Astroglial glutamate transporters trigger glutaminergic gliotransmission

Rapid exchange of molecular signals between synapses and the surrounding astroglia has recently emerged as an essential player in regulating neural circuit activities in the brain. This conceptual leap was prompted in large part by early findings demonstrating that electrically non-excitable glia could, in fact, generate and propagate relatively rapid, physiologically informative signals via internal Ca2+ waves (Parpura et al. 1994). Astrocytes have been found to respond with internal Ca2+ transients to the common fast neurotransmitters glutamate and GABA through the target receptors expressed in their plasma membranes. In turn, astroglia could generate and dispatch their own Ca2+-dependent messages to neurons, by releasing a variety of signalling molecules including ATP, glutamate, d-serine or tumour necrosis factor α, although the cellular mechanisms of such actions remain under intense investigation (Hamilton & Attwell, 2010). Outshined by this newly acquired prominence of astrocytes, their long-established, classical functions have been somewhat moved from centre stage. In fact, the ubiquitous processes of glutamate uptake and potassium buffering by astroglia have long been known to occur in the brain on a scale that must ensure their substantial contribution to neural function. In their recent elegant work in this issue of The Journal of Physiology, Uwechue and colleagues (2012) have focused on the immediate consequences of glutamate uptake in astrocytes that surround the giant glutamatergic synapse of the calyx of Held in the rat medial nucleus of the trapezoid body (MNTB). This classical subject of synaptic studies enables direct access to readily identifiable pre- and postsynaptic elements of the synapse and is therefore ideally suited for controlled probing of mechanisms involved in astroglia–synapse exchange. It has long been proposed that replenishment of glutamate in excitatory synaptic terminals depends mainly on local uptake of glutamine supplied by glia. Intra-glial conversion of transported glutamate into glutamine completes this metabolic cycle. The study by Uwechue and colleagues unveils a previously unrecognised and potentially important aspect of this machinery. The authors found that, by engaging neuronal system A transporters, glutamine released by astroglia can rapidly depolarise the local neuronal membrane. This observation appears to suggest that mere metabolic glutamine supply by astroglia actually triggers what could be considered as an excitatory feedback signal promoted by local synaptic discharges. The authors have ruled out the involvement of glutamate in this feedback signal by dissecting pharmacologically the known glutamate receptors and transporters. Conversely, to probe astroglial transporter currents in isolation they used application of d-aspartate, a non-glutamate activator of glutamate transporters, thus excluding the involvement of glutamate receptors in transporter-dependent glial glutamine release. By combining these approaches with astrocytic sodium imaging and dual-patch recordings from both an MNTB cell and an adjacent astrocyte they were able to demonstrate convincingly that glutamate transporter activation in an astrocyte induces a depolarising current in the nearby neuron. The inward current induced by neuronal glutamine uptake following activation of astroglial glutamate transporters was relatively small, in the ∼10 pA range (Uwechue et al. 2012). However, the local current density in such cases is likely to depend strongly on the juxtaposition of glial and synaptic membranes. It is not, therefore, inconceivable that local glutamine uptake may evoke relatively strong depolarisation in small cellular compartments, such as dendritic spines or presynaptic axonal boutons covered by astroglia (Fig. 1). By the same token, enhanced glutamate uptake within local hotspots of glial glutamate transporters (Zheng et al. 2008) might, in principle, boost localised efflux of glutamine. Whether the detected depolarisation has any significant impact on the function of MNTB synapses and whether such influences indeed occur at other central synapses, pre- or postsynaptically, remains an open and intriguing question. In particular, it would be important to understand whether some of the reported changes in synaptic efficacy induced by astroglial activity (Perea & Araque, 2010) involve the action of glial glutamate and neuronal glutamine transporters in the synaptic microenvironment. In any case, the findings of Uwechue and colleagues shed new light on the classical function of astroglia, with some unexpected implications for our understanding of mechanisms that may contribute to regulatory signals sent by astrocytes to their neuronal counterparts. Figure 1 A possible astrocyte–neuron feedback signalling mechanism involving glial glutamate transporters