When astrocytes signal, kainate receptors respond

F or most of the last century, one of the major dogmas of neuroscience has been that the brain is composed of two major cell types: neurons, which perform all of the interesting functions required for cognition, and glia, which perform the essential but humble job of keeping the neurons healthy. However, the last decade has seen a slow but steady erosion of this neuron-centric view. First, it was found that neuronal activity can generate glial calcium responses (1-3); more recently, glia have been found to reciprocate and affect neuronal activity (4-6) through mechanisms that are poorly understood. Much of the available evidence indicates that glial activation leads to calcium-dependent glutamate release (4, 6-8), raising the intriguing possibility that glia can drive neuronal activity through some kind of glutamatergic transmission. In this issue of PNAS, Liu et al. (9) show that astrocytes in the hippocampus can cause y-aminobutyric acid (GABA) release from interneurons through activation of the kainate subtype of ionotropic glutamate receptor. One of the major obstacles in examining glia-neuron interactions is that few methods can be used to selectively activate glia without also activating neurons. To circumvent this problem, Liu et al. loaded astrocytes in area CAl of the hippocampus with caged calcium. They then used focal photolysis to uncage and selectively increase astrocytic calcium levels, which they monitored by using calcium imaging. They simultaneously recorded the responses of neighboring GABAergic interneurons by conventional patch-clamp recording. After photolysis, astrocytic calcium levels were increased, and a coincident flurry of GABAergic spontaneous inhibitory postsynaptic currents (sIPSCs) were recorded in nearby interneurons. How does astrocytic calcium lead to an increased frequency of sIPSCs? sIPSCs can be either action potentialdependent or -independent so, in principle, astrocytes could cause the effect by increasing interneuronal spiking or by increasing the release of action potential-independent, miniature IPSCs (mIPSCs). However, an analysis of mIPSCs studied in isolation revealed that the frequency of mIPSCs is actually reduced by calcium uncaging, indicating that the observed increase in sIPSCs is caused by an excitation of interneurons that synapse onto the recorded interneuFig. 1. A model showing the circuit involved in the experiments of Liu etaL. (9). An astrocyte (orange cell) is loaded with caged calcium. Upon photolysis, the astrocyte releases glutamate (blue), which spreads to activate GluR5-containing kainate receptors (red ovals) on nearby hippocampal interneurons (yellow cells). The activation of kainate receptors leads to increased firing of the interneuron, causing enhanced spontaneous GABA release (green). This enhanced release is detected as an increase in the frequency of sIPSCs on a nearby interneuron, monitored by patch-clamp recording. The range of glutamate after release from the astrocyte is unknown, as is the subcellular location of the interneuronal kainate receptors that sense it.