Regulation of Neuronal Activity in Hypothalamic Vasopressin Neurons

Abstract

Vasopressin is a peptide hormone secreted from the posterior pituitary gland in response to various physiological and/or pathological stimuli, including changes in body fluid volume and osmolality and stress exposure. Vasopressin secretion is controlled by the electrical activity of the vasopressinergic magnocellular neurosecretory cells located in the hypothalamic supraoptic nucleus and paraventricular nucleus. Vasopressin release can occur somatodendritically in the hypothalamus or at the level of pituitary axon terminals. The electrical activity of the vasopressin neurons assumes specific patterns of electrical discharge that are under the control of several factors, including the intrinsic properties of the neuronal membrane and synaptic and hormonal inputs. It is increasingly clear that glial cells perform critical signaling functions that contribute to signal transmission in neural circuits. Astrocytes contribute to neuronal signaling by regulating synaptic and extrasynaptic neurotransmission, as well as by mediating bidirectional neuronal-glial transmission. We recently discovered a novel form of neuronal-glial signaling that exploits the full spatial domain of astrocytes to transmit dendritic retrograde signals from vasopressin neurons to distal upstream neuronal targets. This retrograde trans-neuronal-glial transmission allows the vasopressin neurons to regulate their synaptic inputs by controlling upstream presynaptic neuron firing, thus providing a powerful means of controlling hormonal output.

Keywords: astrocyte; glia; hypothalamus; neuron; paraventricular; supraoptic; synapse; vasopressin.

Figure 1

Amino-acid sequences of vasopressin and oxytocin. Vasopressin and Oxytocin are both 9-amino-acid peptides that differ by only two amino acids.

Figure 2

Vasopressin receptors. There are three known vasopressin receptors, V1a, V1b and V2 receptors, all of which are G protein-coupled receptors. V1a and V1b are coupled to Gq/11 and the IP3/DAG signaling pathway, and V2 receptors are coupled to Gs and the cAMP signaling pathway.

Figure 3

Known modulators of vasopressin neurons: ACh, acetylcholine; 5-HT, serotonin; AII, angiotensin II; ATP, adenosine triphosphate; ANP, atrial natriuretic peptide; NO, nitric oxide; PGE₂, prostaglandin E₂; PACAP, pituitary adenylate cyclase-activating polypeptide; BDNF, brain-derived neurotrophic factor.

Figure 4

Glial regulation of glutamate modulation of magnocellular neurons. Under baseline conditions, astrocytes regulate the activation of presynaptic metabotropic glutamate receptors by uptake of extracellular glutamate by glial transporters, which prevents glutamate access to the receptors. Glial retraction uncovers the presynaptic receptors and allows their activation by glutamate, which provides a feedback autoinhibition of glutamate release.

Figure 5

Synapse-specific actions of endocannabinoids controlled by glial coverage of synapses. Tonic release of anandamide (AEA) provides a retrograde inhibitory tone on GABA release by activating CB1 receptors specifically at GABA synapses on magnocellular neurons. Release of 2-AG evoked by Ca-dependent signaling retrogradely suppresses glutamate release via CB1 receptor activation specifically at glutamatergic excitatory synapses. Physiological or pathological stimulation leads to retraction of astrocyte processes, which allows 2-AG spillover onto GABA synapses and further suppression of GABA release. Tonic AEA actions are not regulated by glial coverage and are limited to GABA synapses.

Figure 6

Model of putative retrograde neuronal-glial-neuronal circuit. Dendritic release of vasopressin stimulates astrocytes, which signal to presynaptic GABA neurons via ATP release. The upstream GABA neurons respond with action potentials and an increase in GABA release back on the vasopressin neurons.