogold labeling, 10 close appositions revealing axoaxonic gap junctions (≈30–70 nm in diameter) were found between pairs of mossy fiber axons (≈100–200 nm in diameter) in the stratum lucidum of the CA3b field of the rat ventral hippocampus, and one axonal gap junction (≈100 connexons) was found on a mossy fiber axon in the CA3c field of the rat dorsal hippocampus. Immunogold labeling with two sizes of gold beads revealed that connexin36 was present in that axonal gap junction. These ultrastructural data support computer modeling and in vitro electrophysiological data suggesting that axoaxonic gap junctions play an important role in the generation of very fast (>70 Hz) network oscillations and in the hypersynchronous electrical activity of epilepsy.

SummaryPerisomatic inhibition provided by a subgroup of GABAergic interneurons plays a critical role in timing the output of pyramidal cells. To test their contribution at the network and the behavioral level, we generated genetically modified mice in which the excitatory drive was selectively reduced either by the knockout of the GluR-D or by conditional ablation of the GluR-A subunit in parvalbumin-positive cells. Comparable cell type-specific reductions of AMPA-mediated currents were obtained. Kainate-induced gamma oscillations exhibited reduced power in hippocampal slices from GluR-D−/− and GluR-APVCre−/− mice. Experimental and modeling data indicated that this alteration could be accounted for by imprecise spike timing of fast-spiking cells (FS) caused by smaller interneuronal EPSPs. GluR-D−/− and GluR-APVCre−/− mice exhibited similar impairments in hippocampus-dependent tasks. These findings directly show the effects of insufficient recruitment of fast-spiking cells at the network and behavioral level and demonstrate the role of this subpopulation for working and episodic-like memory.

The level of arousal in mammals is correlated with metabolic state and specific patterns of cortical neuronal responsivity. In particular, rhythmic transitions between periods of high activity (up phases) and low activity (down phases) vary between wakefulness and deep sleep/anesthesia. Current opinion about changes in cortical response state between sleep and wakefulness is split between neuronal network-mediated mechanisms and neuronal metabolism-related mechanisms. Here, we demonstrate that slow oscillations in network state are a consequence of interactions between both mechanisms. Specifically, recurrent networks of excitatory neurons, whose membrane potential is partly governed by ATP-modulated potassium (K ATP ) channels, mediate response-state oscillations via the interaction between excitatory network activity involving slow, kainate receptor-mediated events and the resulting activation of ATP-dependent homeostatic mechanisms. These findings suggest that K ATP channels function as an interface between neuronal metabolic state and network responsivity in mammalian cortex.

As a structure involved in learning and memory, the hippocampus functions as a network. The functional differentiation along the longitudinal axis of the hippocampus is poorly demarcated in comparison with the transverse axis. Using patch clamp recordings in conjunction with post hoc anatomy, we have examined the pattern of connectivity and the functional differentiation along the long axis of the hippocampus. Here, we provide anatomical and physiological evidence that the prominent rhythmic network activities of the hippocampus, the behavior-specific gamma and theta oscillations, are seen predominantly along the transverse and longitudinal axes respectively. This orthogonal relationship is the result of the axonal field trajectories and the consequential interaction of the principal cells and major interneuron subtypes involved in generating each rhythm. Thus, the axonal arborization patterns of hippocampal inhibitory cells may represent a structural framework for the spatiotemporal distribution of activity observed within the hippocampus.

Persistent gamma frequency (30–70 Hz) network oscillations occur in hippocampal slices under conditions of metabotropic glutamate receptor (mGluR) activation. Excessive mGluR activation generated a bistable pattern of network activity during which epochs of gamma oscillations of increasing amplitude were terminated by synchronized bursts and very fast oscillations (>70 Hz). We provide experimental evidence that, during this behavior, pyramidal cell-to-interneuron synaptic depression takes place, occurring spontaneously during the gamma rhythm and associated with the onset of epileptiform bursts. We further provide evidence that excitatory postsynaptic potentials (EPSPs) in pyramidal cells are potentiated during the interburst gamma oscillation. When these two types of synaptic plasticity are incorporated, phenomenologically, into a network model previously shown to account for many features of persistent gamma oscillations, we find that epochs of gamma do indeed alternate with epochs of very fast oscillations and epileptiform bursts. Thus the same neuronal network can generate either gamma oscillations or epileptiform bursts, in a manner depending on the degree of network drive and network-induced fluctuations in synaptic efficacies.

To better understand population phenomena in thalamocortical neuronal ensembles, we have constructed a preliminary network model with 3,560 multicompartment neurons (containing soma, branching dendrites, and a portion of axon). Types of neurons included superficial pyramids (with regular spiking [RS] and fast rhythmic bursting [FRB] firing behaviors); RS spiny stellates; fast spiking (FS) interneurons, with basket-type and axoaxonic types of connectivity, and located in superficial and deep cortical layers; low threshold spiking (LTS) interneurons, which contacted principal cell dendrites; deep pyramids, which could have RS or intrinsic bursting (IB) firing behaviors, and endowed either with nontufted apical dendrites or with long tufted apical dendrites; thalamocortical relay (TCR) cells; and nucleus reticularis (nRT) cells. To the extent possible, both electrophysiology and synaptic connectivity were based on published data, although many arbitrary choices were necessary. In addition to synaptic connectivity (by AMPA/kainate, NMDA, and GABAAreceptors), we also included electrical coupling between dendrites of interneurons, nRT cells, and TCR cells, and—in various combinations—electrical coupling between the proximal axons of certain cortical principal neurons. Our network model replicates several observed population phenomena, including 1) persistent gamma oscillations; 2) thalamocortical sleep spindles; 3) series of synchronized population bursts, resembling electrographic seizures; 4) isolated double population bursts with superimposed very fast oscillations (>100 Hz, “VFO”); 5) spike-wave, polyspike-wave, and fast runs (about 10 Hz). We show that epileptiform bursts, including double and multiple bursts, containing VFO occur in rat auditory cortex in vitro, in the presence of kainate, when both GABAAand GABABreceptors are blocked. Electrical coupling between axons appears necessary (as reported previously) for persistent gamma and additionally plays a role in the detailed shaping of epileptogenic events. The degree of recurrent synaptic excitation between spiny stellate cells, and their tendency to fire throughout multiple bursts, also appears critical in shaping epileptogenic events.

Persistent in vitro gamma oscillations, induced by bath application of carbachol and kainate (amongst other drugs), were discovered by Eberhard Buhl and collaborators in 1998. The oscillations are robust, in that they can continue for hours; but the oscillations are also intricate in their mechanisms: they depend upon phasic synaptic excitation and inhibition, upon electrical coupling between interneurones and between pyramidal neurones, and – at least in neocortex – they depend upon complex intrinsic properties of some of the neurones.

Using whole-cell patch-clamp recordings in conjunction with post hoc anatomy we investigated the physiological properties of hippocampal stratum oriens and stratum pyramidale inhibitory interneurones, before and following the induction of pharmacologically evoked gamma frequency network oscillations. Prior to kainate-induced transient epochs of gamma activity, two distinct classes of oriens interneurones, oriens lacunosum-moleculare (O-LM) and trilaminar cells, showed prominent differences in their membrane and firing properties, as well as in the amplitude and kinetics of their excitatory postsynaptic events. In the active network both types of neurone received a phasic barrage of gamma frequency excitatory inputs but, due to their differential functional integration, showed clear differences in their output patterns. While O-LM cells fired intermittently at theta frequency, trilaminar interneurones discharged on every gamma cycle and showed a propensity to fire spike doublets. Two other classes of fast spiking interneurones, perisomatic targeting basket and bistratified cells, in the active network discharged predominantly single action potentials on every gamma cycle. Thus, within a locally excited network, O-LM cells are likely to provide a theta-frequency patterned output to distal dendritic segments, whereas basket and bistratified cells are involved in the generation of locally synchronous gamma band oscillations. The anatomy and output profile of trilaminar cells suggest they are involved in the projection of locally generated gamma rhythms to distal sites. Therefore a division of labour appears to exist whereby different frequencies and spatiotemporal properties of hippocampal rhythms are mediated by different interneurone subtypes.

Kainate receptors (KARs) play an important role in synaptic physiology, plasticity, and pathological phenomena such as epilepsy. However, the physiological implications for neuronal networks of the distinct expression patterns of KAR subunits are unknown. Using KAR knock-out mice, we show that subunits glutamate receptor (GluR) 5 and GluR6 play distinct roles in kainate-induced gamma oscillations and epileptiform burst activity. Ablation of GluR5 leads to a higher susceptibility of the network to the oscillogenic and epileptogenic effects of kainate, whereas lack of GluR6 prevents kainate-induced gamma oscillations or epileptiform bursts. Based on experimental and simulated neuronal network data as well as the consequences of GluR5 and GluR6 expression for cellular and synaptic physiology, we propose that the functional interplay of GluR5-containing KARs on axons of interneurons and GluR6-containing KARs in the somatodendritic region of both interneurons and pyramidal cells underlie the oscillogenic and epileptogenic effects of kainate.