Nerve injury and inflammatory cytokines modulate gap junctions in the peripheral nervous system

In the peripheral nervous system (PNS), myelinating Schwann cells express the gap junction protein connexin32 (Cx32) and lower levels of connexin43 (Cx43). Although the function of Cx43 in Schwann cells is not yet known, in adult mammals Cx32 is thought to form reflexive contacts within individual myelinating glial cells and provide direct pathways for intracellular ionic and metabolic exchange from the cell body to the innermost periaxonal cytoplasmic regions. In response to nerve injury, Schwann cells in the degenerating region down-regulate expression of Cx32 and there is increased expression of connexin46 (Cx46) mRNA and protein. The cascade of Schwann cell responses seen after the injury-induced decrease in Cx32, and the observation that dividing Schwann cells express Cx46, and possibly other connexins, and are coupled through gap junction channels, raise the intriguing possibility that there are coordinated changes in Schwann cell proliferation and connexin expression. Moreover, intercellular junctional coupling among cells in general may be important during injury responses. Consistent with this hypothesis, dividing Schwann cells are preferentially coupled through junctional channels as compared to non-dividing cells, which are generally uncoupled. Moreover, the strength of junctional coupling among cultured Schwann cells is modulated by a number of cytokines to which Schwann cells are exposed to in vivo after nerve injury, and Cx46 mRNA and protein levels correlate with the degree of coupling. Other injury-induced cellular changes in connexin expression that may be functionally important during injury responses include a transient increase in Cx43 in endoneurial fibroblasts. This paper reviews what is known about connexin expression and function in the adult mammalian PNS, and focuses on some of the changes that occur following nerve injury. Moreover, evidence that inflammatory cytokines released after injury modulate connexin expression and junctional coupling strength is presented.