An Beckers

Successful optic nerve regeneration in the senescent zebrafish despite age-related decline of cell intrinsic and extrinsic response processes

Dysfunction of the central nervous system (CNS) in neurodegenerative diseases or after brain lesions seriously affects life quality of a growing number of elderly, since the adult CNS lacks the capacity to replace or repair damaged neurons. Despite intensive research efforts, full functional recovery after CNS disease and/or injury remains challenging, especially in an aging environment. As such, there is a rising need for an aging model in which the impact of aging on successful regeneration can be studied. Here, we introduce the senescent zebrafish retinotectal system as a valuable model to elucidate the cellular and molecular processes underlying age-related decline in axonal regeneration capacities. We found both intrinsic and extrinsic response processes to be altered in aged fish. Indeed, expression levels of growth-associated genes are reduced in naive and crushed retinas, and the injury-associated increase in innate immune cell density appears delayed, suggesting retinal inflammaging in old fish. Strikingly, however, despite a clear deceleration in regeneration onset and early axon outgrowth leading to an overall slowing of optic nerve regeneration, reinnervation of the optic tectum and recovery of visual function occurs successfully in the aged zebrafish retinotectal system.

An Antagonistic Axon-Dendrite Interplay Enables Efficient Neuronal Repair in the Adult Zebrafish Central Nervous System

Neural insults and neurodegenerative diseases typically result in permanent functional deficits, making the identification of novel pro-regenerative molecules and mechanisms a primary research topic. Nowadays, neuroregenerative research largely focuses on improving axonal regrowth, leaving the regenerative properties of dendrites largely unstudied. Moreover, whereas developmental studies indicate a strict temporal separation of axogenesis and dendritogenesis and thus suggest a potential interdependency of axonal and dendritic outgrowth, a possible axon-dendrite interaction during regeneration remains unexplored. To unravel the inherent dendritic response of vertebrate neurons undergoing successful axonal regeneration, regeneration-competent adult zebrafish of either sex, subjected to optic nerve crush (ONC), were used. A longitudinal study in which retinal ganglion cell (RGC) dendritic remodeling and axonal regrowth were assessed side-by-side after ONC, revealed that—as during development—RGC axogenesis precedes dendritogenesis during central nervous system (CNS) repair. Moreover, dendrites majorly shrank before the start of axonal regrowth and were only triggered to regrow upon RGC target contact initiation, altogether suggestive for a counteractive interplay between axons and dendrites after neuronal injury. Strikingly, both retinal mechanistic target of rapamycin (mTOR) and broad-spectrum matrix metalloproteinase (MMP) inhibition after ONC consecutively inhibited RGC synapto-dendritic deterioration and axonal regrowth, thus invigorating an antagonistic interplay wherein mature dendrites restrain axonal regrowth. Altogether, this work launches dendritic shrinkage as a prerequisite for efficient axonal regrowth of adult vertebrate neurons, and indicates that molecular/mechanistic analysis of dendritic responses after damage might represent a powerful target-discovery platform for neural repair.