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The Journal of Neuroscience, October 25, 2006, 26(43):10984-10991; doi:10.1523/JNEUROSCI.0304-06.2006

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Cellular/Molecular
Genetic and Physiological Evidence That Oligodendrocyte Gap Junctions Contribute to Spatial Buffering of Potassium Released during Neuronal Activity

Daniela M. Menichella,^1,5 * Marta Majdan,^1 * Rajeshwar Awatramani,³ Daniel A. Goodenough,² Erich Sirkowski,⁴ Steven S. Scherer,⁴ and David L. Paul¹

Departments of ¹Neurobiology and ²Cell Biology, Harvard Medical School, Boston, Massachusetts 02115, ³Department of Neurology and Center for Genetic Medicine, Northwestern University, Chicago, Illinois 60611, ⁴Department of Neurology, The University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania 19104-6077, and ⁵Institute of Neurology, Instituto di Ricovero e Cura a Carattere Scientifico Ospedale Maggiore, Centro Dino Ferrari, University of Milan, 20122 Milan, Italy

Correspondence should be addressed to David L. Paul, Department of Neurobiology, Harvard Medical School, 220 Longwood Avenue, Boston, MA 02115. Email: dpaul{at}hms.harvard.edu

Mice lacking the K⁺ channel Kir4.1 or both connexin32 (Cx32) and Cx47 exhibit myelin-associated vacuoles, raising the possibility that oligodendrocytes, and the connexins they express, contribute to recycling the K⁺ evolved during neuronal activity. To study this possibility, we first examined the effect of neuronal activity on the appearance of vacuoles in mice lacking both Cx32 and Cx47. The size and number of myelin vacuoles was dramatically increased when axonal activity was increased, by either a natural stimulus (eye opening) or pharmacological treatment. Conversely, myelin vacuoles were dramatically reduced when axonal activity was suppressed. Second, we used genetic complementation to test for a relationship between the function of Kir4.1 and oligodendrocyte connexins. In a Cx32-null background, haploinsufficiency of either Cx47 or Kir4.1 did not affect myelin, but double heterozygotes developed vacuoles, consistent with the idea that oligodendrocyte connexins and Kir4.1 function in a common pathway. Together, these results implicate oligodendrocytes and their connexins as having critical roles in the buffering of K⁺ released during neuronal activity.

Key words: demyelination; oligodendrocyte; gap junction; connexin; potassium channel; astrocyte

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Received Jan. 23, 2006; revised Sept. 7, 2006; accepted Sept. 11, 2006.

Correspondence should be addressed to David L. Paul, Department of Neurobiology, Harvard Medical School, 220 Longwood Avenue, Boston, MA 02115. Email: dpaul{at}hms.harvard.edu

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