Eberhard H. Buhl

Inhibition-based rhythms: experimental and mathematical observations on network dynamics.

An increasingly large body of data exists which demonstrates that oscillations of frequency 12-80 Hz are a consequence of, or are inextricably linked to, the behaviour of inhibitory interneurons in the central nervous system. This frequency range covers the EEG bands beta 1 (12-20 Hz), beta 2 (20-30 Hz) and gamma (30-80 Hz). The pharmacological profile of both spontaneous and sensory-evoked EEG potentials reveals a very strong influence on these rhythms by drugs which have direct effects on GABA(A) receptor-mediated synaptic transmission (general anaesthetics, sedative/hypnotics) or indirect effects on inhibitory neuronal function (opiates, ketamine). In addition, a number of experimental models of, in particular, gamma-frequency oscillations, have revealed both common denominators for oscillation generation and function, and subtle differences in network dynamics between the different frequency ranges. Powerful computer and mathematical modelling techniques based around both clinical and experimental observations have recently provided invaluable insight into the behaviour of large networks of interconnected neurons. In particular, the mechanistic profile of oscillations generated as an emergent property of such networks, and the mathematical derivation of this complex phenomenon have much to contribute to our understanding of how and why neurons oscillate. This review will provide the reader with a brief outline of the basic properties of inhibition-based oscillations in the CNS by combining research from laboratory models, large-scale neuronal network simulations, and mathematical analysis.

Proximally targeted GABAergic synapses and gap junctions synchronize cortical interneurons

Networks of GABAergic interneurons are implicated in synchronizing cortical activity at gamma frequencies (30–70 Hz). Here we demonstrate that the combined electrical and GABAergic synaptic coupling of basket cells instantaneously entrained gamma-frequency postsynaptic firing in layers 2/3 of rat somatosensory cortex. This entrainment was mediated by rapid curtailment of gap junctional coupling potentials by GABAA receptor-mediated IPSPs. Electron microscopy revealed spatial proximity of gap junctions and GABAergic synapses on somata and dendrites. Electrical coupling alone entrained postsynaptic firing with a phase lag, whereas unitary GABAergic connections were ineffective in gamma-frequency phasing. These observations demonstrate precise spatiotemporal mechanisms underlying action potential timing in oscillating interneuronal networks.

Impaired Electrical Signaling Disrupts Gamma Frequency Oscillations in Connexin 36-Deficient Mice

Neural processing occurs in parallel in distant cortical areas even for simple perceptual tasks. Associated cognitive binding is believed to occur through the interareal synchronization of rhythmic activity in the gamma (30-80 Hz) range. Such oscillations arise as an emergent property of the neuronal network and require conventional chemical neurotransmission. To test the potential role of gap junction-mediated electrical signaling in this network property, we generated mice lacking connexin 36, the major neuronal connexin. Here we show that the loss of this protein disrupts gamma frequency network oscillations in vitro but leaves high frequency (150 Hz) rhythms, which may involve gap junctions between principal cells (Schmitz et al., 2001), unaffected. Thus, specific connexins differentially deployed throughout cortical networks are likely to regulate different functional aspects of neuronal information processing in the mature brain.

Axo-Axonal Coupling: A Novel Mechanism for Ultrafast Neuronal Communication

We provide physiological, pharmacological, and structural evidence that axons of hippocampal principal cells are electrically coupled, with prepotentials or spikelets forming the physiological substrate of electrical coupling as observed in cell somata. Antidromic activation of neighboring axons induced somatic spikelet potentials in neurons of CA3, CA1, and dentate gyrus areas of rat hippocampal slices. Somatic invasion by these spikelets was dependent on the activation of fast Na(+) channels in the postjunctional neuron. Antidromically elicited spikelets were suppressed by gap junction blockers and low intracellular pH. Paired axo-somatic and somato-dendritic recordings revealed that the coupling potentials appeared in the axon before invading the soma and the dendrite. Using confocal laser scanning microscopy we found that putative axons of principal cells were dye coupled. Our data thus suggest that hippocampal neurons are coupled by axo-axonal junctions, providing a novel mechanism for very fast electrical communication.

A Possible Role for Gap Junctions in Generation of Very Fast EEG Oscillations Preceding the Onset of, and Perhaps Initiating, Seizures

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.

Differential involvement of oriens/pyramidale interneurones in hippocampal network oscillations in vitro

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.

A model of atropine-resistant theta oscillations in rat hippocampal area CA1.

Theta frequency oscillations are a predominant feature of rhythmic activity in the hippocampus. We demonstrate that hippocampal area CA1 generates atropine‐resistant theta population oscillations in response to metabotropic glutamate receptor activation under conditions of reduced AMPA receptor activation. This activity occurred in the absence of inputs from area CA3 and extra‐ammonic areas. Field theta oscillations were co‐expressed with pyramidal distal apical dendritic burst spiking and were temporally related to trains of IPSPs with slow kinetics. Pyramidal somatic responses showed theta oscillations consisted of compound inhibitory synaptic potentials with initial IPSPs with slow kinetics followed by trains of smaller, faster IPSPs. Pharmacological modulation of IPSPs altered the theta oscillation suggesting an inhibitory network origin. Somatic IPSPs, dendritic burst firing and stratum pyramidale interneuron activity were all temporally correlated with spiking in stratum oriens interneurons demonstrating intrinsic theta‐frequency oscillations. Disruption of spiking in these interneurons was accompanied by a loss of both field theta and theta frequency IPSP trains. We suggest that population theta oscillations can be generated as a consequence of intrinsic theta frequency spiking activity in a subset of stratum oriens interneurons controlling electrogenesis in pyramidal cell apical dendrites.

GABA-enhanced collective behavior in neuronal axons underlies persistent gamma-frequency oscillations

Gamma (30–80 Hz) oscillations occur in mammalian electroencephalogram in a manner that indicates cognitive relevance. In vitro models of gamma oscillations demonstrate two forms of oscillation: one occurring transiently and driven by discrete afferent input and the second occurring persistently in response to activation of excitatory metabotropic receptors. The mechanism underlying persistent gamma oscillations has been suggested to involve gap-junctional communication between axons of principal neurons, but the precise relationship between this neuronal activity and the gamma oscillation has remained elusive. Here we demonstrate that gamma oscillations coexist with high-frequency oscillations (>90 Hz). High-frequency oscillations can be generated in the axonal plexus even when it is physically isolated from pyramidal cell bodies. They were enhanced in networks by nonsomatic γ-aminobutyric acid type A (GABAA) receptor activation, were modulated by perisomatic GABAA receptor-mediated synaptic input to principal cells, and provided the phasic input to interneurons required to generate persistent gamma-frequency oscillations. The data suggest that high-frequency oscillations occurred as a consequence of random activity within the axonal plexus. Interneurons provide a mechanism by which this random activity is both amplified and organized into a coherent network rhythm.

Contrasting roles of axonal (pyramidal cell) and dendritic (interneuron) electrical coupling in the generation of neuronal network oscillations

Electrical coupling between pyramidal cell axons, and between interneuron dendrites, have both been described in the hippocampus. What are the functional roles of the two types of coupling? Interneuron gap junctions enhance synchrony of γ oscillations (25–70 Hz) in isolated interneuron networks and also in networks containing both interneurons and principal cells, as shown in mice with a knockout of the neuronal (primarily interneuronal) connexin36. We have recently shown that pharmacological gap junction blockade abolishes kainate-induced γ oscillations in connexin36 knockout mice; without such gap junction blockade, γ oscillations do occur in the knockout mice, albeit at reduced power compared with wild-type mice. As interneuronal dendritic electrical coupling is almost absent in the knockout mice, these pharmacological data indicate a role of axonal electrical coupling in generating the γ oscillations. We construct a network model of an experimental γ oscillation, known to be regulated by both types of electrical coupling. In our model, axonal electrical coupling is required for the γ oscillation to occur at all; interneuron dendritic gap junctions exert a modulatory effect.

Fast network oscillations induced by potassium transients in the rat hippocampus in vitro

Brief pressure ejection of solutions containing potassium, caesium or rubidium ions into stratum radiatum of the CA1 or CA3 regions of the hippocampal slice evoked a fast network oscillation. The activity evoked lasted ∼3–25 s with the predominant frequency component being in the gamma frequency range (30–80 Hz), although beta frequency (15–30 Hz) and ultrafast (> 80 Hz) components could also be seen. The gamma frequency component of the oscillation remained constant, even when large changes in power occurred, and was synchronous across the CA1 region. Measurements with potassium ion‐sensitive electrodes revealed that the network oscillation was accompanied by increases (0.5 to 2.0 mm) in the extracellular potassium concentration [K+]o. Bath application of the N‐methyl‐d‐aspartate (NMDA) receptor antagonists d(–)‐2‐amino‐5‐phosphonopentanoic acid (d‐AP5; 50 μM) had no significant effect but the α‐amino‐3‐hydroxy‐5‐methyl‐4‐isooxazolepropionic acid (AMPA)/kainate receptor antagonist 2,3,‐dioxo‐6‐nitro‐1,2,3,4‐tetrahydrobenzo[f]quinoxaline‐7‐sulphonamide disodium (NBQX; 20 μM) caused a significant reduction (86.7 ± 4.5 %) in the power in the gamma frequency range. Residual rhythmic activity, presumably arising in the interneuronal network, was blocked by the GABAA receptor antagonist bicuculline. The putative gap junction blocker octanol caused a decrease in the power of the gamma frequency component of 75.5 ± 5.6 %, while carbenoxolone produced a reduction of only 14 ± 42 %. These experiments demonstrate that a modest increase in exogenous [K+]o in the hippocampus in vitro is sufficient to evoke a fast network oscillation, which is an emergent property of the synaptically and electrically interconnected neuronal network.