Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P01178 (oxytocin)
 15,767 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

F3/contactin is a cell adhesion/recognition molecule of the immunoglobulin superfamily implicated in axonal growth. We examined its subcellular distribution and mobilization to the cell surface in oxytocin- (OT-) secreting neurons, which express it throughout life and the axons of which undergo activity-dependent remodelling. This was performed in hypothalamic organotypic slice cultures containing OT neurons with properties of adult neurosecretory cells. Immunocytochemistry and immunoblot analysis confirmed that OT neurons express high levels of F3/contactin in vitro. Light and confocal microscopy of cultures that underwent double immunofluorescence after fixation showed F3/contactin immunoreactivity throughout the cytoplasm of OT somata, dendrites and axons, and also in non-OT axons and in putative synaptic boutons which contacted OT neurons. By contrast, after treatment of live cultures with anti-F3/contactin antibodies followed by double immunofluorescence for the glycoprotein and OT, F3/contactin immunoreactivity was visible only on the surface of axons, whether or not OT-immunoreactivity was present. Because of its glycosylphosphatidyl-inositol (GPI) linkage, F3/contactin can occur in a membrane-bound or soluble form. As seen from immunocytochemistry of live cells and immunoblot analysis, treatment of cultures with a GPI-specific phospholipase C (GPI-PLC) resulted in loss of F3/contactin immunoreactivity from all cell surfaces. F3/contactin immunoreactivity reappeared on axonal surfaces within 5 h after enzyme washout. Such re-expression was accelerated by neuronal activity facilitation (by K+ depolarization or gamma-aminobutyric acid (GABA)-A receptor blockade with bicuculline) and inhibited by neuronal activity repression [by blockade of Ca2+ channels with Mn2+, Na+ channels with tetrodotoxin (TTX) or excitatory inputs with glutamate antagonists]. Our observations establish therefore that F3/contactin surface expression in hypothalamic neurons is polarized to the axons where it occurs mainly in a GPI-linked form. We also provide direct evidence that externalization of F3/contactin depends on Ca2+ entry and neuronal electrical activity. Taken together with our earlier finding that the glycoprotein is localized in neurosecretory granules, we demonstrate that F3/contactin is mobilized to the axonal surface via the activity-dependent regulated pathway, thus arriving at the correct place and time to intervene in activity-dependent remodelling of axons.
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PMID:Mobilization of the cell adhesion glycoprotein F3/contactin to axonal surfaces is activity dependent. 1155 89

Oxytocin-secreting neurons of the hypothalamoneurohypophysial system undergo reversible morphological changes whenever they are strongly stimulated. In the hypothalamus, such structural plasticity is represented by modifications in the size and shape of their somata and dendrites, in the extent to which their surfaces are covered by glia, and in the density of their synapses. In the neurohypophysis, there is a parallel reduction in glial (pituicyte) coverage of their axons together, with retraction of pituicyte processes from the perivascular basal lamina and an increase in the number and size of their terminals. These changes occur rapidly, within a few hours. On the other hand, the system returns to its prestimulated condition on arrest of stimulation at a rate that depends on the length of time it has remained activated. Such neuronal-glial changes have several functional consequences. In the hypothalamic nuclei, reduction in astrocytic coverage of oxytocinergic neurons and their synapses modifies extracellular ionic homeostasis and glutamate clearance and, therefore, their overall excitability. Since it results in extensive dendritic bundling, it may also lead to ephaptic interactions and may facilitate dendritic electrotonic coupling. A most important indirect effect may be to permit synaptic remodeling that occurs concomitantly and that results in significant increases in the number of excitatory and inhibitory synapses driving their activity. In the stimulated neurohypophysis, glial retraction results in increased levels of extracellular K+ which can enhance neurohormone release while an enlarged neurovascular contact zone may facilitate diffusion of neurohormone into the circulation. Ongoing work aims to unravel the cell mechanisms and factors underlying such plasticity and has revealed that neurons and glia of the hypothalamoneurohypophysial system continue to express juvenile molecular features associated with similar neuronglial interactions and synaptic events during development and regeneration. They include strong expression of cell surface adhesion molecules like F3/contactin and polysialylated neural cell adhesion molecule, extracellular matrix glycoproteins like tenascin C, and cytoskeletal proteins like vimentin and microtubule-associated protein 1D. Some of these molecules reach the cell surface constitutively while others follow the activity-dependent regulated pathway. We consider many of these molecular features permissive, allowing oxytocin neurons and their glia to undergo morphological remodeling throughout life, provided the proper stimulus intervenes. In the hypothalamic nuclei, one such stimulus is centrally released oxytocin; in the neurohypophysis, an adrenergic, cAMP-mediated mechanism appears responsible.
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PMID:Oxytocin-secreting neurons: A physiological model of morphological neuronal and glial plasticity in the adult hypothalamus. 1190 4

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.
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PMID:Neuronal-glial remodeling: a structural basis for neuronal-glial interactions in the adult hypothalamus. 1244 93

Mouse models of neuropsychiatric diseases provide a platform for mechanistic understanding and development of new therapies. We previously demonstrated that knockout of the mouse homolog of CNTNAP2 (contactin-associated protein-like 2), in which mutations cause cortical dysplasia and focal epilepsy (CDFE) syndrome, displays many features that parallel those of the human disorder. Because CDFE has high penetrance for autism spectrum disorder (ASD), we performed an in vivo screen for drugs that ameliorate abnormal social behavior in Cntnap2 mutant mice and found that acute administration of the neuropeptide oxytocin improved social deficits. We found a decrease in the number of oxytocin immunoreactive neurons in the paraventricular nucleus (PVN) of the hypothalamus in mutant mice and an overall decrease in brain oxytocin levels. Administration of a selective melanocortin receptor 4 agonist, which causes endogenous oxytocin release, also acutely rescued the social deficits, an effect blocked by an oxytocin antagonist. We confirmed that oxytocin neurons mediated the behavioral improvement by activating endogenous oxytocin neurons in the paraventricular hypothalamus with Designer Receptors Exclusively Activated by Designer Drugs (DREADD). Last, we showed that chronic early postnatal treatment with oxytocin led to more lasting behavioral recovery and restored oxytocin immunoreactivity in the PVN. These data demonstrate dysregulation of the oxytocin system in Cntnap2 knockout mice and suggest that there may be critical developmental windows for optimal treatment to rectify this deficit.
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PMID:Exogenous and evoked oxytocin restores social behavior in the Cntnap2 mouse model of autism. 2560 68