Short-term Alteration of Developmental Neural Activity Enhances Neurite Outgrowth of Retinal Explants.

Abstract

It is well known that the gradual loss of axon growth ability of retinal ganglion cells (RGCs) during development is largely determined by extrinsic signals rather than being programmed intrinsically. Spontaneous retinal waves are the major neural activity during retinal development. Thus restoring the developmental environment by providing the proper neural activity may be able to help axon regeneration of RGCs. Retinal explants from P5 and P11 C57BL/6 mice were treated pharmacologically or stimulated electrically, and cultured with or without brain-derived neurotrophic factor (BDNF) on coverslips or a multielectrode array for 5 days to examine the neurite outgrowth capacity of RGCs. Here we have demonstrated that neurite outgrowth of retinal explants was not affected when acetylcholine transmission was blocked pharmacologically in retinas that normally display stage II retinal waves. However, short-term induction of globally correlated neural activity at 1- to 2-minute intervals in retinas that normally display stage III retinal waves by blocking inhibitory neural transmission was found to greatly promote neurite outgrowth even in the absence of exogenous neurotrophic factors. Moreover, short-term electrical stimulation with a temporal pattern of 1- to 2-minute intervals rather than simply increasing the neural activity greatly enhanced neurite outgrowth of retinal explants of the same age. These results suggest that short-term alteration of neural activity with a specific temporal pattern in retinas of later developmental stages is sufficient to enhance neurite outgrowth of retinal explants. This finding could lead to a therapeutic strategy that is able to prevent the gradual loss of the axon growth ability of RGCs in more mature retinas.