Key Points
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Neurons use more than 100 different peptides as chemical signals to communicate information, and these have a role in information processing that is quite unlike that of conventional neurotransmitters. Neuropeptides are released from all parts of a neuron, including the axon, soma and, especially, the dendrites, and so are not restricted spatially by synaptic wiring.
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Depending on the nature of the afferent or physiological stimulus, the dendritic release and axonal release of peptides can be regulated wholly independently. Exocytosis of vasopressin and oxytocin from axon terminals is linked to electrical activity, whereas some chemical signals, notably oxytocin and vasopressin themselves, can elicit dendritic peptide release without increasing electrical activity. Activation of peptide receptors on the dendrites or soma elevates intracellular Ca2+ concentrations and triggers exocytosis, and once dendritic peptide release is triggered, feedback allows the release to be self-sustaining and therefore long-lasting. One function of dendritically released peptides is to autoregulate the cells of origin.
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Signals that mobilize intracellular Ca2+ stores have another important consequence: they can 'prime' dendritic stores of peptides to make them available for subsequent activity-dependent release. Spike activity in oxytocin or vasopressin neurons in vivo does not always result in measurable dendritic peptide release, but agents that mobilize Ca2+ from intracellular stores induce dendritic release directly. Moreover, after exposure to these agents, subsequent activation evokes large amounts of dendritic peptide release.
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Many neuropeptides have profound effects on behaviours that are exerted at sites that, in some cases, richly express peptide receptors but are innervated by few peptide-containing projections. Here, we review evidence that dendrites are a major source of peptides released in the brain; this release is not specifically targeted at synapses, and the long half-life of peptides in the CNS and their abundance in the extracellular fluid mean that, after release, they can diffuse to distant targets. At their targets, the process of priming allows peptides to functionally reorganize neuronal networks, providing a substrate for prolonged behavioural effects.
Abstract
Neuropeptides that are released from dendrites, such as oxytocin and vasopressin, function as autocrine or paracrine signals at their site of origin, but can also act at distant brain targets to evoke long-lasting changes in behaviour. Oxytocin, for instance, has profound effects on social bonding that are exerted at sites that richly express oxytocin receptors, but which are innervated by few, if any, oxytocin-containing projections. How can a prolonged, diffuse signal have coherent behavioural consequences? The recently demonstrated ability of neuropeptides to prime vesicle stores for activity-dependent release could lead to a temporary functional reorganization of neuronal networks harbouring specific peptide receptors, providing a substrate for long-lasting effects.
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Acknowledgements
This work was supported by grants from the European Commission, the Wellcome Trust, UK, and the Biotechnology and Biological Sciences Research Council (BBSRC), UK. We thank V. Tobin for help with the production of the immunofluorescence pictures.
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Glossary
- Arcuate nucleus
-
A cell group located in the mediobasal hypothalamus. It is involved in regulating the secretion of prolactin and growth hormone, and in appetite and metabolism.
- Priming
-
In this context, priming refers to the process by which LDCVs are prepared and made available for subsequent activity-dependent release.
- Small synaptic vesicle
-
(SSV). A small secretory vesicle (∼50 nm in diameter) containing neurotransmitters that are released during calcium-regulated exocytosis. Release occurs mainly at the presynaptic terminal into the synaptic cleft. Under the electron microscope, the vesicle appears clear.
- Large dense-core vesicle
-
(LDCV). A large secretory vesicle (100–150 nm in diameter) that contains protein or peptide, which can be released from all parts of a neuron. Under the electron microscope, a large dense core can be seen at the centre of the vesicle.
- Magnocellular neuron
-
A large neuron (20–30 μm in diameter) of the supraoptic and paraventricular nuclei of the hypothalamus that projects to the posterior pituitary and releases oxytocin or vasopressin into the blood.
- Parvocellular neuron
-
Neurons of the paraventricular nucleus that do not project to the posterior pituitary. Some of these project to various brain regions and some project to the median eminence to regulate hormone secretion from the anterior pituitary.
- Omega fusion profile
-
An omega-shaped figure of the cell membrane that is visible during exocytosis, denoting release of a single dense-core vesicle.
- Microdialysis
-
A technique in which semi-permeable membranes are used to sample from, or deliver molecules to, the extracellular environment in living tissue.
- Osmotic stimulation
-
An experimentally induced change in plasma osmolality to alter the electrical activity of vasopressin neurons, which determines the rate of vasopressin secretion into blood.
- c-fos
-
An immediate-early gene that is 'turned on' transiently and rapidly in response to a wide variety of cellular stimuli. It is commonly used as a marker of neuronal activation.
- Thapsigargin-sensitive intracellular store
-
Intracellular stores of the sarcoplasmic or endoplasmic reticulum. The plant extract thapsigargin specifically inhibits the endoplasmic reticulum Ca2+-ATPase, and can discharge Ca2+ from these stores.
- Self-priming
-
The process by which a secreted product 'primes' further release of the same product. Ovulation is triggered when LHRH release triggers a surge of luteinizing hormone secretion from the anterior pituitary. After exposure to oestrogen, the gonadotroph response to LHRH escalates with successive exposures to LHRH, partly because of an intracellular action of LHRH whereby the readily releasable pool of luteinizing hormone is augmented.
- Gonadotrophs
-
Endocrine cells of the anterior pituitary gland that synthesize and secrete the gonadotrophic hormones luteinizing hormone and follicle-stimulating hormone. The gonadotrophic hormones regulate spermatogenesis in males and the ovarian cycle in females.
- Constant-collision stimulation
-
A technique that involves activating the neighbours of a recorded cell synchronously in an activity-dependent manner, mimicking the coordination of neuronal activity that precedes reflex milk-ejection.
- Hormone
-
A chemical messenger from one group of cells that acts on another, distant group of cells. Hormones are secreted directly into the bloodstream or other body fluids.
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Ludwig, M., Leng, G. Dendritic peptide release and peptide-dependent behaviours. Nat Rev Neurosci 7, 126–136 (2006). https://doi.org/10.1038/nrn1845
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DOI: https://doi.org/10.1038/nrn1845
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