Brain connexins in demyelinating diseases: Therapeutic potential of glial targets

Division of Glia Disease and Therapeutics, Center for Translational Neuromedicine, University of Rochester Medical School, Rochester, NY 14640, USA.
Brain research (Impact Factor: 2.84). 07/2012; 1487. DOI: 10.1016/j.brainres.2012.07.003
Source: PubMed


Several demyelinating syndromes have been linked to mutations in glial gap junction proteins, the connexins. Although mutations in connexins of the myelinating cells, Schwann cells and oligodendrocytes, were initially described, recent data have shown that astrocytes also play a major role in the demyelination process. Alterations in astrocytic proteins directly affect the oligodendrocytes' ability to maintain myelin structure, and associated astrocytic proteins that regulate water and ionic fluxes, including aquaporins, can also regulate myelin integrity. Here, we will review the main evidence from human disorders and transgenic mouse models that implicate glial gap junction proteins in demyelinating diseases and the therapeutic potential of some of these targets. This article is part of a Special Issue entitled Electrical Synapses.

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    • "Some of the neuronal support functions of astrocytes (Haydon and Carmignoto, 2006; Volterra and Meldolesi, 2005) strongly depend on astrocytes' ability to communicate with each other and with other cells through gap junctions and hemichannels (Cotrina and Nedergaard, 2012; Figiel et al., 2007; Giaume et al., 1997; Rouach et al., 2002), mainly composed of the protein connexin 43 (Cx43), with a smaller involvement of connexin 30 (Cx30). Thus, deficient expression or modifications of Cx43 could contribute to prefrontal physiopathology. "
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    ABSTRACT: Reduced density of glial cells and low levels of some astrocyte proteins have been described in the orbitofrontal cortex (OFC) in depression and alcoholism, two disorders often comorbid. These regressive changes may also involve the communication between astrocytes via gap junctions and hemichannels, which play important regulatory roles in neurotransmission. We determined levels and morphological immunostaining parameters of connexin 43 (Cx43), the main protein subunit of astrocyte gap junctions/hemichannels, in the OFC of subjects with depression, alcoholism or comorbid depression/alcoholism as compared to non-psychiatric subjects. Postmortem brain samples from 23 subjects with major depressive disorder (MDD), 16 with alcohol dependence, 13 with comorbid MDD and alcohol dependence, and 20 psychiatrically-normal comparison subjects were processed for western blots to determine Cx43 levels. Area fraction of Cx43 immunoreactivity, and density and average size of immunoreactive puncta were measured in histological sections. There was a significant, larger than 60 percent decrease in Cx43 level in the three psychiatric groups as compared to controls. Area fraction of immunoreactivity and immunoreactive punctum size were reduced in all psychiatric groups, but Cx43-immunoreactive puncta density was reduced only in alcohol-dependent subjects. Among psychiatric subjects, no difference in Cx43 levels or immunostaining was found between suicides and non-suicides. The present data suggest that dysfunction of the OFC is accompanied by reduction in the levels of gap junction protein Cx43 in depression and alcoholism, and reduction in density of Cx43 immunoreactive puncta only in alcoholism, pointing to altered gap junction or hemichannel-based communication in the pathophysiology of those disorders.
    Journal of Psychiatric Research 04/2014; 55(1). DOI:10.1016/j.jpsychires.2014.04.007 · 3.96 Impact Factor
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    • "Although we only reported mRNA expression in this study, our previous study has shown that the alteration in protein expression of MBP is consistent with that of mRNA in adolescent brains [8]. The membrane-associated proteins such as MAL and GJE3 interact with neighbor cells to support myelin structure and function [11] [40]. Other proteins, such as PLP1 and CNP, are less involved in myelination but help shape the underlying axon and also support axon function [19] [26]. "
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    ABSTRACT: Abnormal myelin gene expression in the central nervous system (CNS) is associated with many mental illnesses, including psychiatric disorders and drug addiction. We have previously shown that prenatal exposure to nicotine, the major psychoactive component in cigarette smoke, alters myelin gene expression in the CNS of adolescent rats. To examine whether this effect is specific for adolescents, we examined myelin gene expression in the CNS of juveniles and adults. Pregnant Sprague-Dawley rats were treated with nicotine (3mg/kg/day; GN) or saline (GS) via osmotic mini pumps from gestational days 4 to 18. Both male and female offspring were sacrificed at postnatal day P20-21 (juveniles), P35-36 (adolescents), or P59-60 (adults). Three limbic brain regions, the prefrontal cortex (PFC), caudate putamen (CPu), and nucleus accumbens (NAc), were dissected. The expression of genes encoding major myelin components was evaluated using quantitative RT-PCR. We found that GN altered myelin gene expression in juveniles with brain region and sex differences. The pattern of alteration was different from that observed in adolescents. Although these genes were expressed normally in male adults, we observed decreased expression in GN-treated female adults, especially in the CPu. Thus, GN altered myelin gene expression throughout postnatal development and adulthood. The effect on adolescents was quite different from that at other ages, which correlated with the unique symptoms of many psychiatric disorders during adolescence.
    Neuroscience Letters 08/2013; 553. DOI:10.1016/j.neulet.2013.08.012 · 2.03 Impact Factor
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    • "Numerous pathologies have been associated with alterations of astroglial networks and GJ permeability. In particular, changes in connexin expression occur following acute injuries or in the process of chronic diseases, including demyelinating and neurodegenerative diseases (Kielian and Esen, 2004; Giaume et al., 2010; Cotrina and Nedergaard, 2012). Both increases and decreases in astrocyte connexin expression and GJ permeability to passive dyes have been reported, depending on the model, species, and connexin type (Giaume et al., 2010). "
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    ABSTRACT: The strategic position of astrocytic processes between blood capillaries and neurons, provided the early insight that astrocytes play a key role in supplying energy substrates to neurons in an activity-dependent manner. The central role of astrocytes in neurometabolic coupling has been first established at the level of single cell. Since then, exciting recent work based on cellular imaging and electrophysiological recordings has provided new mechanistic insights into this phenomenon, revealing the crucial role of gap junction (GJ)-mediated networks of astrocytes. Indeed, astrocytes define the local availability of energy substrates by regulating blood flow. Subsequently, in order to efficiently reach distal neurons, these substrates can be taken up, and distributed through networks of astrocytes connected by GJs, a process modulated by neuronal activity. Astrocytic networks can be morphologically and/or functionally altered in the course of various pathological conditions, raising the intriguing possibility of a direct contribution from these networks to neuronal dysfunction. The present review upgrades the current view of neuroglial metabolic coupling, by including the recently unravelled properties of astroglial metabolic networks and their potential contribution to normal and pathological neuronal activity.
    Frontiers in Neuroenergetics 04/2013; 5:4. DOI:10.3389/fnene.2013.00004
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