Rev Neurosci. 2017 Feb 1;28(2):113-132. doi: 10.1515/revneuro-2016-0051.

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

Guidolin D, Marcoli M, Maura G, Agnati LF.

Department of Biomedical Sciences and Department of Diagnostic, Clinical Medicine and Public Health, University of Modena and Reggio Emilia, via G. Campi, 287, I-41125 Modena, Italy

Department of Neuroscience, Karolinska Institutet, Stockholm, Sweden


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.e. the mapping of the communication channels made by cell components such as axons and synapses, and volume transmission (VT), i.e. the chemical signal diffusion along the interstitial brain fluid pathways. Considering both processes can further expand the connectomics concept, since both WT-connectomics and VT-connectomics contribute to the structure of the brain connectome. A consensus exists that such a structure follows a hierarchical or nested architecture, and macro-, meso- and microscales have been defined. In this respect, however, several lines of evidence indicate that a nanoscale (nano-connectomics) should also be considered to capture direct protein-protein allosteric interactions such as those occurring, for example, in receptor-receptor interactions at the plasma membrane level. In addition, emerging evidence points to novel mechanisms likely playing a significant role in the modulation of intercellular connectivity, increasing the plasticity of the system and adding complexity to its structure. In particular, the roamer type of VT (i.e. the intercellular transfer of RNA, proteins and receptors by extracellular vesicles) will be discussed since it allowed us to introduce a new concept of ‘transient changes of cell phenotype’, that is the transient acquisition of new signal release capabilities and/or new recognition/decoding apparatuses.

PMID: 28030363



The current view on the organization of the central nervous system (CNS) is basically anchored to the paradigm describing the brain as formed by networks of neurons interconnected by synapses. Synaptic contacts are, of course, a fundamental characteristic for describing CNS operations, and the comprehensive study of neuronal connectivity is of key importance to reach a deeper level of understanding of CNS functions.  Increasing evidence accumulated in the last 30 years, however, pointed to a refinement of this view. At least three aspects broadening classical connectomics could be identified:

  1. Communication between cells in the CNS involve a spectrum of processes that can be classified according to a dichotomous criterion [1]: wiring transmission (WT, occurring through physically delimited channels as in the synaptic transmission between neurons) and volume transmission (VT, exploiting diffusion in the extracellular space). These signaling backbones involve not only neurons, but also other types of cells in the CNS, especially astrocytes and microglial cells [1]. Hence, the concept of ‘complex cellular networks’ has been introduced to indicate the set of cells of any type that exchanging signals in a certain volume of brain tissue are capable not only of integrating multiple inputs to give out appropriate outputs but also of supporting each other’s survival.
  2. CNS extends over a range of up to five orders of magnitude of scales: from microns for cell structures at one end to centimeters for inter-areal neuronal connections at the other. A hierarchical or nested architecture has been suggested as a suitable model providing a unified view of the different spatial scales characterizing the brain network organization. In this respect, an almost general consensus exists in targeting at least three levels of organization: macroscale (in which connections among brain regions and areas are considered), mesoscale (involving complex cellular networks in brain regions) and microscale (in which the basic network’s elements are single cells in the complex cellular networks). However, to better capture properties concerning the strength and plasticity of synapses and VT connections a ‘nanoscale’ level should also be considered. At this further level of miniaturization, molecular networks can be found. Of particular interest are the ‘receptor mosaics’, i.e. macromolecular complexes formed at the membrane level by G protein-coupled receptors (GPCR) as a consequence of direct allosteric receptor-receptor interactions (RRI). The term RRI refers to an interaction requiring a direct physical contact between the involved receptor proteins leading to the formation of receptor complexes (dimers or high-order oligomers) at the cell membrane. The cooperativity that emerges in the actions of orthosteric and allosteric ligands of the GPCR forming the assembly provides the cell decoding apparatus with sophisticated dynamics [2].
  3. The experience-based reshaping of the brain structures is a general feature that deeply characterizes the nervous system and processes changing connectivity are well known at the level of neurons. They include changes in dendritic branches, creation of new connections and/or reactivation of ‘silent’ synapses when needed, and molecular mechanisms regulating synaptic efficiency. Emerging evidence, however, points to novel mechanisms likely playing a significant role in the modulation of intercellular connectivity. In particular, it indicates that the cross-talk between perisynaptic astrocytes and neurons can mediate synaptogenesis, synapse elimination and structural plasticity through a variety of secreted and contact-dependent signals. Furthermore, the motile nature of perisynaptic astrocyte processes (PAP) enwrapping synapses (Figure 1) can provide a control of the transmitter spillover from the synaptic cleft and a modulation of VT connections [3]. In addition, a specific form of VT, involving the transfer of receptors and receptor complexes by microvesicles (MV), could represent a further mechanism modulating neuron-neuron and glia-neuronal connectivity [4]. In fact, the diffusion of MV released by nerve cells in the extracellular space is quite extended (Figure 2) and can lead to the transient acquisition by the target cell of a new phenotype, enabling it to recognize/decode transmitters and/or modulators for which the cell does not express the pertinent cognate receptors.



Fig.1: Color enhanced transmission electron micrograph of a rat hippocampal synapse showing the pre- and post-synaptic elements in green and their relationship with PAP (in yellow).


Fig.2: Section of rat striatum showing MV diffusing in the extracellular space (left) [4]: GFP-labeled MV appear green, Dapi-stained nuclei blue. A 3D-reconstruction of the MV distribution, obtained from serial sections, is also shown (right).



Diego Guidolin PhD, Department of Neuroscience, University of Padova, via Gabelli, 65, I-35121 Padova, Italy. e-mail:;

Prof. Luigi F. Agnati, Department of Biomedical Sciences and Department of Diagnostic, Clinical Medicine and Public Health, University of Modena and Reggio Emilia, via G. Campi, 287, I-41125 Modena, Italy; Department of Neuroscience, Karolinska Institutet, Stockholm, Sweden. e-mail:



[1] L.F. Agnati, D. Guidolin, M. Guescini, S. Genedani, K. Fuxe, Understanding wiring and volume transmission. Brain Res.Rev. 64(2010): 137-159.

[2] D. Guidolin, L.F. Agnati, M. Marcoli, D.O. Borroto-Escuela, K. Fuxe, G-protein-coupled receptor type A heteromers as an emerging therapeutic target. Expert Opin. Ther. Targets 19(2015): 265-283.

[3] M. Marcoli, L.F. Agnati, F. Benedetti, S. Genedani, D. Guidolin, L. Ferraro, G. Maura, K. Fuxe, On the role of the extracellular space on the holistic behavior of the brain. Rev. Neurosci. 26(2015): 489–506.

[4] L.F. Agnati, D. Guidolin, G. Maura, M. Marcoli, G. Leo, C. Carone, R. De Caro, S. Genedani, D.O. Borroto-Escuela, K. Fuxe, Information handling by the brain: proposal of a new “paradigm” involving the roamer type of volume transmission and the tunneling nanotube type of wiring transmission. J. Neural Transm. 121(2014): 1431-1449.