Purinergic signalling in neuron–glia interactions

Abstract

Activity-dependent release of ATP from synapses, axons and glia activates purinergic membrane receptors that modulate intracellular calcium and cyclic AMP. This enables glia to detect neural activity and communicate among other glial cells by releasing ATP through membrane channels and vesicles. Through purinergic signalling, impulse activity regulates glial proliferation, motility, survival, differentiation and myelination, and facilitates interactions between neurons, and vascular and immune system cells. Interactions among purinergic, growth factor and cytokine signalling regulate synaptic strength, development and responses to injury. We review the involvement of ATP and adenosine receptors in neuron-glia signalling, including the release and hydrolysis of ATP, how the receptors signal, the pharmacological tools used to study them, and their functional significance.Functional interactions between neurons and glia have been suspected for decades, but how glia might detect neural activity, communicate with other glial cells, and influence neuronal function have proved to be difficult questions to answer. Before purinergic signalling was considered, several other mechanisms were explored for neuron-glia communication, but each of these was comparatively limited. Astrocytes can communicate through gap junctions 1 , but this was viewed in the context of maintaining homeostasis of extracellular potassium. Bursts of action potentials fired by axons release potassium, which is taken up by astrocytes and dispersed through an astrocytic syncytium coupled by gap junctions. The build up of potassium during prolonged high-frequency stimulation can produce calcium transients in myelinating glia (Schwann cells) in the sciatic nerve 2 , but stimulation in the normal physiological range does not have this effect. Glial membrane receptors can be activated by many different neurotransmitters 3 , although this is most relevant to glia having access to neurotransmitter spreading beyond the synaptic cleft 4 . Purinergic signalling has emerged as the most pervasive mechanism for intercellular communication in the nervous system, affecting communication between many types of neurons, all types of glia, and vascular cells 5,6 . NIH-PA Author ManuscriptNIH-PA Author Manuscript NIH-PA Author ManuscriptHere we examine the history and recent developments of neuron-glia signalling and the prominent role of extracellular ATP in these interactions. We review the mechanisms of ATP release from cells and the large family of membrane receptors for extracellular ATP and adenosine. The pharmacology and expression of these receptors in glia are summarized, and the consequences of purinergic signalling in neuron-glia communication are discussed, with an emphasis on glial regulation of synaptic transmission, activity-dependent myelination, and nervous system response to injury. ATP in cell-cell signallingATP has long been recognized as an intracellular energy source, although its acceptance as an extracellular signalling molecule has take...

Activity-dependent neuron–glial signaling by ATP and leukemia-inhibitory factor promotes hippocampal glial cell development

“…The importance of astrocytes and morphological contacts formed between astrocytic processes and synapses is apparent as astrocytes and astrocyte-conditioned media promote synapse formation (Pfrieger and Barres, 1997;Ullian et al, 2001) and both LTP and LTD are affected by astrocytes acting through several mechanisms. Astrocytes directly regulate NMDA-receptor-dependent LTP and plasticity through glial-derived D-serine (Yang et al, 2003;Panatier et al, 2006), ATP and adenosine (Pascual et al, 2005;Fields and Burnstock, 2006), glutamate reuptake and release (Haydon and Carmignoto, 2006) and extracellular K + handling (Wallraff et al, 2006;Djukic et al, 2007;Ge and Duan, 2007). Our findings on activity-dependent astrocyte differentiation by ATP and LIF in vitro and the observation of behavioral impairments in LIF −/− mice (Pechnick et al, 2004) and LIF over-expressing mice (Pechnick et al, 2004) suggest that LIF may be important in hippocampal development and plasticity in vivo through astrocytes.…”

“…We therefore sought to identify the cellular signaling mechanism responsible for activity-dependent regulation of glial development in hippocampus. Although many growth factors could be released in an activitydependent manner from neurons to affect glial development, purinergic signaling has recently become appreciated as an important component of activity-dependent neuron-glial signaling (Fields and Stevens, 2000;Fields and Burnstock, 2006;North and Verkhratsky, 2006). In other contexts, previous research has shown that purinergic signaling through P 2 Y receptors on astrocytes increases the expression and release of LIF (Ishibashi et al, 2006).…”

Adenosine dysfunction in astrogliosis: cause for seizure generation?

“…Purinergic signalling plays an important role in mediating neuron-glia interactions (Fields and Burnstock, 2006;Halassa et al, 2007). In particular, astrocytes play a key role in regulating synaptic levels of adenosine -and thus in the modulation of neuronal activity -based on astrocyte-mediated release of the adenosine precursor ATP (Pascual et al, 2005;Haydon and Carmignoto, 2006), and based on ADK-driven reuptake of adenosine into astrocytes (Boison, 2006;, 2007b;2007a).…”

The adenosine kinase hypothesis of epileptogenesis

“…Most cells in the brain, including neurons and astrocytes, can release ATP via regulated vesicular transport (Fields and Burnstock, 2006). Extracellular ATP is then cleaved into adenosine by a cascade of ectonucleotidases (Cunha, 2001;Zimmermann, 2000).…”