Connexin-Dependent Neuroglial Networking as a New Therapeutic Target

Abstract

Astrocytes and neurons dynamically interact during physiological processes, and it is now widely accepted that they are both organized in plastic and tightly regulated networks. Astrocytes are connected through connexin-based gap junction channels, with brain region specificities, and those networks modulate neuronal activities, such as those involved in sleep-wake cycle, cognitive, or sensory functions. Additionally, astrocyte domains have been involved in neurogenesis and neuronal differentiation during development; they participate in the "tripartite synapse" with both pre-synaptic and post-synaptic neurons by tuning down or up neuronal activities through the control of neuronal synaptic strength. Connexin-based hemichannels are also involved in those regulations of neuronal activities, however, this feature will not be considered in the present review. Furthermore, neuronal processes, transmitting electrical signals to chemical synapses, stringently control astroglial connexin expression, and channel functions. Long-range energy trafficking toward neurons through connexin-coupled astrocytes and plasticity of those networks are hence largely dependent on neuronal activity. Such reciprocal interactions between neurons and astrocyte networks involve neurotransmitters, cytokines, endogenous lipids, and peptides released by neurons but also other brain cell types, including microglial and endothelial cells. Over the past 10 years, knowledge about neuroglial interactions has widened and now includes effects of CNS-targeting drugs such as antidepressants, antipsychotics, psychostimulants, or sedatives drugs as potential modulators of connexin function and thus astrocyte networking activity. In physiological situations, neuroglial networking is consequently resulting from a two-way interaction between astrocyte gap junction-mediated networks and those made by neurons. As both cell types are modulated by CNS drugs we postulate that neuroglial networking may emerge as new therapeutic targets in neurological and psychiatric disorders.

Keywords: astrocyte network; connexin; gap junction; glia; neuroglial interaction.

Figure 1

Glucose and glutamate pathways in astrocyte networks and interactions with neurons. In addition to a direct pathway to neurons by the extracellular space, glucose from blood vessels is taken-up through astrocytic end-feet or through GLUT1 (Glucose transporter 1) facilitated transport, and by neurons through GLUT3 (Glucose transporter 3) transport. In astrocytes, glucose is metabolized to lactate, which is exported through MCT1/4 (Mono-Carboxylate Transporter 1/4); lactate is shuffled into neurons by MCT2 (Mono-Carboxylate Transporter 2) and participates in the synthesis of glutamate, further stored in vesicles until exocytotic release. After neuronal firing, glutamate released into the synaptic cleft is removed by astrocytes through EAAT (Excitatory Amino Acid Transporter) and recycled as glutamine. This glutamate-glutamine cycling and the associated sodium entry consumes energy, which drives astrocytic glycolysis and results in lactate production (Pellerin et al., 2007). Glucose, lactate, and glutamate are transferred between connected astrocytes through GJs (Cx30 and Cx43; Leybaert, ; Orellana et al., ; Escartin and Rouach, 2013).

Figure 2

K⁺ pathway in astrocyte networks and interactions with neurons. Gap junctions play a central role in the dissipation of K⁺ and its spatial buffering by astrocytes. Indeed, glial networking disperses local extracellular K⁺ increases by transferring K⁺ from sites of elevated concentrations to sites of lower concentrations through gap junctions. Potassium ions are taken-up through Kir1.4 (Potassium inwardly-rectifying channel 1.4), EAAT or K⁺/Na⁺-ATP-ase (Rouach et al., , , ; Kofuji and Newman, ; Giaume et al., ; Pannasch and Rouach, 2013). In addition, at least in olfactory glomeruli, high external K⁺ concentrations increases Cx30-mediated intercellular coupling which facilitates K⁺ buffering by astroglial networks (Roux et al., 2011).

Figure 3

Intercellular Ca²⁺ waves in astrocyte networks and interactions with neurons. The rise of intracellular Ca²⁺ concentration in astrocytes usually involves the activation of G-protein-coupled receptors, activation of phospholipase C (PLC), and the production of inositol trisphosphate (IP₃), which leads to Ca²⁺ release from the endoplasmic reticulum (ER). Elevation of cytoplasmic Ca²⁺ concentration further affects several plasma membrane proteins, such as metabotropic receptors, K⁺ and Ca²⁺ channels, Na⁺/Ca²⁺ exchanger, and Ca²⁺-ATPase. Once triggered, intracellular Ca²⁺ waves can be transmitted as intercellular Ca²⁺ waves to neighboring cells through the diffusion of inositol trisphosphate (IP₃) production and Ca²⁺ through gap junctions, and subsequent release of Ca²⁺ from the endoplasmic reticulum (Cotrina et al., ; Leybaert et al., ; Scemes et al., ; Scemes and Giaume, ; Leybaert and Sanderson, ; De Bock et al., 2014). Ca²⁺-dependent release of gliotransmitters then target neuronal receptor but also astroglial receptors that participate to and amplify the process of propagation of intercellular Ca²⁺ waves (Scemes and Giaume, 2006).

Figure 4

Putative role of astroglial connexins in the modulation of the CNS drug profiles. Neuronal and astrocyte networking activities are mutually regulated. Neuronal activity leads to an up-regulation of astrocyte Cx expression and channel function (Rouach et al., , , ; Koulakoff et al., ; Giaume et al., ; Pannasch et al., , , ; Roux et al., 2011). Interestingly, certain CNS-targeting drugs also appear to impact astrocyte Cxs (Giaume and Liu, ; Liu et al., , ; Duchêne et al., ; Jeanson et al., 2016a,b). As presented in the three panels and based on literature, it can be hypothesized that optimal neuronal reactivity could be associated with an optimal size of local astroglial network (B), as too large (C) or too reduced (A) syncytium might not adequately fuel metabolically active synapses during treatment with CNS drugs. Including aspects of drug action at the level of astrocytes, and more generally at the level of glial cells, opens up new avenues for potentially novel therapeutic applications.