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

Abstract

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. They include the two basic modes of intercellular communication identified (i.e., wiring and volume transmission) and mechanisms modulating the intercellular signaling, such as cotransmission and allosteric receptor–receptor interactions. These features may also open new possibilities for the development of novel pharmacological approaches to address central nervous system diseases. This aspect, with a potential major impact on molecular medicine, will be also briefly discussed.

Modulation of Neuron and Astrocyte Dopamine Receptors via Receptor–Receptor Interactions

“…Furthermore, it extensively interacts with other critical signaling pathways [6]. Such a complex intercellular communication occurs through both synaptic and volume transmission (see [64]) and is mediated by a set of GPCRs.…”

“…In this context, of particular interest is the possibility of direct RRI involving DA receptors with the formation of receptor complexes at the cell membrane [63,64]. In receptor complexes, indeed, the chain of events linking the recognition of a ligand by the single protomers to the signal transduction also depends on the neighboring receptors.…”

“…In the 1980s, however, Agnati, Fuxe, and collaborators [23,66], through in vitro and in vivo experiments, provided indirect evidence that GPCR monomers can establish structural interactions (see [63] for historical details). These findings led to the hypothesis that neuron activity could be modulated by receptor complexes present at the cell membrane and formed by different types of GPCRs [64], a mechanism allowing (already at the membrane level) some integration of synaptic (wiring transmission) and extra-synaptic (volume transmission) signals [64]. The term RRI was subsequently proposed to emphasize the concept of an interaction between receptors requiring a direct physical contact between the molecules and leading to the formation of dimers or high-order molecular complexes at the cell membrane [67].…”

Modulating brain integrative actions as a new perspective on pharmacological approaches to neuropsychiatric diseases

“…Therefore, in this context is often cited the famous Monod’s sentence stating that “allostery” for protein functions should be considered as “the second secret of life,” since it is only second as importance to the genetic code ( 77 – 79 ). As our group has discussed in previous papers, the actions of the orthosteric and allosteric ligands of the GPCRs that form an assembly provide the cellular decoding apparatus with sophisticated dynamics ( 80 ) in terms of binding modulation, G-protein-mediated signaling and selectivity, receptor desensitization, and switching to β-arrestin-dependent signaling (see ( 81 ) for a recent review).…”

“…Thus, early evidence on RRIs was indirect evidence based on a coarse co-localization of two receptors obtained by computer-assisted immunocytochemical image analyses. Biochemical approaches led to results that showed that, in membrane preparations from discrete brain regions, the ligand binding to one of the two receptors in a heteromer modulated the binding to the other receptor ( ( 96 , 97 ); see ( 81 ) for a review). Such evidence was further supported by functional studies carried out in vivo assessing the functional relevance of the in vitro findings in both physiological conditions and in animal models of CNS disease ( 31 , 98 – 101 ).…”