Long-term regenerated nerve fibres retain sensitivity to potassium channel blocking agents

Abstract

Mammalian myelinated peripheral nerve fibres display a remarkable degree of regeneration following a discrete nerve crush¹. Nerve crush disrupts the axon cylinder, but leaves the basement membrane of the Schwann cell intact. These intact endoneurial tubes provide pathways to guide the regenerating axon sprouts. After contact with the periphery is established, the regenerating fibres enlarge and myelinate. Conduction velocity recovers to nearly normal and functional recovery is, in many cases, nearly complete. A distinct feature of normal mature myelinated axons is the insensitivity of these fibres to potassium channel blocking agents^2–4. In contrast, immature myelinated axons are exquisitely sensitive to the K channel blocking agent 4-aminopyridine (4-AP)^4,5. Application of 4-AP to immature myelinated fibres leads to a delayed membrane depolarization with action potential burst activity in response to a single stimulus⁵. This sensitivity to 4-AP is attenuated as the fibres mature. Previous studies^4,6 have demonstrated a sensitivity to 4-AP in regenerating nerve fibres; this sensitivity differentiates the regenerating axon segments from their normal parent axon segments. Such studies have not, however, examined the question of whether regenerated fibres, which have re-established peripheral connections and are functionally active, fully recapitulate the functional organization of normal mature myelinated fibres. We demonstrate here that while sensitivity to the potassium channel blocking agents 4-AP and 3, 4-diaminopyridine (3, 4-DAP) is lost in the normal course of myelinated axon maturation, this property is present in long-term regenerated axons. This suggests that long-term regenerated mammalian axons are characterized by a functional organization that bears a closer resemblance to that of immature myelinated fibres than to that of adult myelinated fibres.