The supraoptic (SON) and paraventricular (PVN) magnocellular nuclei of the hypothalamus undergo reversible anatomical remodeling under conditions of intense secretion of neurohypophysial hormones, such as lactation and chronic dehydration. This morphological plasticity is characterized by a pronounced reduction in astrocytic coverage of neurons, which results in an increased number and extent of directly juxtaposed somatic and dendritic surfaces. As a consequence, astrocyte-mediated clearance of glutamate from the extracellular space is altered, which causes an increased concentration and range of action of the excitatory amino acid in the extracellular space. This leads to a reduction of synaptic efficacy at excitatory and inhibitory inputs through the activation of presynaptic metabotropic glutamate receptors. By contrast, the action of glio transmitters released from astrocytes and acting on adjacent magnocellular neurons is limited during such anatomical remodeling. This includes glia derived ATP mediating potentiation of glutamatergic transmission, a process compromised by the neuronal-glial reorganization.Together, these studies on hypothalamic magnocellular nuclei provide new insights on the contribution of glial cells on neuronal activity.