Control of Dopamine Signal in High-Order Receptor Complex on Striatal Astrocytes.

The receptor-receptor interaction (RRI) of G protein-coupled receptors (GPCRs) leads to new functional entities that are conceptually distinct from the simple addition of signals mediated by the activation of the receptors that form the heteromers. Focusing on astrocytes, there is evidence for the existence of inhibitory and facilitatory RRIs, including the heteromers formed by the adenosine A2A and the dopamine D2 receptors, by A2A and the oxytocin receptor (OTR), and the D2-OTR heteromers. The possible involvement of these receptors in mosaicism has never been investigated in striatal astrocytes.

A Self-Similarity Logic May Shape the Organization of the Nervous System.

From the morphological point of view, the nervous system exhibits a fractal, self-similar geometry at various levels of observations, from single cells up to cell networks. From the functional point of view, it is characterized by a hierarchical organization in which self-similar structures (networks) of different miniaturizations are nested within each other. In particular, neuronal networks, interconnected to form neuronal systems, are formed by neurons, which operate thanks to their molecular networks, mainly having proteins as components that via protein-protein interactions can be assembled in multimeric complexes working as micro-devices.

Modulation of Neuron and Astrocyte Dopamine Receptors via Receptor-Receptor Interactions.

Dopamine neurotransmission plays critical roles in regulating complex cognitive and behavioral processes including reward, motivation, reinforcement learning, and movement. Dopamine receptors are classified into five subtypes, widely distributed across the brain, including regions responsible for motor functions and specific areas related to cognitive and emotional functions. Dopamine also acts on astrocytes, which express dopamine receptors as well.

Striatal astrocytic A2A-D2 receptor-receptor interactions and their role in neuropsychiatric disorders.

It is now generally accepted that astrocytes are active players in synaptic transmission, so that a neurocentric perspective of the integrative signal communication in the central nervous system is shifting towards a neuro-astrocentric perspective. Astrocytes respond to synaptic activity, release chemical signals (gliotransmitters) and express neurotransmitter receptors (G protein-coupled and ionotropic receptors), thus behaving as co-actors with neurons in signal communication in the central nervous system. The ability of G protein-coupled receptors to physically interact through heteromerization, forming heteromers and receptor mosaics with new distinct signal recognition and transduction pathways, has been intensively studied at neuronal plasma membrane, and has changed the view of the integrative signal communication in the central nervous system.

Receptor-receptor interactions and microvesicle exchange as mechanisms modulating signaling between neurons and astrocytes.

It is well known that astrocytes play a significant metabolic role in the nervous tissue, maintaining the homeostasis of the extracellular space and of the blood-brain barrier, and providing trophic support to neurons. In addition, however, evidence exists indicating astrocytes as important elements for brain activity through signaling exchange with neurons. Astrocytes, indeed, can sense synaptic activity and their molecular machinery responds to neurotransmitters released by neurons with cytoplasmic Ca elevations that, in turn, stimulate the release of neuroactive substances (gliotransmitters) influencing nearby neurons.

Heteromerization of Dopamine D2 and Oxytocin Receptor in Adult Striatal Astrocytes.

The ability of oxytocin (OT) to interact with the dopaminergic system through facilitatory D2-OT receptor (OTR) receptor-receptor interaction in the limbic system is increasingly considered to play roles in social or emotional behavior, and suggested to serve as a potential therapeutic target. Although roles of astrocytes in the modulatory effects of OT and dopamine in the central nervous system are well recognized, the possibility of D2-OTR receptor-receptor interaction in astrocytes has been neglected. In purified astrocyte processes from adult rat striatum, we assessed OTR and dopamine D2 receptor expression by confocal analysis.

Intercellular Communication in the Central Nervous System as Deduced by Chemical Neuroanatomy and Quantitative Analysis of Images: Impact on Neuropharmacology.

In the last decades, new evidence on brain structure and function has been acquired by morphological investigations based on synergic interactions between biochemical anatomy approaches, new techniques in microscopy and brain imaging, and quantitative analysis of the obtained images. This effort produced an expanded view on brain architecture, illustrating the central nervous system as a huge network of cells and regions in which intercellular communication processes, involving not only neurons but also other cell populations, virtually determine all aspects of the integrative function performed by the system. The main features of these processes are described.

Heterodimer of A2A and Oxytocin Receptors Regulating Glutamate Release in Adult Striatal Astrocytes.

Background: Roles of astrocytes in the modulatory effects of oxytocin (OT) in central nervous system are increasingly considered. Nevertheless, OT effects on gliotransmitter release have been neglected.

Methods: In purified astrocyte processes from adult rat striatum, we assessed OT receptor (OTR) and adenosine A2A receptor expression by confocal analysis.

Receptor-Receptor Interactions and Glial Cell Functions with a Special Focus on G Protein-Coupled Receptors.

The discovery that receptors from all families can establish allosteric receptor-receptor interactions and variably associate to form receptor complexes operating as integrative input units endowed with a high functional and structural plasticity has expanded our understanding of intercellular communication. Regarding the nervous system, most research in the field has focused on neuronal populations and has led to the identification of many receptor complexes representing an important mechanism to fine-tune synaptic efficiency. Receptor-receptor interactions, however, also modulate glia-neuron and glia-glia intercellular communication, with significant consequences on synaptic activity and brain network plasticity.

Man is a "Rope" Stretched Between Virosphere and Humanoid Robots: On the Urgent Need of an Ethical Code for Ecosystem Survival.

In this paper we compare the strategies applied by two successful biological components of the ecosystem, the viruses and the human beings, to interact with the environment. Viruses have had and still exert deep and vast actions on the ecosystem especially at the genome level of most of its biotic components. We discuss on the importance of the human being as contraptions maker in particular of robots, hence of machines capable of automatically carrying out complex series of actions.

Adenosine A-dopamine D receptor-receptor interaction in neurons and astrocytes: Evidence and perspectives.

The discovery of receptor-receptor interactions in the early 1980s, together with a more accurate focusing of allosteric mechanisms in proteins, expanded the knowledge on the G protein-coupled receptor (GPCR)-mediated signaling processes. GPCRs were seen to operate not only as monomers, but also as quaternary structures shaped by allosteric interactions. These integrative mechanisms can change the function of the GPCRs involved, leading to a sophisticated dynamic of the receptor assembly in terms of modulation of recognition and signaling.

Exosomes From Astrocyte Processes: Signaling to Neurons.

It is widely recognized that extracellular vesicles subserve non-classical signal transmission in the central nervous system. Here we assess if the astrocyte processes, that are recognized to play crucial roles in intercellular communication at the synapses and in neuron-astrocyte networks, could convey messages through extracellular vesicles. Our findings indicate, for the first time that freshly isolated astrocyte processes prepared from adult rat cerebral cortex, can indeed participate to signal transmission in central nervous system by releasing exosomes that by volume transmission might target near or long-distance sites.

A New Integrative Theory of Brain-Body-Ecosystem Medicine: From the Hippocratic Holistic View of Medicine to Our Modern Society.

Humans are increasingly aware that their fate will depend on the wisdom they apply in interacting with the ecosystem. Its health is defined as the condition in which the ecosystem can deliver and continuously renew its fundamental services. A healthy ecosystem allows optimal interactions between humans and the other biotic/abiotic components, and only in a healthy ecosystem can humans survive and efficiently reproduce.

Receptor-Receptor Interactions as a Widespread Phenomenon: Novel Targets for Drug Development?

The discovery of receptor-receptor interactions (RRI) has expanded our understanding of the role that G protein-coupled receptors (GPCRs) play in intercellular communication. The finding that GPCRs can operate as receptor complexes, and not only as monomers, suggests that several different incoming signals could already be integrated at the plasma membrane level via direct allosteric interactions between the protomers that form the complex. Most research in this field has focused on neuronal populations and has led to the identification of a large number of RRI.

Homocysteine and A2A-D2 Receptor-Receptor Interaction at Striatal Astrocyte Processes.

The interaction between adenosine A2A and dopamine D2 receptors in striatal neurons is a well-established phenomenon and has opened up new perspectives on the molecular mechanisms involved in Parkinson's disease. However, it has barely been investigated in astrocytes. Here, we show by immunofluorescence that both A2A and D2 receptors are expressed in adult rat striatal astrocytes in situ, and investigate on presence, function, and interactions of the receptors in the astrocyte processes-acutely prepared from the adult rat striatum-and on the effects of homocysteine on the A2A-D2 receptor-receptor interaction.

Near-infrared laser photons induce glutamate release from cerebrocortical nerve terminals.

Although photons have been repeatedly shown to affect the functioning of the nervous system, their effects on neurotransmitter release have never been investigated. We exploited in vitro models that allow effects involving neuron-astrocyte network functioning to be detected (mouse cerebrocortical slices) and dissected these effects at cerebrocortical nerve endings and astrocyte processes. Infrared light proved able to induce glutamate release by stimulating glutamatergic nerve endings.

Receptor-Receptor Interactions of G Protein-Coupled Receptors in the Carotid Body: A Working Hypothesis.

In the carotid body (CB), a wide series of neurotransmitters and neuromodulators have been identified. They are mainly produced and released by type I cells and act on many different ionotropic and metabotropic receptors located in afferent nerve fibers, type I and II cells. Most metabotropic receptors are G protein-coupled receptors (GPCRs).

G protein-coupled receptor-receptor interactions give integrative dynamics to intercellular communication.

The proposal of receptor-receptor interactions (RRIs) in the early 1980s broadened the view on the role of G protein-coupled receptors (GPCR) in the dynamics of the intercellular communication. RRIs, indeed, allow GPCR to operate not only as monomers but also as receptor complexes, in which the integration of the incoming signals depends on the number, spatial arrangement, and order of activation of the protomers forming the complex. The main biochemical mechanisms controlling the functional interplay of GPCR in the receptor complexes are direct allosteric interactions between protomer domains.

The brain as a "hyper-network": the key role of neural networks as main producers of the integrated brain actions especially via the "broadcasted" neuroconnectomics.

Investigations of brain complex integrative actions should consider beside neural networks, glial, extracellular molecular, and fluid channels networks. The present paper proposes that all these networks are assembled into the brain hyper-network that has as fundamental components, the tetra-partite synapses, formed by neural, glial, and extracellular molecular networks. Furthermore, peri-synaptic astrocytic processes by modulating the perviousness of extracellular fluid channels control the signals impinging on the tetra-partite synapses.

New dimensions of connectomics and network plasticity in the central nervous system.

Cellular network architecture plays a crucial role as the structural substrate for the brain functions. Therefore, it represents the main rationale for the emerging field of connectomics, defined as the comprehensive study of all aspects of central nervous system connectivity. Accordingly, in the present paper the main emphasis will be on the communication processes in the brain, namely wiring transmission (WT), i.