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Release of chemical transmitters from cell bodies and dendrites of nerve cells









The Royal Society, London, 6-9 Carlton House Terrace, London, SW1Y 5AG


Scientific discussion meeting organised by Professor John Nicholls FRS and Professor Francisco F De-Miguel

Event Details

Recent experiments have shown that cell bodies and dendrites of neurons can liberate transmitter molecules.  In this discussion the mechanism of such release will be compared with that occurring in presynaptic terminals, glial cells and endocrine cells. A major focus will concern the way in which release from cell bodies influences essential functions of the central nervous system.

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Attending this event

This event is intended for researchers in relevant fields and is free to attend. There are a limited number of places and registration is essential. An optional lunch is offered and should be booked during registration (all major credit cards accepted).

This meeting is immediately followed by a related, two-day satellite meeting, Present and future of the study of extrasynaptic neurotransmission at the Royal Society at Chicheley Hall, home of the Kavli Royal Society International Centre.

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Schedule of talks

Somatic exocytosis and its functions in the nervous system

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Introduction to extrasynaptic release of transmitters

Professor John Nicholls FRS, International School for Advanced Studies, Trieste, Italy

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Serotonin exocytosis from the neuronal cell body

Professor Francisco F De Miguel, National Autonomous University of Mexico


Serotonin, a signalling molecule that modulates multiple functions in the nervous system, is released extrasynaptically from neuronal cell bodies, axons and dendrites. This paper describes how serotonin is released from cell bodies of Retzius neurones in the CNS of the leech and its effects on neighbouring glia and neurones. These large cells contain dense core vesicles filled with serotonin. Electrical stimulation with 10 impulses at 1 Hz fails to evoke exocytosis from the cell body, but the same number of impulses at 20-Hz promotes exocytosis via a multi-step process. Calcium entry into the neurone triggers calcium-induced calcium release, which promotes the active transport of about 100 clusters of vesicles to the plasma membrane. There, exocytosis occurs for several minutes. Serotonin that has been released activates autoreceptors that induce an IP3-dependent calcium increase, which produces further exocytosis. This positive feedback mechanism finishes when the last vesicles fuse and calcium returns to basal levels. Serotonin released from the cell body is taken up by glia, and released elsewhere in the CNS. The same stimulation pattern synchronises the electrical activity of multiple neurones for several hours. In this way, a brief train of impulses is translated in long-term modulation in the nervous system.

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Dendritic oxytocin and vasopressin release

Professor Mike Ludwig, University of Edinburgh, UK


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 the dendrites, and so are not restricted spatially by synaptic wiring. Neuropeptides 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 physiology and behaviour.

Here, I will present a series of recent studies that show that dendritically-released vasopressin from magnocellular neurons of the paraventricular nucleus of the hypothalamus affects the activity of distant presympathetic neurons, resulting in an integrated sympatho-excitatory population response to a hyperosmotic challenge.
Furthermore, the rat olfactory bulb contains a large number of interneurons which express and release vasopressin. I will show that vasopressin affects information processing of olfactory bulb neurons involved in the modulation of social recognition behaviour.

Tobin et al., Nature 2010; Son et al., Neuron 2013

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Striatal synaptic plasticity in experimental models of Parkinson’s disease

Dr Paolo Calabresi, University of Perugia, Italy


Parkinson’s disease (PD) is a neurodegenerative disorder characterised by a loss of dopaminergic neurons of the substantia nigra compacta resulting in decrease of striatal dopamine (DA) concentration and presence of distinctive α-synuclein (α-syn) inclusions. The α-syn inclusions are considered the pathological hallmark of PD. Recent studies highlight the role of α-syn inclusions in synaptic transmission and DAergic neuron physiology. Different α-syn transgenic mice show different levels of DAergic alterations, morphological and physiological age-dependent changes and may allow to assess specific aspects of PD pathogenesis and role of striatal synaptic plasticity. Clinical signs of PD usually appear when the content of striatal DA is less than 70% of control levels, after that normal striatal function and physiology of striatal medium spiny neurons (MSNs) are altered. Although a critical role of endogenous DA in the formation of striatal long-term potentiation (LTP) in MSNs has been demonstrated the question whether differential levels of DA denervation alter the activity and plasticity of MSNs and specific interneurons is still open. We have characterized the effect of distinct levels of DA denervation on synaptic plasticity in both MSNs and striatal interneurons in toxic and transgenic α-syn models of PD. Current therapies are primarily based on pharmacological DA replacement through administration of DA precursor L-DOPA. However, L-DOPA treatment can result in side effects related to PD progression. In advanced PD, the vast majority of patients experience dyskinesias in response to medication. We have also demonstrated that in experimental PD dyskinesias are correlated to a maladaptive form of synaptic plasticity such as lack of reversal of previously-induced LTP. We suggest new strategies to prevent the induction of dyskinesia.

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Structural basis of neurotransmitter exocytosis at the neuromuscular junction at nanometer spatial resolution

Professor U J McMahan, Texas A&M University, USA

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Monoamine extrasynaptic exocytosis

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Extrasynaptic release of GABA and dopamine by retinal dopaminergic neurons

Professor Elio Raviola, Harvard Medical School, USA


In the mouse retina, dopaminergic amacrine (DA) cells synthesize both dopamine and GABA. Both transmitters are released extrasynaptically and act on neighbouring and distant retinal neurons by volume transmission.

In simultaneous recordings of dopamine and GABA release from isolated, perikarya of DA cells, a proportion of the events of dopamine and GABA exocytosis were simultaneous, suggesting co-release.

In addition, DA cells establish GABAergic synapses onto AII amacrines, the neurons that transfer rod bipolar signals to cone bipolars. GABAA but not dopamine receptors are clustered in the postsynaptic membrane. Therefore, dopamine, irrespective of its site of release –synaptic or extrasynaptic– exclusively acts by volume transmission.

Dopamine is released upon illumination and sets the gain of retinal neurons for vision in bright light. The GABA released at DA cells’ synapses probably prevents signals from the saturated rods from entering the cone pathway when the dark-adapted retina is exposed to bright illumination.

The GABA released extrasynaptically by DA and other amacrine cells, probably sets a “GABAergic tone” in the inner plexiform layer and thus counteracts the effects of a spillover of glutamate released at the bipolar cell synapses of adjacent OFF- and ON-strata, thus preserving segregation of signals between ON- and OFF- pathways.

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Somatodendritic Dopamine Release

Professor Margaret Rice, New York University, USA


Dopamine (DA) is a key transmitter in motor and emotive pathways of the brain; dysfunction of DA systems has been implicated in disorders that include Parkinson's disease, addiction, and schizophrenia.  Located in the midbrain, DAergic neurons of in the substantia nigra pars compacta (SNc) and the ventral tegmental area (VTA) send axon projections via the medial forebrain bundle that provide the sole source of DA to forebrain structures.  The DAergic neurons of the SNc project to the dorsal striatum (caudate putamen) and those of the VTA axons project to ventral striatum (nucleus accumbens) and prefrontal cortex.  In addition to exhibiting classical vesicular release of DA from their axon terminals, a special feature of these midbrain neurons is that they release DA from their cell bodies and dendrites.  Somatodendritic DA release leads to activation of D2 autoreceptors on DAergic neurons that inhibit the firing of these cells via G-protein-coupled inwardly rectifying K+ channels; this local auto-inhibition helps determine the pattern of DA signaling at distant axonal release sites.  Somatodendritic DA release also acts via volume transmission to modulate local transmitter release and neuronal activity in midbrain.  Somatodendritic release is therefore a pivotal intrinsic feature of DAergic neurons that must be well defined to understand their physiology and pathophysiology.  Recent studies have provided mechanistic insight into the novel Ca2+ dependence of somatodendritic DA release and the potential role of exocytotic proteins in the release process to be discussed in this lecture.

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Serotonin somatic release in mammals

Professor Sudipta Maiti, Tata Institute of Fundamental Research, India

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Exocytosis from chromaffin cells: Hydrostatic pressure slows vesicle fusion

Professor Walter Stühmer, Max Planck Institute for Experimental Medicine, Germany


Changes in reaction kinetics and equilibrium by hydrostatic pressure are a standard thermodynamic parameter for studying chemical reactions. Here kinetic changes in secretion from chromaffin cells, measured as capacitance changes using the patch clamp technique at pressures of up to 20 MPa (200 Atm), are presented. It is known that these high pressures drastically slow down, in general, physiological functions and increase the effect of general anaesthetics. High hydrostatic pressure only slightly decreases the kinetics of ion channel gating, in particular of voltage-gated Ca2+ channels, albeit it drastically slows down synaptic transmission. This reduction in kinetics by pressure is linked to reactions directly linked to exocytosis of large dense core vesicles in chromaffin cells. Fusion kinetic is slowed down because intermediate steps during the fusion process have a higher equivalent volume (activation volume). The results obtained indicate a similar activation volume of 390±57 Å3 for large dense core vesicle fusion in chromaffin cells and for the degranulation of mast cells. This information will be useful in finding possible protein conformational changes during the reactions involved in vesicle fusion.

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Transmitter release from different cell types

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On the role of transmitter diffusion and flow versus extracellular vesicles in volume transmission in the brain neural-glial networks with aspects on the relevance of the heteroreceptor complexes for signal integration

Professor Kjell Fuxe, Karolinska Institutet, Sweden


Two major types of intercellular communication are found in the Central Nervous System, namely wiring transmission (WT; point-to-point communication, the prototype being synaptic transmission with axons and terminals) and volume transmission (VT; communication in the extracellular fluid and in the cerebrospinal fluid). Volume and synaptic transmission become integrated because their chemical signals activate different types of interacting receptors in heteroreceptor complexes located synaptically and extrasynaptically in the plasma membrane. The demonstration of extracellular DA and 5-HT fluorescence around the DA and 5-HT nerve cell bodies with the Falck-Hillarp formaldehyde fluorescence method for the cellular localization of catecholamines and 5-HT after treatment with amphetamine and chlorimipramine, respectively gave the first indications of the existence of VT in the brain ,at least at the soma level. There exist different forms of VT. In the beginning VT only included diffusion and convection of soluble biological signals, especially transmitters and modulators, a communication called extrasynaptic (short-distance) and long distance (paraaxonal and paravascular and CSF pathways) VT. Now also the extracellular-vesicle type of VT was introduced. The exosomes appear to be the major vesicular carrier for VT but the larger microvesicles also participate. They can transfer lipids and proteins, including receptors, Rab GTPases, tetraspanins, cholesterol, sphingolipids and ceramide. Within them you can also find subsets of mRNAs and noncoding regulatory microRNAs. At the soma-dendritic level dynamic heteroreceptor complexes involve GPCR autoreceptors, ion-channel receptors and RTKs and may represent the molecular basis for learning and memory. At the nerve terminal level the prejunctional heteroreceptor complexes likely undergo plastic changes to favour the persistence of the new pattern of release to be learned by the heteroreceptor complexes in the postjunctional membrane.

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A regulation mechanism of quantal norepinephrine release from soma of Locus Coeruleus slice neurons

Professor Zhuan Zhou, Peking University, China


Locus coeruleus (LC), a population of noradrenergic neurons, putatively plays important roles in attention regulation and drug addiction. The potent addiction drug cocaine increases norepinephrine (NE) overflow in LC. Previous studies held the view that the underlying mechanism of cocaine reward and addictive effects was by blocking the reuptake of the dopamine (DA) and/or NE. However, whether cocaine affects monoamine release is still illusive. Here, by using electrochemical detection, we directly probed the actions of cocaine on somatodendritic NE release in LC brain slices. Also in combination with electrophysiology, pharmacology, biochemistry and behaviors methods, we found that cocaine increased quantal frequency of NE vesicle release, probably through facilitating vesicles docking at the somatodendretic region. NE transporter (NET) was responsible for cocaine facilitation, evidenced by the abolishment of the phenomenon in cocaine-insensitive NE transporter (NET-CI) mice. NET-CI mice exhibited hyperactivity to a single cocaine injection and, surprisingly, an attenuated reinstatement of cocaine conditioned place preference (CPP). Taken together, these results identified a new mechanism of cocaine NET-dependent effects on NE release and suggested NE regulation of cocaine addiction.

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Co-transmission in the nitric oxide system in L-DOPA induced dyskinesia

Professor Elaine Del-Bel, University of Sao Paulo, Brazil

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ATP release through pannexon channels

Professor Gerhard Dahl, University of Miami, USA


Extracellular ATP serves as a signal for diverse physiological functions, including spread of calcium waves between astrocytes, control of vascular oxygen supply and control of ciliary beat in the airways. ATP can be released from cells by exocytosis, through specific channels or transporters or through compromised cell membranes. This article focuses on channel mediated ATP release and its main enabler, Pannexin1 (Panx1). Although originally discovered as a gap junction protein, Panx1 appears to exclusively form nonjunctional membrane channels. Depending on the mode of stimulation, the Panx1 channel has large conductance (500 pS) and unselective permeability to molecules <1.5 kD or is a small (50 pS), chloride selective channel. Most physiological and pathological stimuli induce the large channel conformation, while the small conformation so far has only been observed with exclusive voltage activation of the channel. The interaction between Panx1 and ATP is intimate. Panx1 is not only the conduit for ATP, permitting ATP efflux from cells following its concentration gradient, but the Panx1 channel is also modulated by ATP. The channel can by activated by ATP through purinergic receptors. Both ionotropic P2X receptors as well as metabotropic P2Y receptors are capable of Panx1 activation. Activation of an ATP release channel by ATP represents a positive feedback loop, which in the absence of a control mechanism, would lead to cell death due to the linkage of purinergic receptors with apoptotic processes. Such control is provided by ATP binding (with lower affinity) to the Panx1 protein and gating the channel shut.

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Modulation of neuronal function

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Extrasynaptic receptors and dentritic spikes

Dr Srdjan D Antic, University of Connecticut, USA

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Regulation of neuronal excitability by release of proteins from glial cells

Professor Dr Irmgard D Dietzel, Ruhr-Universität Bochum, Germany


Effects of glial cells on electrical isolation and shaping of synaptic transmission between neurons are well-known. Here we present evidence, that, in addition, the release of proteins from astrocytes as well as microglia may regulate voltage-activated Na+ currents in neurons, thereby increasing  excitability and speed of transmission in neurons kept at distance from each other by specialized glial cells. As a first example we show that basic fibroblast growth factor and neurotrophin-3, which  are released from astrocytes by thyroid hormone exposure, influence each other to enhance Na+current density in cultured hippocampal neurons. As a second example we show, that the presence of microglia in hippocampal cultures can up-regulate Na+ current density as well, which can be boosted by lipopolysaccharides, bacterial membrane –derived  stimulators of microglial activation. Comparable effects are induced by the exposure of neuron-enriched hippocampal cultures to tumor necrosis factor-alpha, but not interleukin-1 alpha or interleukin-6, all factors released from stimulated microglia. Taken together, our findings suggest, that release of proteins from various types of glial cells can alter neuronal excitability over a time course of several days and explain changes in neuronal excitability occurring in states of thyroid hormone imbalance and possibly also in seizures triggered by brain infections.

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Glial Cell Regulation of Neuronal Activity and Blood Flow in the Retina by Release of Gliotransmitters

Dr Eric A Newman, University of Minnesota, USA


Astrocytes in the brain release gliotransmitters that actively modulate neuronal excitability and synaptic efficacy. Astrocytes also release vasoactive agents that contribute to neurovascular coupling. As reviewed in this chapter, Müller cells, the principal retinal glial cells, modulate neuronal activity and blood flow in the retina. Stimulated Müller cells release ATP which, following its conversion to adenosine by ectoenzymes, hyperpolarizes retinal ganglion cells by activation of A1 adenosine receptors and opening of G protein-coupled inwardly-rectifying potassium (GIRK) channels and small conductance Ca2+-activated K+ (SK) channels. Tonic release of ATP also contributes to the generation of tone in the retinal vasculature by activation of P2X receptors on vascular smooth muscle cells. Vascular tone is lost when glial cells are poisoned with the gliotoxin fluorocitrate. The glial release of vasoactive metabolites of arachidonic acid, including prostaglandin E2 (PGE2) and epoxyeicosatrienoic acids (EETs), contributes to neurovascular coupling in the retina. Neurovascular coupling is reduced when neuronal stimulation of glial cells is interrupted and when the synthesis of arachidonic acid metabolites is blocked. Neurovascular coupling is compromised in diabetic retinopathy due to the loss of glial-mediated vasodilation. This loss can be reversed by inhibiting inducible nitric oxide synthase. Future research will undoubtedly reveal additional important functions of the release of transmitters from glial cells.

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Release of chemical transmitters from cell bodies and dendrites of nerve cells

Scientific discussion meeting organised by Professor John Nicholls FRS and Professor Francisco F De-Miguel

The Royal Society, London 6-9 Carlton House Terrace London SW1Y 5AG UK
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