Neuronal-glial remodeling: a structural basis for neuronal-glial interactions in the adult hypothalamus.

Increasing evidence is establishing that adult neurons and their associated glia can undergo state-dependent changes in their morphology and in consequence, in their relationships and functional interactions. A neuronal system that illustrates this kind of neuronal-glial plasticity in an exemplary fashion is that responsible for the secretion of the neurohormone oxytocin (OT). As shown by comparative ultrastructural analysis, during physiological conditions like lactation and dehydration, which result in enhanced peripheral and central release of the peptide, astrocytic coverage of OT neurons is markedly reduced and their surfaces are left directly juxtaposed. Such reduced glial coverage is of consequence to neuronal activity since it modifies extracellular ionic homeostasis and glutamate neurotransmission. In addition, it is probably prerequisite to the synaptic remodeling that occurs concurrently, and results in an enhanced number of inhibitory (GABAergic) and excitatory (glutamatergic, noradrenergic) synapses, thus further affecting neuronal function. The neuronal-glial and synaptic changes occur rapidly, within a matter of hours, and are reversible with termination of stimulation. The adult OT system retains many juvenile molecular features that may allow such plasticity, including expression of cell adhesion molecules implicated in neuronal-glial interactions during development, like polysialylated NCAM, F3/contactin and its ligand, the matrix glycoprotein, tenascin-C. On the other hand, OT itself can induce the changes since in vivo (ventricular microinfusion) or in vitro (on acute hypothalamic slices) application leads to glial and neuronal transformations similar to those induced by physiological stimuli.

Oxytocin and estrogen promote rapid formation of functional GABA synapses in the adult supraoptic nucleus.

We here investigated inhibitory synapse turnover in the adult brain using the hypothalamic supraoptic nucleus where new synapses form during different physiological conditions, in particular on oxytocin neurons largely controlled by GABAergic inputs and locally released oxytocin. Patch clamp recordings and ultrastructural analysis of the nucleus in acute slices from late gestating rats showed that oxytocin and estrogen promoted rapid formation of inhibitory synapses. Thus, after 2-h exposure to a combination of oxytocin and 17-beta estradiol, the frequency of miniature inhibitory postsynaptic currents was significantly enhanced. Since their amplitude and presynaptic GABA release probability were unmodified, this indicated an increased number of synapses. Electron microscopy confirmed increased densities of symmetric, putative GABAergic synapses within 2-h exposure to the peptide or steroid, effects which were reversible and oxytocin receptor mediated. Our observations thus offer direct evidence that hypothalamic GABAergic microcircuitries can undergo rapid and functional remodeling under changing neuroendocrine conditions.

Induction of rapid, activity-dependent neuronal-glial remodelling in the adult rat hypothalamus in vitro.

The hypothalamic oxytocinergic system offers a remarkable model of morphological plasticity in the adult because its neurons and astrocytes undergo mutual remodelling in relation to differing physiological conditions. Among various factors involved in such plasticity, oxytocin (OT) itself appears of primary importance as its central administration resulted in morphological changes similar to those brought on by physiological stimuli. In the present study, we applied OT on acute hypothalamic slices from adult rats that included the supraoptic nucleus. Using ultrastructural morphometric analyses, we found that it induced a significant reduction of astrocytic coverage of OT neurons, leaving their surfaces directly juxtaposed, to an extent similar to that detected in vivo under conditions like lactation. These neuronal-glial changes were rapid and reversible, occurring within a few hours, and specifically mediated via OT receptors. They were potentiated by oestrogen and depended on calcium mobilization and de novo protein synthesis. Moreover, they depended on concurrent neuronal activation brought on by hyperosmotic stimulation or blockade of inhibitory GABAergic neurotransmission; they were inhibited by blockade of glutamatergic receptors. Taken together, our observations show that intrahypothalamic release of OT affects not only neuronal activation of the OT system but its morphological plasticity as well. Moreover, the activity dependence of the OT-induced changes strongly suggests that astrocytes can sense the level of activity of adjacent neurons and/or afferent input and this can subsequently act as a signal to bring on the neuronal and glial conformational changes.