Activity-dependent regulation of Schwann cell development by extracellular ATP

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During development, the importance of activity-dependent plasticity in neurons is widely appreciated, but comparatively less is known of the role of electrical activity in controlling glial development. Schwann cells (SCs)--the myelinating cells in the peripheral nervous system--are critically dependent on axons during the perinatal period, but axonal signals controlling SC development and myelination have remained elusive. The onset of high frequency action potential activity along developing peripheral nerves corresponds to the period when SCs are exiting the cell cycle and initiating myelination. We postulated that neural impulse activity could play an instructive role in regulating SC gene expression and function during development.

To address these questions, a neuron/SC co-culture system equipped with stimulating electrodes was used to evoke action potentials in dorsal root ganglion neurons (DRGs), and study the ensuing effects in pre-myelinating SCs.  We found that SCs can detect neural impulse activity in pre-myelinated axons, and the activity-dependent axon-Schwann cell signaling molecule was identified as extracellular ATP.  Activity-dependent release of ATP activated multiple intracellular signaling pathways in SCs, and increased levels of several transcription factors, including CREB, c-fos, and krox-24.  Importantly, we found that ATP has profound effects on SC development. Activity-dependent ATP release significantly inhibited SC proliferation, arrested SC differentiation, and completely prevented the formation of myelin.

Extracellular ATP can activate multiple types of purinergic receptors; therefore we explored the specific purinergic receptors and signaling pathways that could mediate this form of activity-dependent neuron-SC communication.  Using a combination of pharmacological and molecular approaches, we found that pre-myelinating SCs express a far more complex array of ATP receptors (P2X and P2Y) that previously thought.  Surprisingly, we discovered that pre-myelinating SCs also express a class of functional adenosine receptors (A2), which are positively coupled to cAMP.  Extracellular adenosine, a breakdown product of ATP, regulated MAP Kinase signaling and proliferation in SCs independently of ATP.  Collectively, our findings suggest that ATP and adenosine released from electrically active axons activate a complex intracellular signaling network in SCs, whereby ATP and adenosine act together to regulate SC function during development and nervous system plasticity.