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Excitotoxicity represents a neuropathological process, describing the toxic actions of excitatory neurotransmitters, where the excessive or prolonged activation of glutamate receptors triggers a cascade of events leading to neuronal injury or death. Under conditions of reduced energy availability and increased oxidative stress neurons become particularly vulnerable to excitotoxicity and a large body of available evidence indicates that excitotoxicity represents a central mechanism in the pathogenesis of acute and degenerative diseases of the central nervous system. Astrocytes represent key elements in the regulation of glutamate homeostasis by their opposing functions of glutamate uptake and release, and microglial cells play an important role in the response to damage. Depending on the phenotype they assume when activated, microglial cells can trigger immune defense or neuroprotective processes. To perform their functions both glial cell populations monitor the extracellular space through a panel of receptors. Furthermore, a variety of signaling pathways also contribute to the modulation of the glutamatergic transmission, acting on specific cell receptors expressed by neurons, astrocytes, and microglia. In the last decades, evidence has been provided that receptors of almost all families can establish structural receptor-receptor interactions, leading to the formation of heteroreceptor complexes at the cell membrane of neurons and glial cells. The cooperativity that emerges in the actions of ligands of the monomers forming these assemblies provides the cell decoding apparatus with flexible dynamics in terms of recognition and signal transduction and allows an integration of the incoming signals already at the membrane level. Available data on possible modulatory roles played by heteroreceptor complexes in excitotoxic processes will be here reviewed and discussed. From the pharmacological standpoint, these findings may offer possibilities to explore novel therapeutic strategies targeting receptor complexes to address disorders of the central nervous system associated with dysregulation of glutamatergic signaling.

A critical aspect of drug development in the therapy of neuropsychiatric diseases is the “Target Problem”, that is, the selection of a proper target after not simply the etiopathological classification but rather the detection of the supposed structural and/or functional alterations in the brain networks. There are novel ways of approaching the development of drugs capable of overcoming or at least reducing the deficits without triggering deleterious side effects. For this purpose, a model of brain network organization is needed, and the main aspects of its integrative actions must also be established. Thus, to this aim we here propose an updated model of the brain as a hyper-network in which i) the penta-partite synapses are suggested as key nodes of the brain hyper-network and ii) interacting cell surface receptors appear as both decoders of signals arriving to the network and targets of central nervous system diseases. The integrative actions of the brain networks follow the “Russian Doll organization” including the micro (i.e., synaptic) and nano (i.e., molecular) levels. In this scenario, integrative actions result primarily from protein-protein interactions. Importantly, the macromolecular complexes arising from these interactions often have novel structural binding sites of allosteric nature. Taking G protein-coupled receptors (GPCRs) as potential targets, GPCRs heteromers offer a way to increase the selectivity of pharmacological treatments if proper allosteric drugs are designed. This assumption is founded on the possible selectivity of allosteric interventions on G protein-coupled receptors especially when organized as “Receptor Mosaics” at penta-partite synapse level.

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. The discovery of direct receptor–receptor interactions, leading to the formation of multimeric receptor complexes at the cell membrane and providing the cell decoding apparatus with flexible dynamics in terms of recognition and signal transduction, has expanded the knowledge of the G-protein-coupled receptor-mediated signaling processes. The purpose of this review article is to provide an overview of currently identified receptor complexes containing dopamine receptors and of their modulatory action on dopamine-mediated signaling between neurons and between neurons and astrocytes. Pharmacological possibilities offered by targeting receptor complexes in terms of addressing neuropsychiatric disorders associated with altered dopamine signaling will also be briefly discussed.

We present a brief historical and epistemological outline of investigations on the brain’s structure and functions. These investigations have mainly been based on the intermingling of chemical anatomy, new techniques in the field of microscopy and computer-assisted morphometric methods. This intermingling has enabled extraordinary investigations to be carried out on brain circuits, leading to the development of a new discipline: “brain connectomics”. This new approach has led to the characterization of the brain’s structure and function in physiological and pathological conditions, and to the development of new therapeutic strategies. In this context, the conceptual model of the brain as a hyper-network with a hierarchical, nested architecture, arranged in a “Russian doll” pattern, has been proposed. Our investigations focused on the main characteristics of the modes of communication between nodes at the various miniaturization levels, in order to describe the brain’s integrative actions. Special attention was paid to the nano-level, i.e., to the allosteric interactions among G protein-coupled receptors organized in receptor mosaics, as a promising field in which to obtain a new view of synaptic plasticity and to develop new, more selective drugs. The brain’s multi-level organization and the multi-faceted aspects of communication modes point to an emerging picture of the brain as a very peculiar system, in which continuous self-organization and remodeling take place under the action of external stimuli from the environment, from peripheral organs and from ongoing integrative actions.

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. Spermine is a neuromodulator of a number of ionotropic glutamate receptors and types of ion channels. In this respect, the Dach-SMOX mouse model overexpressing spermine oxidase in the neocortex neurons was revealed to be a model of chronic oxidative stress, excitotoxicity and neuronal damage. Reactive astrocytosis, chronic oxidative and excitotoxic stress, neuron loss and the susceptibility to seizure in the Dach-SMOX are discussed here. This genetic model would help researchers understand the linkage between polyamine dysregulation and neurodegeneration and unveil the roles of polyamines in the crosstalk between astrocytes and neurons in neuroprotection or neurodegeneration.

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. Spermine oxidase, specifically oxidized spermine, is a neuromodulator of several types of ion channel and ionotropic glutamate receptors, and its deregulated activity has been linked to several brain pathologies, including epilepsy. The Dach-SMOX mouse line was generated using a Cre/loxP-based recombination approach to study the complex and critical functions carried out by spermine oxidase and spermine in the mammalian brain. This mouse genetic model overexpresses spermine oxidase in the neocortex and is a chronic model of excitotoxic/oxidative injury and neuron vulnerability to oxidative stress and excitotoxic, since its phenotype revealed to be more susceptible to different acute oxidative insults. In this review, the molecular mechanisms underlined the Dach-SMOX phenotype, linked to reactive astrocytosis, neuron loss, chronic oxidative and excitotoxic stress, and susceptibility to seizures have been discussed in detail. The Dach-SMOX mouse model overexpressing SMOX may help in shedding lights on the susceptibility to epileptic seizures, possibly helping to understand the mechanisms underlying epileptogenesis in vulnerable individuals and contributing to provide new molecular mechanism targets to search for novel antiepileptic drugs.