Figure 6. Cartoon summary of synaptic scaling by ATP acting on P2X receptors in magnocellular neurons (MCNs) of the hypothalamus.

Based on work by the Bains lab (Gordon et al., 2005; Gordon et al., 2009). Glutamate and noradrenaline cause release of intracellular Ca²⁺ within astrocyte processes, leading to ATP release in to the extracellular milieu. This activates extrasynaptic P2X receptors, which through a Ca²⁺- and PI3K-dependent mechanism, leads to synaptic scaling by insertion of AMPA receptors into dendritic spines of MCNs. The astrocyte Ca²⁺ signals may spread within astrocytes leading to similar effects at other synapses. The effects of glutamate and noradrenaline in this context are both reduced when astrocyte processes withdraw from MCNs during lactation and dehydration (see text for details). In this context, the astrocyte process is not actively contributing to synaptic transmission, but rather via ATP it is exerting a strong activation-dependent neuromodulation. Similar responses at other brain synapses with astrocyte processes nearby ought to be explored.