Electrical activity suppresses intrinsic growth competence in adult primary sensory neurons

Enes, Joana (2009): Electrical activity suppresses intrinsic growth competence in adult primary sensory neurons: Implications for spinal cord regeneration. Dissertation, LMU München: Fakultät für Biologie

Abstract

The ability of neurons to regenerate in the adult mammalian central nervous system (CNS) is often poor, leading to persistent deficits after injury. Failure of axon regeneration in the CNS has been attributed to the presence of an extrinsic inhibitory environment and to an intrinsic limitation to support growth. Remarkably, in adult primary sensory neurons of the dorsal root ganglia (DRG), a peripheral lesion primes neurons to grow and to override the inhibitory environment. Under this condition not only their peripheral axons regrow, but also their injured central axons coursing in the spinal cord regenerate. However, the nature of the signal that is sensed by the cell upon peripheral lesion to initiate the regenerative response is poorly understood. This study started from the hypothesis that electrical silencing caused by peripheral deafferentiation is an important signal to trigger axon regrowth in adult DRG neurons. I first examined the effect of electrical activity on axon growth of cultured DRG neurons. I found that either chronic depolarization or electrical field stimulation strongly inhibits axon outgrowth in cultured DRG neurons. The inhibitory effect depends on Ca2+ influx through L-type voltage-gated calcium channels and involves transcriptional changes. Consistently, after a peripheral lesion, L-type current is diminished and the L-type pore-forming subunit Cav1.2 is downregulated. To determine whether the lack of L-type channels is sufficient to promote axon growth, mice lacking the pore-forming subunit of L-type channel, Cav1.2, in the nervous system were generated. Neurons isolated from adult Cav1.2 knockout (KO) mice grew more extensively than those from their control littermates. Taken together, these data provide evidence that electrical activity is a limiting factor for axon growth in adult DRG neurons and that releasing this “brake” is sufficient to induce axon growth. My results further suggest that electrical silencing might promote axon regeneration in vivo. Consequently, I have attempted to apply this knowledge to a model of spinal cord injury. However, these in vivo experiments have been so far hampered by technical limitations. Further endeavors are currently in progress.

• Dokumententyp: Dissertationen (Dissertation, LMU München)
• Keywords: primary sensory DRG neurons; electrical activity; L-type calcium channels; axon growth; spinal cord regeneration
• Themengebiete: 500 Naturwissenschaften und Mathematik ; 500 Naturwissenschaften und Mathematik > 570 Biowissenschaften, Biologie
• Fakultäten: Fakultät für Biologie
• Sprache der Hochschulschrift: Englisch
• Datum der mündlichen Prüfung: 13. Mai 2009
• 1. Bericht­erstatter:in: Grothe, Benedikt