Nat. Rev. Endocrinol. doi:10.1038/nrendo.2017.124 Figure 2 The effects of the structural plasticity of astrocytes in the magnocellular neurosecretory system on the extracellular concentration and diffusion of transmitters Figure 2 | The effects of the structural plasticity of astrocytes in the magnocellular neurosecretory system on the extracellular concentration and diffusion of transmitters. a | Astrocytic processes envelop synapses and take up transmitters through the activity of transporters such as glutamate transporter 1 (GLT1), endocannabinoid membrane transporter (EMT) and GABA transporter 3 (GAT3), decreasing their concentration and diffusion through the extracellular space. At the glutamatergic terminal, glutamate that is released into the synaptic cleft targets the postsynaptic NMDA receptor (NMDAR) and the AMPA receptor (AMPAR). Excess glutamate is quickly removed from the synaptic cleft by the GLT1 located on astrocytic processes, thereby limiting the diffusion of the neurotransmitter through the extracellular space35. During membrane depolarization (ΔVm), induced by a voltage step applied during whole-cell patch clamp recording, magnocellular neurons can produce and release the endocannabinoid 2-arachidonoylglycerol (2-AG)50, which is an inhibitory retrograde messenger. EMT on astrocytic processes transports 2-AG from the synaptic cleft into the astrocytic process, which prevents 2-AG from diffusing away from the synapse and from binding to presynaptic cannabinoid receptor 1 (CB1) located on GABAergic terminals. At the GABAergic synapse, GABA released into the synaptic cleft targets the postsynaptic GABAA receptor (GABAAR). GAT3 on astrocytic processes takes up GABA into astrocytic processes, therefore preventing excess GABA from diffusing away from its release site42,44,45. b | During physiological challenges, such lactation or dehydration, the withdrawal of astrocytic processes results in increases in the extracellular concentrations of 2-AG, GABA and glutamate and facilitates their diffusion through the extracellular space. Excess glutamate around the synapse can activate presynaptic metabotropic glutamate receptors (mGluRs) to inhibit glutamate release35,36. Glutamate can also diffuse away from the synapse to target presynaptic kainate receptors (KAR)40 and metabotropic glutamate receptors33 located on GABAergic terminals and inhibit GABA release. Glutamate can also act postsynaptically on extrasynaptic NMDARs. Calcium (Ca2+) entry through extrasynaptic NMDARs increases the intracellular concentration of calcium in the magnocellular neuron, which stimulates kinase activity and results in the inhibition of the IA-type K+ channel43 and the potentiation of GABAAR activation38. During the withdrawal of astrocytic processes, 2-AG released by the magnocellular neuron during membrane depolarization can diffuse towards the presynaptic CB1 located on GABAergic terminals to inhibit GABA release50. Similarly to glutamate, excess GABA around the synapse caused by the withdrawal of astrocytic processes can act postsynaptically on the extrasynaptic GABAARs42,45. Clasadonte, J. & Prevot, V. (2017) The special relationship: glia–neuron interactions in the neuroendocrine hypothalamus Nat. Rev. Endocrinol. doi:10.1038/nrendo.2017.124