, 2012). One of the best examples BTK inhibitor of neuromodulation by ATP acting at P2X receptors is in magnocellular neurons (MCNs) of the hypothalamus (Figure 6). Endogenous ATP acting at extrasynaptic P2X receptors plays a crucial role in modulating excitatory synaptic transmission in MCNs (Gordon et al., 2005, 2009). Early work suggested that ATP mediates part of the excitatory drive to MCNs following activation of catecholamine containing cells (Day et al., 1993), and electrophysiological studies showed that MCNs expressed functional P2X receptors that mediated membrane potential depolarization and increases in membrane conductance (Hiruma and Bourque, 1995). Later studies found ample evidence

for the presence of P2X receptor mRNAs and proteins that mediated ATP-evoked inward currents and strong elevations in intracellular Ca2+ levels in MCNs. It seems MCNs express a mixture of P2X receptors containing

P2X2, P2X4, and possibly P2X7 subunits (Vavra et al., 2011). It has been shown that P2X receptor signaling mediates the effect of noradrenaline (NA) on AMPA receptor-mediated mEPSCs arriving onto MCNs of the rat paraventricular nucleus (Gordon et al., 2005). Brief applications of NA increased mEPSC amplitudes for ABT-263 clinical trial long periods of time, perhaps permanently, by increasing AMPA receptor insertion into synapses (Figure 6). NA did not act postsynaptically via adrenoceptors in MCNs; instead, NA acted on astrocytes to release ATP. This paper provided

strong evidence that ATP acting via P2X receptors resulted in modulation of glutamatergic synaptic efficacy, and astrocytes were directly implicated as the source of endogenous ATP (Gordon et al., 2005). Bains and colleagues have established found that the ATP signaling mechanism is engaged during afferent activity, thus demonstrating that the effects of endogenous astrocyte derived ATP are likely to be utilized in vivo during physiological action potential firing impinging on MCNs (Gordon et al., 2009). The work on MCNs also provides several interesting points that may be relevant more broadly to the study of brain P2X receptor-mediated signaling. First, the authors failed to find fast ATP synaptic transmission. Second, they found that the sources of endogenous ATP were astrocytes rather than neurons, and that bursts of action potentials were needed to engage astrocyte signaling. Third, activation of P2X receptors resulted in multiplicative scaling of all synapses in MCNs. Multiplicative scaling is a form of homeostatic plasticity, whose underpinnings are only beginning to be explored. Perhaps P2X receptors are also involved in other areas of the brain in this form of plasticity? Fourth, the effect of P2X receptor activation on synaptic efficacy in MCNs took many minutes to develop, even though P2X receptor activation occurs in seconds once ATP is bound (Vavra et al., 2011).