Special issue on neuron-glia interactions.

What is the physiological importance of bidirectional neuron–glia dynamic signaling in the brain? The amazing architecture of the brain consists of hundreds of billions of neurons, as well as trillions of supporting cells called glia which comprise approximately half the volume of the adult mammalian brain. Glial cells, divided into oligodendrocytes, microglia, and astrocytes, are organized into distinct non-overlapping domains whose boundaries are intimately in contact with synapses and cerebrovascular pathways. Since the first systematic studies of the central nervous system, the information communication and processing roles of neurons were clearly recognized, while the electrically non-excitable glial cells were investigated for their contribution to different physiological processes, such as differentiation, proliferation, and neurotrophic support. Astrocytes are now thought to go beyond these contributions, being involved in almost all aspects of the brain function. There is growing evidence that astrocytes are able to partition the extracellular space, altering and influencing the synaptic microenvironment, as well as neurons’ growth. Astrocytes can alter the positioning and the diffusion of neuroactive substances, attracting cells able to repair neurons. Moreover, astrocytes synergistically regulate neuronal activities and blood circulation, thus influencing the neuronal metabolism. It is worth mentioning the relationship between astrocytes and several neurological disorders, i.e., epilepsy, stroke, Alzheimer’s disease, Parkinson’s disease, and amyotrophic lateral sclerosis. In the mid-1990s, evidence demonstrated how astrocytes show a different form of excitability, undergoing elevations in intracellular calcium concentration in response to the release of synaptic neurotransmitters rather than electrical changes in the membrane potential. Many cells employ a network of biochemical reactions for calcium signaling to carry information from the extracellular side to internal targets. But what underlying information do the glia acquire from the synapse? Democritus of Abdera would say: “we know nothing really; for truth lies at the bottom.” Thus, many efforts have been recently devoted to understanding the functional role of the calcium response in order to decipher how this complex dynamical response is regulated by the biochemical network of signal transduction pathways in the central nervous system. Several experiments indicated how calcium signals are generated in response to external stimuli encoding information via frequency, amplitude, or both modulations. Consequently, these observations were captured by several models consisting of dynamical variables and/or intracellular diffusion mechanisms exhibiting the above-mentioned modulations as well as different and more advanced encoding modes. This demonstrated how astrocytes are active participants in brain information processing and key elements in the physiology of the nervous system. Going further, some authors are fascinated by an “astrocentric hypothesis,” where astrocytes are being considered as the final stage of conscious processing. Following these observations, some of the mechanisms underlying synaptic physiology are now becoming clearer. New reports are constantly enhancing our understanding of the bidirectional signaling between neurons and glia, opening fascinating new perspectives on their role. The underlying mechanisms and the crucial modulating role of glia are becoming clearer through the study of synaptic activities. Re-examinations and refinements of existing studies on the dynamics of neuron–glia interactions are under investigation with the aim to discover self-consistent models of the neuron–glia information processes able to capture the dynamical and computational properties of the synapse. All these efforts will have an impact both in brain neurophysiology and in network and nonlinear dynamics theory, defining a new path for neuroscience. The novel concept of the “tripartite synapse,” for the astrocyte processes’ close contact with the neuronal synapse, has been introduced. Astrocytes are considered to regulate the synaptic signaling currents between neurons, modulating the amount of neurotrasmitters, including glutamate or adenosine–triphosphate, in the synaptic cleft through inter- and intracellular calcium dynamics. The tripartite synapse involves a pre-synaptic neuron releasing neurotransmitters to activate or inhibit the activity of a post-synaptic neuron, the post-synaptic neuron, and the astrocyte that protects cells by taking up glutamate to prevent overexcitation and secretes growth factors. The astrocyte provides energy via glucose and modulates receptor function by locally released neurotrasmitters. They are accurate sensors of neuronal activity and respond to the synaptic release of glutamate with oscillations in the intracellular calcium concentration. Glutamate elevations in the astrocyte domain trigger the internal release of inositol 1,4,5-trisphosphate, which stimulates intracellular calcium dynamics. The properties of intracellular calcium oscillations generated in astrocytes, including their amplitude, frequency, and propagation, are governed by the intrinsic properties of both neuronal inputs and astrocytes. Astrocytes discriminate neuronal inputs of different origins and can integrate concomitant inputs responding to calcium elevations. Calcium dynamics is controlled by the interplay of calcium-induced calcium release, a nonlinear amplification method dependent on the calcium-dependent opening of channels to calcium stores such as the endoplasmic reticulum, and the action of active transporters that enable a reverse flux. The level of inositol 1,4,5-trisphosphate is directly controlled by signals impinging on the cell from its external environment. The elevation of the intracellular calcium level in astrocytes, promoted by the extracellular glutamate, triggers the release of glutamate from the astrocyte, modulating the pre-synaptic and post-synaptic neural activities by promoting a depolarizing current in neurons. As a reflection of the growing importance of neuron–glia investigations, the focus of this Special Issue of the Journal of Biological Physics is to publish outstanding recent results, challenging mathematical efforts, biophysically consistent models and in-depth analysis, as well as new perspectives, on neuron–glia interactions, roles, and signaling. This issue contains papers discussing a part of the brain that is largely unexplored and facing controversial neurophysiological processes. I definitely hope that this special issue will benefit, encourage, and inspire researchers looking beyond neurons, opening new exciting perspectives both in biological physics and in brain neurophysiology.