Accelerated hippocampal spreading depression and enhanced locomotory activity in mice with astrocyte-directed inactivation of connexin43.
Using a human glial fibrillary acidic protein (hGFAP) promoter-driven cre transgene, we have achieved efficient inactivation of a floxed connexin43 (Cx43) gene in astrocytes of adult mice. The loss of Cx43 expression was monitored in a cell-autonomous manner via conditional replacement of the Cx43-coding region by a lacZ reporter gene. In this way, we bypassed the early postnatal lethality previously reported for Cx43 null mice and characterized the phenotypic consequences of Cx43 deficiency in the CNS. Mice lacking Cx43 in astrocytes were viable and showed no evidence of either neurodegeneration or astrogliosis. Spreading depression (SD) is a pathophysiological phenomenon observed in the CNS that is characterized by a propagating wave of depolarization followed by neuronal inactivation. Inhibitors of gap junctional communication have previously been shown to block initiation and propagation of SD. In contrast, we observed an increase in the velocity of hippocampal SD in the stratum radiatum of mice lacking Cx43 in astrocytes. In the same brain subregion, dye-coupling experiments revealed a reduction in overall astrocytic intercellular communication by approximately 50%. This strongly suggests separate and different neuronal and glial contributions of gap junctional intercellular communication to SD. Concomitant with increased velocity of spreading depression, we observed enhanced locomotory activity in mice lacking Cx43 in astrocytes.
Theis
Martin
M
Institut für Genetik, Abteilung Molekulargenetik, Universität Bonn, D-53117 Bonn, Germany.
Jauch
Regina
R
Zhuo
Lang
L
Speidel
Dina
D
Wallraff
Anke
A
Döring
Britta
B
Frisch
Christian
C
Söhl
Goran
G
Teubner
Barbara
B
Euwens
Carsten
C
Huston
Joseph
J
Steinhäuser
Christian
C
Messing
Albee
A
Heinemann
Uwe
U
Willecke
Klaus
K
D000818:Animals; D001253:Astrocytes / Q000166:cytology / Q000378:metabolism*; D001522:Behavior, Animal / Q000502:physiology; D002455:Cell Division / Q000235:genetics; D002478:Cells, Cultured; D002490:Central Nervous System / Q000502:physiology; D004396:Coloring Agents; D018031:Connexin 43 / Q000172:deficiency / Q000235:genetics* / Q000378:metabolism*; D013181:Cortical Spreading Depression / Q000235:genetics / Q000502:physiology*; D005328:Fetal Viability; D017930:Genes, Reporter; D005904:Glial Fibrillary Acidic Protein / Q000235:genetics; D006624:Hippocampus / Q000502:physiology*; D006801:Humans; D019426:Integrases; D007763:Lac Operon; D051379:Mice; D008822:Mice, Transgenic; D009043:Motor Activity / Q000502:physiology*; D018408:Patch-Clamp Techniques; D010641:Phenotype; D011401:Promoter Regions, Genetic / Q000502:physiology; D019076:Transgenes; D014764:Viral Proteins
D004396:Coloring Agents; D018031:Connexin 43; D005904:Glial Fibrillary Acidic Protein; D014764:Viral Proteins; C045073:Cre recombinase; D019426:Integrases