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The Journal of Neuroscience, October 21, 2009, 29(42):13242-13254; doi:10.1523/JNEUROSCI.3376-09.2009

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Neurobiology of Disease
Disruption of the Axon Initial Segment Cytoskeleton Is a New Mechanism for Neuronal Injury

Dorothy P. Schafer,¹ Smita Jha,² Fudong Liu,¹ Trupti Akella,¹ Louise D. McCullough,¹ and Matthew N. Rasband^1,2

¹Department of Neuroscience, University of Connecticut Health Center, Farmington, Connecticut 06032, and ²Department of Neuroscience, Baylor College of Medicine, Houston, Texas 77030

Correspondence should be addressed to: Dr. Matthew N. Rasband, Department of Neuroscience, Baylor College of Medicine, One Baylor Plaza, Houston, TX 77030. Email: Rasband{at}bcm.edu

Many factors contribute to nervous system dysfunction and failure to regenerate after injury or disease. Here, we describe a previously unrecognized mechanism for nervous system injury. We show that neuronal injury causes rapid, irreversible, and preferential proteolysis of the axon initial segment (AIS) cytoskeleton independently of cell death or axon degeneration, leading to loss of both ion channel clusters and neuronal polarity. Furthermore, we show this is caused by proteolysis of the AIS cytoskeletal proteins ankyrinG and βIV spectrin by the calcium-dependent cysteine protease calpain. Importantly, calpain inhibition is sufficient to preserve the molecular organization of the AIS both in vitro and in vivo. We conclude that loss of AIS ion channel clusters and neuronal polarity are important contributors to neuronal dysfunction after injury, and that strategies to facilitate recovery must preserve or repair the AIS cytoskeleton.

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Received July 14, 2009; revised Aug. 12, 2009; accepted Sept. 11, 2009.

Correspondence should be addressed to: Dr. Matthew N. Rasband, Department of Neuroscience, Baylor College of Medicine, One Baylor Plaza, Houston, TX 77030. Email: Rasband{at}bcm.edu

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