Electrical activity suppresses intrinsic growth competence in adult primary sensory neurons

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.