ReviewUnderstanding wiring and volume transmission
Introduction
In 1986 we published our original proposal on the existence of two main modes of intercellular communication in the CNS: the wiring transmission (WT) and the volume transmission (VT) (Agnati et al., 1986), which was aimed to complement the Cajal's and Sherrington's view of the central nervous system (CNS) as a computational apparatus basically formed by neurons interacting via specialized sites of “contiguity,” namely the synaptic contacts (Cajal, 1906, Sherrington, 1906) (Fig. 1). Our proposal was influenced by previous important contributions on communication in the CNS (Golgi, 1914, Guillemin, 1978, Nicholson, 1979, Schmitt, 1984, Descarries et al., 1991, Nieuwenhuys, 2000, Bach-Y-Rita, 2005) and based on a number of observations, especially on the central monoamine neurons (for reviews: Fuxe and Agnati, 1991a, Fuxe and Agnati, 1991b, Agnati and Fuxe, 2000). The concept of VT introduced the extracellular space and the ventricular system as important channels for chemical transmission in the CNS complementary to WT with diffusion and flow of transmitters, ions, trophic factors, ... in the extracellular fluid (ECF) and cerebrospinal fluid (CSF). Furthermore, our proposal in 1986 considered that the VT signals could interconnect not only neurons in neuronal networks but rather cells of any type (neurons, glia, microglia, ependymal cells, macrophages,…) in what we have called the “complex cellular networks” (CCNs) of the brain (Agnati and Fuxe, 2000). Thus, these signals migrating in the ECF of the CNS could affect multiple targets in the CCNs.
In some instances they could even lead to a new output from the same CCN as surmised within the concept of “polymorphic networks” (Getting and Denkin, 1985) (see Fig. 2 for an example of a VT modulation of a “polymorphic neuronal network”). The existence of VT has also made it possible to suggest different informational models for memory processes (Agnati and Fuxe, 2000, Guidolin et al., 2007) and its relevance for neuropsychopharmacology (Zoli et al., 1999) has been underlined.
It is our opinion that the basic dichotomic classification of intercellular communication in the brain proposed more than two decades ago is still valid. However, we are fully aware that evidence on the existence of new specialized structures for intercellular communication, such as microvesicles (for a review, see Cocucci et al., 2009) and tunnelling nanotubes (Rustom et al., 2004, Baluška et al., 2006, Goncharova and Tarakanov, 2008) (Fig. 3), calls for an updating of our original conceptual model. This also includes the introduction by our concept that communication via both WT and VT belongs to the fundamental features of all neurons, the ratio of which can vary from one neuron system to the other and with the structural and functional state of each neuron system.
The criteria which can be applied to characterize WT and VT and their sub-classes will be deduced not only from structural and neurochemical findings, but also from concepts and from the lexicon offered by informatics (Hopcroft and Ullman, 1979). Our presentation will follow a historical frame moving from the well established modes toward novel modes of cell–cell communications. Thus, after a condensed summary of the main features of the “classical” modes of WT and VT (Agnati and Fuxe, 2000) tunnelling nanotubes and microvesicles will be discussed as novel types of WT and VT, respectively.
Furthermore, recent experimental findings of our group on these new types of WT and VT will be presented and, finally, their potential relevance for the physiology and pathology of the CNS will be discussed.
Taking advantage of some concepts and the lexicon offered by informatics (Hopcroft and Ullman, 1979, Le Boudec and Thiran, 2001), it becomes possible to classify the intercellular communication in the CNS according to a series of criteria based on the characteristics of the communication channel, of the transmitted signal and of the formed network. They are illustrated in Table 1, where a possible approach (Ramanathan et al., 2007) to a more formal definition is also outlined.
In this respect it has to be observed that the one and main criterion which allows differentiating WT from VT are the characteristics of the communication channel and more precisely the physical boundaries of the channel, which are well delimited for WT but not for VT.
The classification (in particular when VT based intercellular communication pathways are concerned), however, could be further detailed by taking into account the other signal features illustrated in Table 1 (see also legend to Table 2):
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Signal privacy: It is proposed that we are dealing with a signal characterized by high privacy (i.e., a “reserved signal”) if only cells endowed with a specific recognition/decoding apparatus (as, for instance, specific receptors) can have access to it. On the contrary, we are dealing with a low privacy signal (i.e., a “broadcasted signal”) when any cell reached by the signal can have access to it.
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Signal safety: As far as the safety is concerned, we are dealing with a “safe signal” if it is not altered during its conduction from the source to the target cell and with an “unsafe signal” if it can be altered during its pathway, as occurring, for instance, to some VT signals that can be broken down or modified (e.g., by enzymes) in the extracellular space (ECS).
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Connectivity: If the connections between cells can be rapidly formed or removed, they provide a “dynamic network.” On the contrary, the structure of a communication network is “static” when the pattern of connections is almost stable in time.
Thus, based on these concepts, a unitary scheme could be devised for a more detailed characterization of WT and VT and of their subtypes. Let us now briefly examine them.
Section snippets
Wiring transmission
The specific feature of this mode of intercellular communication is the existence of a virtual wire connecting the cell source of the signal (message) with the cell target of the signal. The different subclasses of WT are indicated in Table 2, together with the properties they exhibit in terms of the criteria to classify modes of communication in cellular networks of the CNS (Table 1).
The most important and well known is certainly the synaptic transmission. However, two more subclasses of WT
Volume transmission
Interneuronal wiring communication is certainly a basic feature of the CNS and has been the main foundation of neuroscience as we know it. In the 1970s and 1980s, however, the functional assumption of a diffuse mode of intercellular communication affecting and modulating the activity of entire brain regions was gaining support from studies on monoaminergic (see Ungerstedt et al., 1969, Geffen et al., 1976) and peptidergic neurons (Fuxe et al., 1977, Bloom and Segal, 1980, Burbach, 1982, De Wied
Putative novel types of wiring and volume transmission
As mentioned above, TNTs and exosomes may represent novel types of WT and VT, respectively. It has to be pointed out, however, that it is still a matter of investigation whether TNTs exist in vivo, in particular in the brain (see below). On the other hand, there are several findings demonstrating the existence of exosomes (more generally of micro-vesicles, see below) in vivo both in physiological and in pathological conditions. However, their specific relevance for cell–cell communication,
On the role of the extracellular space in intercellular communication
The intercellular space fulfils active tasks in the elaboration of the information since it may address the diffusion of electrochemical messages in an anisotropic fashion favoring or preventing the communication between two brain areas contributing to compartment formation. Furthermore, the ECM is not an amorphous filling between the different cell types of the CNS. On the contrary, it may affect the messages released by the CNS cells, for example, leading to the formation of different sets of
Concluding remarks
Brain integrative action mainly depends on neural networks and on the synaptic transmission (Sherrington, 1906), This signaling backbone, however, is significantly complemented by complex cellular networks (involving neurons, astrocytes, microglial cells, oligodendroglial cells, ependymal cells). Elements of these networks communicate basically via two classes of connections (WT and VT). This enlarged view is in agreement with Golgi's proposal that can be paraphrased by stating that different
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