Connexin30‐deficient mice show increased emotionality and decreased rearing activity in the open‐field along with neurochemical changes

Dere, Ekrem; Souza-Silva, M. A. De; Frisch, Christian; Teubner, Barbara; Söhl, Goran; Willecke, Klaus; Huston, Joseph P.

doi:10.1046/j.1460-9568.2003.02784.x

Cited by 97 publications

(72 citation statements)

References 42 publications

(88 reference statements)

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“…Indeed, it has been shown that Cx30 KO mice exhibit altered reactivity to novel environmental stimuli implying a role of Cx30 on neuronal activity (Dere et al, 2003). In this study, we found an interesting relationship between the monomeric and dimeric forms of Cx30 in activated astrocytes by Western blot analysis.…”

Section: Discussionsupporting

confidence: 58%

Modulation of connexin expression and gap junction communication in astrocytes by the gram‐positive bacterium S. aureus

Esen

Shuffield

Syed

et al. 2006

Glia

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Gap junctions establish direct intercellular conduits between adjacent cells and are formed by the hexameric organization of protein subunits called connexins (Cx). It is unknown whether the proinflammatory milieu that ensues during CNS infection with S. aureus, one of the main etiologic agents of brain abscess in humans, is capable of eliciting regional changes in astrocyte homocellular gap junction communication (GJC) and, by extension, influencing neuron homeostasis at sites distant from the primary focus of infection. Here we investigated the effects of S. aureus and its cell wall product peptidoglycan (PGN) on Cx43, Cx30, and Cx26 expression, the main Cx isoforms found in astrocytes. Both bacterial stimuli led to a time-dependent decrease in Cx43 and Cx30 expression; however, Cx26 levels were elevated following bacterial exposure. Functional examination of dye coupling, as revealed by single-cell microinjections of Lucifer yellow, demonstrated that both S. aureus and PGN inhibited astrocyte GJC. Inhibition of protein synthesis with cyclohexamide (CHX) revealed that S. aureus directly modulates, in part, Cx43 and Cx30 expression, whereas Cx26 levels appear to be regulated by a factor(s) that requires de novo protein production; however, CHX did not alter the inhibitory effects of S. aureus on astrocyte GJC. The p38 MAPK inhibitor SB202190 was capable of partially restoring the S. aureus-mediated decrease in astrocyte GJC to that of unstimulated cells, suggesting the involvement of p38 MAPK-dependent pathway(s). These findings could have important implications for limiting the long-term detrimental effects of abscess formation in the brain which may include seizures and cognitive deficits.

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Section: Discussionsupporting

confidence: 58%

Modulation of connexin expression and gap junction communication in astrocytes by the gram‐positive bacterium S. aureus

Esen

Shuffield

Syed

et al. 2006

Glia

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“…38 Gait abnormalities due to cerebellar dysfunction 39 or neurodegeneration have been reported in mouse models for lysosomal storage diseases, 40,41 genes within the Down syndrome critical region, 42 genes encoding presynaptic proteins, 43 deficiency of transcription factors, 20,21 musculoskeletal disorders, 44 and polyglutamine diseases. 45 Although the number of polymorphic polyglutamine repeats in human RAI1 is implicated in modulating the onset of spinocerebellar ataxia, 46 mice carry only four glutamines in this region, and polymorphic CAG repeats have not been reported.…”

Section: Discussionmentioning

confidence: 99%

How much is too much? Phenotypic consequences of Rai1 overexpression in mice

et al. 2008

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The retinoic acid induced 1 (RAI1) gene when deleted or mutated results in Smith-Magenis syndrome (SMS), while duplication of 17p11.2, including RAI1, results in the dup(17)(p11.2) syndrome characterized by mental retardation, growth and developmental delays, and hyperactivity. Mouse models for these human syndromes may help define critical roles for RAI1 in mammalian development and homeostasis that otherwise cannot be deduced from patient studies. A mouse model for duplication, Dp(11)17 þ , involving Rai1 has been reported. However, this mutant was engineered on a mixed genetic background confounding phenotypic effects due to possible modifier genes. We have therefore created and evaluated mice with a graded series of four (hemizygous) and six (homozygous) copies of Rai1, and overexpressing Rai1 41.5-fold and 42-fold, respectively. Data show that Rai1-transgenic mice have growth retardation, increased locomotor activity, and abnormal anxiety-related behavior compared to wild-type littermates. Rai1-transgenic mice also have an altered gait with short strides and long sways, impaired ability on a cagetop hang test, decreased forelimb grip strength, and a dominant social behavior. Further, analyses of homozygous transgenic mice revealed a dosage-dependent exacerbation of the phenotype, including extreme growth retardation, severe neurological deficits, and increased hyperactivity. Our results show that Rai1 dosage has major consequences on molecular processes involved in growth, development, and neurological and behavioral functions, thus providing evidence for several dosage-thresholds for phenotypic manifestations causing dup(17)(p11.2) syndrome or SMS in humans.

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“…Targeted loss of astrocyte Cx43 expression inhibits glucose delivery to OPCs and OPC proliferation, which in turn can influence oligodendrogenesis and oligodendrocyte metabolic support (76). In addition, double knockouts for the astrocyte hemichannels Cx43 and Cx30 develop widespread white matter pathology with impairment of oligodendrocyte maturation and myelin vacuolation, whereas mice with astrocyte-targeted loss of Cx43 or Cx30-null mice do not show signs of abnormal myelination (85)(86)(87). Double knockouts affecting both oligodendrocyte and astrocyte hemichannels (Cx47/ Cx30) develop a progressive phenotype with early vacuolization of myelin with microgliosis, astrogliosis, motor impairment, and early death (88).…”

Section: Mct1mentioning

confidence: 99%