Our studies show that different cell adhesion molecules (CAM) are regulated by different patterns of neural impulses, and that this has functional effects on key developmental processes in the nervous system. Expression of both calcium-dependent and calcium-independent classes of CAMs is regulated by neural impulse activity in DRG neurons, but different CAMs respond differently to different patterns of stimulation. Low-frequency stimulation down-regulates L1 mRNA and protein levels, but NCAM is not affected. Expression of N-cadherin is down-regulated by higher frequencies of stimulation than those affecting L1 expression. Studies in vivo show that levels of L1 mRNA decrease abruptly in DRG neurons at the embryonic period when spontaneous impulse activity begins, which is consistent with decreased expression of L1 following low-frequency stimulation in cultured DRG neurons. Activity-dependent regulation of L1 induces defasciculation of axon terminals, reduces adhesion and the mitotic rate of Schwann cells on axons stimulated at frequencies that lower L1 expression. Exposure to specific neurotrophins and appropriate target neurons from the spinal cord prevents the activity-dependent down-regulation of L1 in cultured DRG neurons. Studies of how intracellular signaling pathways in neurons integrate and transmit information coded in the temporal pattern of neural impulses support a mechanism in which the differing kinetics of parallel intracellular signaling reactions confers sensitivity to different temporal patterns of activation and thereby activates distinct intracellular pathways controlling gene expression and other neuronal and synaptic functions. These results are based on studies of the signaling pathways (second messengers, protein kinases, and transcription factors) that activate the immediate early gene c-fos in response to different patterns of action potential stimulation in vitro.
Showing the most recent 10 out of 29 publications
