P2X7 receptors and pannexin1 hemichannels shape presynaptic transmission.

Over the last decades, since the discovery of ATP as a transmitter, accumulating evidence has been reported about the role of this nucleotide and purinergic receptors, in particular P2X7 receptors, in the modulation of synaptic strength and plasticity. Purinergic signaling has emerged as a crucial player in orchestrating the molecular interaction between the components of the tripartite synapse, and much progress has been made in how this neuron-glia interaction impacts neuronal physiology under basal and pathological conditions. On the other hand, pannexin1 hemichannels, which are functionally linked to P2X7 receptors, have appeared more recently as important modulators of excitatory synaptic function and plasticity under diverse contexts. In this review, we will discuss the contribution of ATP, P2X7 receptors, and pannexin hemichannels to the modulation of presynaptic strength and its impact on motor function, sensory processing, synaptic plasticity, and neuroglial communication, with special focus on the P2X7 receptor/pannexin hemichannel interplay. We also address major hypotheses about the role of this interaction in physiological and pathological circumstances.

Synaptic neuron-astrocyte communication is supported by an order of magnitude analysis of inositol tris-phosphate diffusion at the nanoscale in a model of peri-synaptic astrocyte projection.

BACKGROUND: Astrocytes were conceived for decades only as supporting cells of the brain. However, the observation of Ca2+ waves in astrocyte synctitia, their neurotransmitter receptor expression and gliotransmitter secretion suggested a role in information handling, conception that has some controversies. Synaptic Neuron-Astrocyte metabotropic communication mediated by Inositol tris-phosphate (SN-AmcIP3) is supported by different reports. However, some models contradict this idea and Ca2+ stores are 1000 ± 325 nm apart from the Postsynaptic Density in the Perisynaptic Astrocyte Projections (PAP's), suggesting that SN-AmcIP3 is extrasynaptic. However, this assumption does not consider IP3 Diffusion Coefficient (Dab), that activates IP3 Receptor (IP3R) releasing Ca2+ from intracellular stores. RESULTS: In this work we idealized a model of a PAP (PAPm) to perform an order of magnitude analysis of IP3 diffusion using a transient mass diffusion model. This model shows that IP3 forms a concentration gradient along the PAPm that reaches the steady state in milliseconds, three orders of magnitude before IP3 degradation. The model predicts that IP3 concentration near the Ca2+ stores may activate IP3R, depending upon Phospholipase C (PLC) number and activity. Moreover, the PAPm supports that IP3 and extracellular Ca2+ entry synergize to promote global Ca2+ transients. CONCLUSION: The model presented here indicates that Ca2+ stores position in PAP's does not limit SN-AmcIP3.

Hemichannels: new roles in astroglial function.

The role of astrocytes in brain function has evolved over the last decade, from support cells to active participants in the neuronal synapse through the release of "gliotransmitters."Astrocytes express receptors for most neurotransmitters and respond to them through Ca(2+) intracellular oscillations and propagation of intercellular Ca(2+) waves. While such waves are able to propagate among neighboring astrocytes through gap junctions, thereby activating several astrocytes simultaneously, they can also trigger the release of gliotransmitters, including glutamate, d-serine, glycine, ATP, adenosine, or GABA. There are several mechanisms by which gliotransmitter release occurs, including functional hemichannels. These gliotransmitters can activate neighboring astrocytes and participate in the propagation of intercellular Ca(2+) waves, or activate pre- and post-synaptic receptors, including NMDA, AMPA, and purinergic receptors. In consequence, hemichannels could play a pivotal role in astrocyte-to-astrocyte communication and astrocyte-to-neuron cross-talk. Recent evidence suggests that astroglial hemichannels are involved in higher brain functions including memory and glucose sensing. The present review will focus on the role of hemichannels in astrocyte-to-astrocyte and astrocyte-to neuron communication and in brain physiology.

Glial cells modulate the synaptic transmission of NTS neurons sending projections to ventral medulla of Wistar rats.

There is evidence that sympathoexcitatory and respiratory responses to chemoreflex activation involve ventrolateral medulla-projecting nucleus tractus solitarius (NTS) neurons (NTS-VLM neurons) and also that ATP modulates this neurotransmission. Here, we evaluated whether or not astrocytes is the source of endogenous ATP modulating the synaptic transmission in NTS-VLM neurons. Synaptic activities of putative astrocytes or NTS-VLM neurons were recorded using whole cell patch clamp. Tractus solitarius (TS) stimulation induced TS-evoked excitatory postsynaptic currents (TS-eEPSCs) in NTS-VLM neurons as well in NTS putative astrocytes, which were also identified by previous labeling. Fluoracetate (FAC), an inhibitor of glial metabolism, reduced TS-eEPSCs amplitude (-85.6 ± 16 vs. -39 ± 7.1 pA, n = 12) and sEPSCs frequency (2.8 ± 0.5 vs. 1.8 ± 0.46 Hz, n = 10) in recorded NTS-VLM neurons, indicating a gliomodulation of glutamatergic currents. To verify the involvement of endogenous ATP a purinergic antagonist was used, which reduced the TS-eEPSCs amplitude (-207 ± 50 vs. -149 ± 50 pA, n = 6), the sEPSCs frequency (1.19 ± 0.2 vs. 0.62 ± 0.11 Hz, n = 6), and increased the paired-pulse ratio (PPR) values (∼20%) in NTS-VLM neurons. Simultaneous perfusion of Pyridoxalphosphate-6-azophenyl-2',5'-disulfonic acid (iso-PPADS) and FAC produced reduction in TS-eEPSCs similar to that observed with iso-PPADS or FAC alone, indicating that glial cells are the source of ATP released after TS stimulation. Extracellular ATP measurement showed that FAC reduced evoked and spontaneous ATP release. All together these data show that putative astrocytes are the source of endogenous ATP, which via activation of presynaptic P2X receptors, facilitates the evoked glutamate release and increases the synaptic transmission efficacy in the NTS-VLM neurons probably involved with the peripheral chemoreflex pathways.

Recent advances in brain physiology and cognitive processing.

The discovery of participation of astrocytes as active elements in glutamatergic tripartite synapses (composed by functional units of two neurons and one astrocyte) has led to the construction of models of cognitive functioning in the human brain, focusing on associative learning, sensory integration, conscious processing and memory formation/retrieval. We have modelled human cognitive functions by means of an ensemble of functional units (tripartite synapses) connected by gap junctions that link distributed astrocytes, allowing the formation of intra- and intercellular calcium waves that putatively mediate large-scale cognitive information processing. The model contains a diagram of molecular mechanisms present in tripartite synapses and contributes to explain the physiological bases of cognitive functions. It can be potentially expanded to explain emotional functions and psychiatric phenomena.