Deletion of Astrocyte Connexins 43 and 30 Leads to a Dysmyelinating Phenotype and Hippocampal CA1 Vacuolation

Abstract

Astrocytes are coupled via gap junctions (GJs) comprising connexin 43 (Cx43) (Gja1) and Cx30 (Gjb6), which facilitate intercellular exchange of ions. Astrocyte connexins also form heterotypic GJs with oligodendrocytic somata and lamellae. Loss of oligodendrocyte gap junctions results in oligodendrocyte and myelin pathology. However, whether loss of astrocyte GJs affects oligodendrocytes and myelin is not known. To address this question, mice with astrocyte-targeted deletion of Cx43 and global loss of Cx30 [double knock-out (dKO)] were studied using Western blotting, immunohistochemistry, electron microscopy, and functional assays. Commencing around postnatal day 23 and persisting into old age, we found widespread pathology of white matter tracts comprising vacuolated oligodendrocytes and intramyelinic edema. In contrast, gray matter pathology was restricted to the CA1 region of the hippocampus, and consisted of edematous astrocytes. No differences were observed in synaptic density or total NeuN ϩ cells in the hippocampus, or olig2 ϩ cells in the corpus callosum. However, in dKO mice, fewer CC1-positive mature oligodendrocytes were detected, and Western blotting indicated reduced myelin basic protein. Pathology was not noted in mice expressing a single allele of either Cx43 or Cx30. When compared with single connexin knock-outs, dKO mice were impaired in sensorimotor (rotarod, balance beam assays) and spatial memory tasks (object recognition assays). We conclude that loss of astrocytic GJs can result in white matter pathology that has functional consequences.

Panglial Gap Junctional Communication is Essential for Maintenance of Myelin in the CNS

“…In contrast to Cx30 Ϫ/Ϫ /Cx47 Ϫ/Ϫ mice, astrocytic Cx30/Cx43 double-KO mice show only mild myelin disturbances (Lutz et al, 2009). Furthermore, Cx30/Cx43 dKO mice exhibit attenuated astrocytic to oligodendrocytic coupling and are deprived of interastrocytic coupling in the hippocampus (Wallraff et al, 2006;Maglione et al, 2010).…”

Oligodendroglia: metabolic supporters of neurons

“…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).…”

Morphological plasticity of astroglia: Understanding synaptic microenvironment

“…Astrocytes devoid of the gap junction protein invade the synaptic cleft, leading to decreased AMPAR‐mediated synaptic transmission as glutamate was taken up by the astrocytes before it reached the postsynapse (Pannasch et al, 2014). Moreover, astrocytes lacking Cx43, or Cx30 and Cx43 (Chever et al, 2014; Lutz et al, 2009; Pannasch et al, 2011) but not Cx30 alone (Pannasch et al, 2014) appear swollen, which suggests a mechanism for controlling the astrocyte volume and PAP displacement.…”