Exciting you: signals from another kingdom

Calcium oscillations in the developing brain have been shown to play a crucial role in the development of neuronal networks. In neurons, spontaneous oscillatory electrical activity and changes in the concentration of intracellular calcium have been well described. However, in the human brain, glial cells, not neurons, are the major cell population, comprising ∼90% of brain cells. Glial cells are important companions for neurons; they not only give structural and metabolic support but, in the case of astrocytes, ensheath synapses and are integrated in synaptic transmission through their efficient neurotransmitter reuptake mechanisms. Signaling between neurons and astrocytes has been well characterized, but the astrocytic signals are detected usually in response to neuronal activation. Parri et al. now show that astrocytes are capable of generating signals and transmitting them to neurons spontaneously 1xSpontaneous astrocytic Ca2+ oscillations in situ drive NMDAR-mediated neuronal excitation. Parri, H.R. et al. Nat. Neurosci. 2001; 4: 803–812Crossref | PubMed | Scopus (348)See all References1.The authors loaded acute brain slices from 5–17-day-old rat ventrobasal thalamus with a membrane-permeable form of a calcium-sensitive dye. The loading paradigm used leads to a preferential loading of astrocytes. Spontaneous calcium increases were observed in all slices (for movies, see http://neurosci.nature.com/web_specials), remaining constant until postnatal day 9, whereafter it declined significantly up to postnatal day 14. In the presence of the sodium-channel blocker tetrodotoxin, the glutamate receptor antagonist kynurenic acid and the GABAA-receptor antagonist bicuculline, the nature of the signal was not altered, suggesting that the increases in the level of calcium were glial in origin. By contrast, the L-type calcium-channel blocker nifedipine and the intracellular calcium-store depletors thapsigargin and cyclopiazonic acid abolished virtually all activity. This suggests a combined mechanism involving extracellular and intracellular calcium sources, leading to the observed increases in the level of intracellular calcium. However, extracellular calcium was not required for the expression of a signal, leading the authors to conclude that the initiation of the signal involves the release of calcium from internal stores with a possible store-refilling mechanism through dihydropyridine-sensitive high-voltage-activated calcium channels.Using cross-correlation analysis, Parri et al. show that neighboring astrocytes exhibit coincident calcium transients, meaning that the signal propagates between astrocytes. Because it could be shown that the astrocytes in this preparation were not coupled by gap junctions, a chemical transmitter is probably involved in the propagation of the signal, which spreads at about 3.7 μm s−1 between astrocytes. Furthermore, using the patch-clamp technique and filling neurons with a calcium-sensitive dye through the patch pipette, Parri et al. showed that not only could the astrocytes signal between themselves, but an astrocytic calcium signal of sufficient magnitude could induce a significant neuronal NMDA-receptor-mediated inward current and subsequent increase in neuronal calcium levels.This work provides evidence that astrocytic activity in vivo can cause NMDA-receptor-mediated neuronal excitation and indicates that the astrocytes in question are capable of generating rapid long-range signals in the brain. Together with the findings that astrocytes are able to respond to neuronal activity and are capable of releasing neurotransmitters, these data add yet another facet to the repertoire of astrocytic activities in the brain and could lead us to change our view of synaptic transmission as being purely neuronal in origin. As such, it is probable that astrocytic activity must be taken into consideration with regard to any plastic changes in the brain, including development, learning and memory.