Chronic psychotropic drug treatment causes differential expression of connexin 43 and GFAP in frontal cortex of rats

Fatemi, S. Hossein; Folsom, Timothy D.; Reutiman, Teri J.; Pandian, T.K.; Braun, Natalie N.; Haug, Kari Bente Foss

doi:10.1016/j.schres.2008.05.016

Cited by 58 publications

(35 citation statements)

References 40 publications

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“…Although we did not find significant alterations in expression of Cx43 mRNA and Cx43 puncta density in CTR animals treated with fluoxetine, we detected the significant increase of Cx43 protein level, consistent with a previous report (Fatemi et al, 2008). The increased Cx43 expression may provide a mechanism contributing to the increased dye diffusion that is observed following antidepressants treatment.…”

Section: Discussionsupporting

confidence: 91%

Gap Junction Dysfunction in the Prefrontal Cortex Induces Depressive-Like Behaviors in Rats

Sun

Liu

Yuan

et al. 2011

Neuropsychopharmacol

219

183

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Growing evidence has implicated glial anomalies in the pathophysiology of major depression disorder (MDD). Gap junctional communication is a main determinant of astrocytic function. However, it is unclear whether gap junction dysfunction is involved in MDD development. This study investigates changes in the function of astrocyte gap junction occurring in the rat prefrontal cortex (PFC) after chronic unpredictable stress (CUS), a rodent model of depression. Animals exposed to CUS and showing behavioral deficits in sucrose preference test (SPT) and novelty suppressed feeding test (NSFT) exhibited significant decreases in diffusion of gap junction channel-permeable dye and expression of connexin 43 (Cx43), a major component of astrocyte gap junction, and abnormal gap junctional ultrastructure in the PFC. Furthermore, we analyzed the effects of typical antidepressants fluoxetine and duloxetine and glucocorticoid receptor (GR) antagonist mifepristone on CUS-induced gap junctional dysfunction and depressive-like behaviors. The cellular and behavioral alterations induced by CUS were reversed and/or blocked by treatment with typical antidepressants or mifepristone, indicating that the mechanism of their antidepressant action may involve the amelioration of gap junction dysfunction and the cellular changes may be related to GR activation. We then investigated the effects of pharmacological gap junction blockade in the PFC on depressive-like behaviors. The results demonstrate that carbenoxolone (CBX) infusions induced anhedonia in SPT, and anxiety in NSFT, and Cx43 mimetic peptides Gap27 and Gap26 also induced anhedonia, a core symptom of depression. Together, this study supports the hypothesis that gap junction dysfunction contributes to the pathophysiology of depression.

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Section: Discussionsupporting

confidence: 91%

Gap Junction Dysfunction in the Prefrontal Cortex Induces Depressive-Like Behaviors in Rats

Sun

Liu

Yuan

et al. 2011

Neuropsychopharmacol

219

183

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“…However, when combining all subjects with depression (MDD+MDA) and then assessing them according to Adep treatment there was no significant difference in packing density of Cx43 puncta between Adep-treated and non-treated subjects. Experiments in rodents reveal that repeated antidepressant treatment increases Cx43 protein levels in the prefrontal cortex (Fatemi et al, 2008). Further duly powered in vitro and in vivo experiments should help clarify whether Adep actions might be partly mediated by changes in Cx43 expression or trafficking (Segretain and Falk, 2004).…”

Section: Discussionmentioning

confidence: 99%

Reduced connexin 43 immunolabeling in the orbitofrontal cortex in alcohol dependence and depression

Miguel-Hidalgo¹,

Wilson²,

Hussain³

et al. 2014

Journal of Psychiatric Research

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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.

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“…Interesting data have been gathered from antidepressant-treated rodents: chronic treatment with fluoxetine (SSRI) increased Cx43 expression in rat prefrontal cortex (Fatemi et al, 2008b). Consistently, it has been shown that stressed rats presented a lower level of Cx43 expression and function in the cortex, while fluoxetine reversed those reductions (Sun et al, 2012).…”

Section: Astroglial Cxs and Brain Pharmacological Agentsmentioning

confidence: 99%

“…Antipsychotic drugs have been developed since the 50s to reduce the symptoms of those disorders, and among them haloperidol, lithium, clozapine, or chlorpromazine. Those drugs generally reduce the expression of astrocyte Cxs (Orellana et al, 2006; Fatemi et al, 2008b). Concerning chlorpromazine, kinetic studies indicate that this reduction is achieved through an indirect mechanism involving a complex signaling cascade from drug application to effects on GJ channels, including modulation by alteredCx43 phosphorylation.…”

Section: Astroglial Cxs and Brain Pharmacological Agentsmentioning

confidence: 99%

Connexin-Dependent Neuroglial Networking as a New Therapeutic Target

Charvériat

Naus

Leybaert

et al. 2017

Front. Cell. Neurosci.

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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.

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Chronic psychotropic drug treatment causes differential expression of connexin 43 and GFAP in frontal cortex of rats

Cited by 58 publications

References 40 publications

Gap Junction Dysfunction in the Prefrontal Cortex Induces Depressive-Like Behaviors in Rats

Gap Junction Dysfunction in the Prefrontal Cortex Induces Depressive-Like Behaviors in Rats

Reduced connexin 43 immunolabeling in the orbitofrontal cortex in alcohol dependence and depression

Connexin-Dependent Neuroglial Networking as a New Therapeutic Target

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