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In Sync—Orchestrating Perfect Harmony in Neuronal Networks

31 Jan 2006

1 February 2006. Flocks of birds do it, schools of fish do it, so why can’t neuronal networks do it? Well, they can, and they do—move in perfect synchrony, that is. But why is that, exactly? Some answers come from back-to-back papers in the January 5 Neuron. The two papers report different, though complementary, mechanisms for regulating the rhythmic firing of GABAergic neurons—ones that use the amino acid derivative γ-aminobutyric acid (GABA) as a neurotransmitter. Peter Jonas and colleagues at the University of Freiburg, Germany, describe how a process called “shunting inhibition” keeps these GABAergic neurons firing together, while Alberto Bacci and John Huguenard at Stanford University School of Medicine, California, reveal that a self-regulatory mechanism ensures that the neurons fire with precise timing. Together, the papers help explain how the so-called γ oscillations, a feature of GABAergic interneurons, are maintained. These oscillations, of between 30 and 90 Hertz, are thought to be indispensable for basic cognitive tasks, such as feature recognition and processing of content- and context-sensitive information. GABA has also been implicated in the pathophysiology of schizophrenia in several different anatomical systems (for a review, see Wassef et al., 2003; Lewis et al., 2005).

The main function of GABAergic interneurons is to modulate the action of excitatory neurons, or principal neurons such as the pyramidal cells, which excite other neurons to generate action potentials. GABAergic neurons are perfectly suited to this role because they are, for the most part, inhibitory (though a prominent exception was reported recently in Science; see below) and they sit in wait between the excitatory cells and their targets (hence, the term interneurons). However, scientists have been puzzled by how GABAergic networks generate synchronous oscillations. In theory, this can happen if a large enough stimulus impacts the network, because it could rapidly propagate an inhibitory pulse throughout the neurons. This would synchronize the network because all the neurons would then recover at the same time. But as Jonas and colleagues point out, synchrony tends to break down if the stimuli from the excitatory cells are not themselves in synch, as happens in vivo. And while a single, very large excitatory stimulus might counteract this tendency sufficiently to set the pace of the network, there is no experimental data to suggest that this is what happens in real life.

Enter shunting inhibition. This is very different from the classic “hyperpolarization” that dampens neuronal activity. When neurons are hyperpolarized, the balance of ions across the cell membrane is shifted so that it becomes harder to depolarize the membrane and get the neuron to fire. In contrast, shunting inhibition, caused by the opening of chloride channels, results in a hint of depolarization because the equilibrium potential for the chloride channel is only slightly more positive than the normal resting potential of the neuron. But more importantly, the open chloride channels clamp, or shunt, the membrane potential at this new level and prevent any other stimuli from depolarizing the cell further.

A few years ago, GABA receptors were shown to mediate depolarizing events (see Stein and Nicoll 2003), while shunting inhibition evoked by activation of the GABAA receptor, which is coupled to chloride channels, has been evoked to explain the rhythmic firing of neurons in the thalamus (see Bazhenov et al., 1999). In this context, Jonas's team tested if shunting inhibition may operate in hippocampal networks. First author Imre Vida and colleagues measured membrane potentials in basket cells, GABAergic interneurons that fire rhythmic bursts in the γ frequency range. The authors found that the GABA-induced synaptic reversal potential was slightly more positive than the resting membrane potential, showing that these neurons are indeed slightly depolarized, or shunted, by GABA. To check if this affects the response of basket cell networks to excitatory stimuli, Vida and colleagues measured mini-networks comprising around 200 neurons, keeping them artificially clamped at this slightly depolarized membrane potential. The researchers found that this simulated shunting inhibition kept the coherence of the mini-network at its highest levels. In contrast, when the network was artificially hyperpolarized, then coherency was almost five times lower. Furthermore, the shunting inhibition model remained coherent even if the excitatory stimuli were fairly low, thus obviating the need for a large excitatory drive to keep the network in synchrony.

How does this depolarizing inhibition keep the network synchronized? Vida and colleagues discovered that it homogenizes the firing rates of the neurons. It makes fast neurons fire more slowly, and slow neurons fire more quickly. Furthermore, shunting inhibition helps the network stay synchronized even when the frequency of the excitatory stimuli, such as those from pyramidal neurons, is not necessarily constant. In other words, this type of inhibition makes the GABAergic network extremely robust.

But these findings do not completely rule out a role for hyperpolarizing inhibition in GABAergic networks. In fact, in the second paper, Bacci and Huguenard report that “autaptic” or self-innervation in GABAergic neurons is mediated by hyperpolarization, and that this helps the neurons keep precise timing.

These authors were interested in comparing how fast-spiking (FS) interneurons and excitatory pyramidal neurons react when neocortical slices were stimulated with an electrical current. They found that, though the pyramidal neurons initially fired together, by the time they fired for the fourth time, they were out of phase. The fast-spiking interneurons, on the other hand, were still in phase after four spikes and even after firing 12 times there was little “jitter” as all the neurons spiked about the same time.

Because pyramidal neurons are not self-innervated, Bacci and Huguenard then tested if autaptic transmission in GABAergic cells could explain the dramatic differences in spike-timing precision between the two types of cells. When they blocked all the interneuron GABAA receptors with the antagonist gabazine, they found that the precision of spike-timing was dramatically weakened—after just four spikes, the interneurons had begun to fire out of phase. But because gabazine blocks all GABAA receptors, this result did not prove that loss of autaptic transmission, per se, was what abolished the timing. However, when Bacci used the dynamic clamp—an electrical device that allows researchers to challenge neurons with different voltages and currents—to restore only autaptic transmission to these gabazine-treated cells, then spike-timing precision returned.

Having determined that autaptic transmission was essential for firing precision, Bacci next asked whether the effect is mediated by shunting inhibition or hyperpolarization. He found that electrically inducing hyperpolarization improved the precision, whereas when shunting was induced, precision actually decreased. “These data indicate that the autaptic effect on FS cell spike timing is due to the hyperpolarizing component of GABAergic autaptic transmission rather than to its shunting mechanism,” write the authors.

How hyperpolarization and shunting inhibition are coordinated within the same network is unclear, but it may be related to what part of the cell is affected by each. Shunting may be going on primarily in the dendrites, whereas autaptic transmission was shown to be limited to the soma, or cell body, and the nearby dendritic tree (see Tamas et al., 1997). Whatever the explanation, “the new insights into the interneuronal rhythms provided by the Bacci and Huguenard and Vida et al. studies lend support to the idea that network oscillations are an integral and important part of cortical information processing,” write Edward Mann and Ole Paulsen at the University of Oxford, England, in an accompanying Neuron preview. “Although oscillations are hard to avoid in feedback-coupled networks, such as the cortex, evolution has apparently developed mechanisms that further enhance rather than suppress their oscillatory behavior,” they add.

Mann and Paulsen also predict that GABAergic neurons may have even more secrets to divulge, which seems prescient given that barely a week later, Gábor Támas and colleagues at the University of Szeged, Hungary, demonstrated that GABAergic neurons are not limited to an inhibitory role—they excite, too. In the January 13 Science, joint first authors János Szabadics and Csaba Varga and their coworkers reported that axo-axonic GABAergic cells, which innervate axons in the cerebral cortex, can depolarize those axons and initiate synaptic events. This work lends support to the earlier suggestion that GABA can have an excitatory role in the cortex under certain circumstances (see Gulledge and Stuart, 2003). For further information on this surprising finding, see the detailed SRF commentary by Guillermo Gonzalez-Burgos, from the University of Pittsburgh.—Tom Fagan.


Vida I, Bartos M, Jonas P. Shunting inhibition improves robustness of gamma oscillations in hippocampal interneuron networks by homogenizing firing rates. Neuron. January 5, 2006;49:107-117. Abstract

Bacci A, Huguenard JR. Enhancement of spike-timing precision by autaptic transmission in neocortical inhibitory interneurons. Neuron. January 5, 2006;49:119-130. Abstract

Mann EO, Paulsen O. Keeping inhibition timely. Neuron. January 5, 2006;49:8-9. Abstract

Szabadics J, Varga C, Molnar G, Olah S, Barzo P, Tamas G. Excitatory effect of GABAergic axo-axonic cells in cortical circuits. Science. January 13, 2006;311:233-235. Abstract