Investigations of a neurotransmitter receptor required for 'background' neuronal inhibition in mice show the importance of such inhibition in keeping neuronal excitability under control.
Why would you put microphones outside a concert hall to record the music inside? All they would pick up is muffled noise, although the sound would vary according to the music's highs and lows. On the other hand, with sufficiently sensitive microphones you could monitor several concert halls simultaneously, and thus keep an ear on the musical life of the whole town. The festival halls of the nervous system are the tiny junctions, called synapses, between nerve cells. And the molecular microphones — neurotransmitter receptors — are indeed found outside synapses, as well as inside them, on the surface of nerve cells1,2 (Fig. 1). In fact, there might be more receptors outside synapses than inside3. But despite their abundance, the function of these 'extrasynaptic' molecular microphones has been elusive. Writing on page 88 of this issue, Brickley and colleagues4 make a significant contribution to deciphering their importance.
Brickley et al. have studied inhibitory neuronal signalling mediated by the neurotransmitter γ-amino-butyric acid (GABA). Inhibition takes place as a consequence of GABA binding to its receptors — the so-called GABAA receptors (Fig. 1). The result is a decrease in the probability that a neuron reaches its threshold for firing an action potential, the signal of a nerve cell. In an earlier study5, the same group described two distinct types of inhibition in a group of neurons — the cerebellar granule cells — that are involved in coordinating movements. 'Phasic' inhibition of these cells is mediated by discrete pulses of high concentrations of GABA released at synapses, where GABA acts on synaptic GABAA receptors. In contrast, 'tonic' (continuous) inhibition is due to the persistent activation of extrasynaptic GABA A receptors by the low concentrations of GABA in the extrasynaptic space — rather like the continuous, muffled music from many concert halls picked up by the microphones.
The GABAA receptors underlying these two forms of inhibition differ in terms of their molecular composition and properties6. Receptors containing α6 and δ subunits are only present outside synapses, whereas receptors comprising the γ2 subunit are concentrated inside synapses7. As a result, the extrasynaptic receptors have higher sensitivity (affinity) for GABA, and are not desensitized by the prolonged presence of this neurotransmitter. This makes them ideal for mediating tonic inhibition. So, to determine the importance of tonic inhibition in controlling neuronal excitability, Brickley et al.4 used mice that had been engineered to lack the α6 subunit8.
The authors could not detect any GABAA-receptor-mediated tonic inhibition in brain slices from the genetically altered mice, an observation that fits well with the known role of the α6-containing extrasynaptic receptors in generating tonic inhibition. In control animals, drugs that block the GABAA receptors have a significant effect on the amount of excitation required to bring a granule cell to its firing threshold. These drugs had no such effect in the α6-deficient animals4. As it is only the tonic form of GABAA-receptor-mediated inhibition that is missing in these mice, this lack of an effect shows that this type of inhibition controls the excitability of granule neurons.
But if extrasynaptic GABAA receptors were truly important, one might expect that deleting them would result in severe alterations in excitability within the neuronal circuits of the cerebellum. This brain region is important in coordinating movements, so specific defects in the behaviour of α6-deficient mice would be predicted. But these mice do not show any measurable behavioural problems8. Had the story ended here, sceptics might have mused that tonic inhibition is not named background inhibition for nothing. Fortunately, Brickley et al. avoided this hasty conclusion, and go on to provide a surprising solution to the puzzle.
The authors show that the amount of excitation needed for granule cells to emit an action potential when the GABAA receptors are not blocked by drugs is similar in control and α6-deficient mice. They argue — on the basis of their electrophysiological and molecular data — that a compensation mechanism is at work in mice lacking the α6 subunit (Fig. 1). They suggest that this mechanism involves the increased expression of a continuously active type of potassium channel. Their results point to the so-called TASK-1 channels9, which also inhibit cellular excitability in a continuous (tonic) manner.
These data are the best evidence yet that the extrasynaptic GABAA receptors regulate neuronal excitability. Given that biology tends not to fix things that are not important, the fact that neurons found a way to compensate precisely for the loss of extrasynaptic GABAA receptors suggests just how significant the receptors are. Although Brickley et al . did their experiments in brain slices in vitro, compensation by the TASK-1 channels took place in the intact brain — a strong indication that tonic inhibition also existed in vivo. But the level of expression of many other GABAA-receptor subunits (as well as that of the TASK-1 channels) is also altered in the α6-deficient mice10. Developing 'inducible-knockout' mice, in which the expression of the α6 or δ subunits can be stopped quickly, might avoid the problems of compensatory alterations and may clarify the roles of tonic inhibition in brain function.
The next major advance in this field might not come from studies of genetically altered mice. The development of drugs that specifically block receptors containing the δ subunit, for example, would provide tools for unravelling the precise function of background inhibition, not just in the cerebellum but also in other brain areas where such receptors are expressed extrasynaptically. The task of understanding the function and importance of extrasynaptic GABA A receptors is an exciting one, and it is clear that neuroscientists have already lost their inhibition about listening to background noise.
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Neuroscience and Behavioral Physiology (2005)