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.

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.

Photons Induce Vesicular Exocytotic Release of Glutamate in a Power-Dependent Way.

Increasing evidence indicates that photobiomodulation, based on tissue irradiation with photons in the red to near-infrared spectrum, may be an effective therapeutic approach to central nervous system disorders. Although nervous system functionality has been shown to be affected by photons in animal models, as well as in preliminary evidence in healthy subjects or in patients with neuropsychiatric disorders, the mechanisms involved in the photobiomodulation effects have not yet been clarified. We previously observed that photobiomodulation could stimulate glutamate release.

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.

Assessment of neurotransmitter release in human iPSC-derived neuronal/glial cells: a missing in vitro assay for regulatory developmental neurotoxicity testing.

Human induced pluripotent stem cell (hiPSC)-derived neural stem cells (NSCs) and their differentiated neuronal/glial derivatives have been recently considered suitable to assess in vitro developmental neurotoxicity (DNT) triggered by exposure to environmental chemicals. The use of human-relevant test systems combined with in vitro assays specific for different neurodevelopmental events, enables a mechanistic understanding of the possible impact of environmental chemicals on the developing brain, avoiding extrapolation uncertainties associated with in vivo studies. Currently proposed in vitro battery for regulatory DNT testing accounts for several assays suitable to study key neurodevelopmental processes, including NSC proliferation and apoptosis, differentiation into neurons and glia, neuronal migration, synaptogenesis, and neuronal network formation.

The Involvement of Polyamines Catabolism in the Crosstalk between Neurons and Astrocytes in Neurodegeneration.

In mammalian cells, the content of polyamines is tightly regulated. Polyamines, including spermine, spermidine and putrescine, are involved in many cellular processes. Spermine oxidase specifically oxidizes spermine, and its deregulated activity has been reported to be linked to brain pathologies involving neuron damage.

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.

Transgenic Mouse Overexpressing Spermine Oxidase in Cerebrocortical Neurons: Astrocyte Dysfunction and Susceptibility to Epileptic Seizures.

Polyamines are organic polycations ubiquitously present in living cells. Polyamines are involved in many cellular processes, and their content in mammalian cells is tightly controlled. Among their function, these molecules modulate the activity of several ion channels.

Reactive Astrocytosis in a Mouse Model of Chronic Polyamine Catabolism Activation.

Background: In the brain, polyamines are mainly synthesized in neurons, but preferentially accumulated in astrocytes, and are proposed to be involved in neurodegenerative/neuroinflammatory disorders and neuron injury. A transgenic mouse overexpressing spermine oxidase (SMOX, which specifically oxidizes spermine) in the neocortex neurons (Dach-SMOX mouse) was proved to be a model of increased susceptibility to excitotoxic injury.

Methods: To investigate possible alterations in synapse functioning in Dach-SMOX mouse, both cerebrocortical nerve terminals (synaptosomes) and astrocytic processes (gliosomes) were analysed by assessing polyamine levels, ezrin and vimentin content, glutamate AMPA receptor activation, calcium influx, and catalase activity.

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.

Positive Allosteric Modulation of CB1 and CB2 Cannabinoid Receptors Enhances the Neuroprotective Activity of a Dual CB1R/CB2R Orthosteric Agonist.

Preclinical studies highlighted that compounds targeting cannabinoid receptors could be useful for developing novel therapies against neurodegenerative disorders. However, the chronic use of orthosteric agonists alone has several disadvantages, limiting their usefulness as clinically relevant drugs. Positive allosteric modulators might represent a promising approach to achieve the potential therapeutic benefits of orthosteric agonists of cannabinoid receptors through increasing their activity and limiting their adverse effects.

The endocannabinoid system dual-target ligand N-cycloheptyl-1,2-dihydro-5-bromo-1-(4-fluorobenzyl)-6-methyl-2-oxo-pyridine-3-carboxamide improves disease severity in a mouse model of multiple sclerosis.

Multiple sclerosis is a chronic inflammatory demyelinating disorder of the central nervous system that eventually leads to progressive neurodegeneration and disability. Recent findings highlighted the emerging role of each target of the endocannabinoid system in controlling the symptoms and disease progression of multiple sclerosis. Therefore, multi-target modulators of the endocannabinoid system could provide a more effective pharmacological strategy as compared to the single target modulation.

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.

Epileptic seizures and oxidative stress in a mouse model over-expressing spermine oxidase.

Several studies have demonstrated high polyamine levels in brain diseases such as epilepsy. Epilepsy is the fourth most common neurological disorder and affects people of all ages. Excitotoxic stress has been associated with epilepsy and it is considered one of the main causes of neuronal degeneration and death.